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DNA methylation is an epigenetic signature consisting of a methyl group at the 5’ cytosine of CpG dinucleotides. Modifications in DNA methylation pattern have been detected in cancer and infectious diseases and may be associated with gene expression changes. In cancer development DNA methylation aberrations are early events whereas in infectious diseases these epigenetic changes may be due to host/pathogen interaction. In particular, in leishmaniasis, a parasitic disease caused by the protozoan Leishmania, DNA methylation alterations have been detected in macrophages upon infection with Leishmania donovani and in skin lesions from patients with cutaneous leishmaniasis. Interestingly, different types of cancers, such as cutaneous malignant lesions, lymphoma and hepatocellular carcinoma, have been diagnosed in patients with a history of leishmaniasis. In fact, it is known that there exists an association between cancer and infectious diseases. Leishmania infection may increase susceptibility to develop cancer, but the mechanisms involved are not entirely clear. Considering these aspects, in this review we discuss the hypothesis that DNA methylation alterations induced by Leishmania may trigger tumorigenesis in long term infection since these epigenetic modifications may enhance and accumulate during chronic leishmaniasis.

Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection. [ABSTRACT FROM AUTHOR]

Background Hepatitis E virus (HEV) variants belonging to Orthohepevirus species A (HEV-A) are the primary cause of human hepatitis E. However, we previously reported that Orthohepevirus species C genotype 1 (HEV-C1), a divergent HEV variant commonly found in rats, also causes hepatitis in humans. Here, we present a clinical-epidemiological investigation of human HEV-C1 infections detected in Hong Kong, with an emphasis on outcomes in immunocompromised individuals. Methods A surveillance system for detecting human HEV-C1 infections was established in Hong Kong. Epidemiological and clinical characteristics of HEV-C1 cases identified via this system between 1 August 2019 and 31 December 2020 were retrieved. Phylogenetic analysis of HEV-C1 strain sequences was performed. Infection outcomes of immunocompromised individuals with HEV-A and HEV-C1 infections were analyzed. Results HEV-C1 accounted for 8 of 53 (15.1%) reverse-transcription polymerase chain reaction (RT-PCR)–confirmed HEV infections in Hong Kong during the study period, raising the total number of HEV-C1 infections detected in the city to 16. Two distinct HEV-C1 strain groups caused human infections. Patients were elderly and/or immunocompromised; half tested negative for HEV immunoglobulin M. Cumulatively, HEV-C1 accounted for 9 of 21 (42.9%) cases of hepatitis E recorded in immunocompromised patients in Hong Kong. Immunocompromised HEV-C1 patients progressed to persistent hepatitis at similar rates (7/9 [77.8%]) as HEV-A patients (10/12 [75%]). HEV-C1 patients responded to oral ribavirin, although response to first course was sometimes poor or delayed. Conclusions Dedicated RT-PCR–based surveillance detected human HEV-C1 cases that evade conventional hepatitis E diagnostic testing. Immunosuppressed HEV-C1–infected patients frequently progress to persistent HEV-C1 infection, for which ribavirin is a suitable treatment option. [ABSTRACT FROM AUTHOR]

Gammaherpesviruses, such as human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), are species-specific, ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses have a natural tropism for B cells and usurp B cell differentiation to drive a unique and robust polyclonal germinal center response to establish a long-term latent reservoir in memory B cells. The robust polyclonal germinal center response driven by gammaherpesvirus infection increases the risk for B cell transformation. Unsurprisingly, many gammaherpesvirus cancers are derived from germinal center or post-germinal center B cells. The viral and host factors that influence the gammaherpesvirus-driven germinal center response are not clearly defined. We previously showed that host interleukin 17 receptor A (IL-17RA) signaling promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we found that T cell-intrinsic IL-17RA signaling recapitulates some proviral aspects of global IL-17RA signaling during MHV68 infection. Specifically, we found that T cell-intrinsic IL-17RA signaling supports the MHV68-driven germinal center response, the establishment of latency in the spleen, and viral reactivation in the spleen and peritoneal cavity. Our study unveils an unexpected finding where the T cell-specific IL-17RA signaling supports the establishment of a latent reservoir of a B cell-tropic gammaherpesvirus. IMPORTANCE Gammaherpesviruses, such as human EBV, establish lifelong infection in .95% of adults and are associated with B cell lymphomas. Gammaherpesviruses usurp the germinal center response to establish latent infection, and the germinal center B cells are thought to be the target of viral transformation. We previously found that global expression of IL-17RA promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we showed that T cell-intrinsic IL-17RA signaling is necessary to promote the MHV68-driven germinal center response by supporting CD41 T follicular helper cell expansion. We also found that T cell-intrinsic IL-17RA signaling contributes to but is not solely responsible for the systemic proviral role of IL-17RA signaling, highlighting the multifaceted function of IL-17RA signaling during MHV68 infection. [ABSTRACT FROM AUTHOR]

Mycetoma describes a heterogeneous group of cutaneous and subcutaneous infections caused by either fungi (eumycetomas) or bacteria (actinomycetomas). It is characterized by a triad of clinical symptoms: painless subcutaneous tumor-like swelling, multiple sinuses and fistulas, and discharged grains in pus. This predominantly affects the feet in more than 70% of patients. It is endemic in the "mycetoma belt" regions, including Africa, South America, and South Asia. Autochthonous mycetoma is rare in the United States of America (USA). We recently reported a Latin American immigrant with eumycetoma in the State of Maryland, USA. With millions of immigrants from endemic regions, the true number of mycetomas in the USA is most likely higher than currently recognized. With the aim to raise the awareness of clinicians about mycetoma, especially dermatologists and podiatrists, we update the development of the epidemiology, etiology, clinical presentations, pathogenesis, diagnosis, differential diagnosis, and treatment of mycetoma. [ABSTRACT FROM AUTHOR]

Brucellosis is considered one of the major zoonoses worldwide, constituting a critical livestock and human health concern with a huge socio-economic burden. Brucella genus, its etiologic agent, is composed of intracellular bacteria that have evolved a prodigious ability to elude and shape host immunity to establish chronic infection. Brucella's intracellular lifestyle and pathogen-associated molecular patterns, such as its specific lipopolysaccharide (LPS), are key factors for hiding and hampering recognition by the immune system. Here, we will review the current knowledge of evading and immunosuppressive mechanisms elicited by Brucella species to persist stealthily in their hosts, such as those triggered by their LPS and cyclic β-1,2-d-glucan or involved in neutrophil and monocyte avoidance, antigen presentation impairment, the modulation of T cell responses and immunometabolism. Attractive strategies exploited by other successful chronic pathogenic bacteria, including Mycobacteria, Salmonella, and Chlamydia, will be also discussed, with a special emphasis on the mechanisms operating in brucellosis, such as granuloma formation, pyroptosis, and manipulation of type I and III IFNs, B cells, innate lymphoid cells, and host lipids. A better understanding of these stratagems is essential to fighting bacterial chronic infections and designing innovative treatments and vaccines. [ABSTRACT FROM AUTHOR]

Background: Hepatitis E virus (HEV), which is the leading cause of acute viral hepatitis worldwide, usually causes self-limited infections in common individuals. However, it can lead to chronic infection in immunocompromised individuals and its mechanisms remain unclear. Rabbits are the natural host of HEV, and chronic HEV infections have been observed in rabbits. Therefore, we aimed to investigate potential key genes in HEV chronicity process in rabbits. In this study, both bioinformatics and experimental analysis were performed to deepen the understanding of hub genes in HEV chronic infection in rabbits. Results: Ninety-four candidate differentially expressed genes (DEGs) and the pathways they enriched were identified to be related with HEV chronicity. A total of 10 hub genes were found by protein–protein interaction (PPI) network construction. Rabbits of group P (n = 4) which showed symptoms of chronic HEV infection were selected to be compared with HEV negative rabbits (group N, n = 6). By detecting the identified hub genes in groups P and N by real-time PCR, we found that the expressions of MX1, OAS2 and IFI44 were significantly higher in group P (P < 0.05). Conclusions: In this work, we presented that MX1, OAS2 and IFI44 were significantly upregulated in HEV chronic infected rabbits, indicating that they may be involved in the pathogenesis of HEV chronicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Murine leprosy is a chronic mycobacterial disease that does not infect the nervous system, however alterations in the prefrontal cortex, ventral hippocampus and amygdala have been associated with neurocognitive impairment. • Murine-leprosy infection elicited a suppressive immune response with high levels of IL-10 and IL-4 and spleno-hepatomegaly. • Chronic infection induces BBB disruption and neuroinflammation. • Murine leprosy atrophy the adrenal glands and increase levels of epinephrine, norepinephrine and corticosterone. • The immunosuppressive environment generated by the infection may affect the nervous and endocrine system integrity and function. Murine leprosy is a systemic infectious disease of mice caused by Mycobacterium lepraemurium (MLM) in which the central nervous system (CNS) is not infected; nevertheless, diseased animals show measurable cognitive alterations. For this reason, in this study, we explored the neurobehavioral changes in mice chronically infected with MLM. BALB/c mice were infected with MLM, and 120 days later, the alterations in mice were evaluated based on immunologic, histologic, endocrine, neurochemical, and behavioral traits. We found increases in the levels of IL-4 and IL-10 associated with high bacillary loads. We also found increase in the serum levels of corticosterone, epinephrine, and norepinephrine in the adrenal gland, suggesting neuroendocrine deregulation. Mice exhibited depression-like behavior in the tail suspension and forced swimming tests and anxiolytic behavior in the open field and elevated plus maze tests. The neurobehavioral alterations of mice were correlated with the histologic damage in the prefrontal cortex, ventral hippocampus, and amygdala, as well as with a blood–brain barrier disruption in the hippocampus. These results reveal an interrelated response of the neuroimmune-–endocrinological axis in unresolved chronic infections that result in neurocognitive deterioration. [ABSTRACT FROM AUTHOR]

Gammaherpesviruses (GHVs) are lymphotropic tumor viruses with a biphasic infectious cycle. Lytic replication at the primary site of infection is necessary for GHVs to spread throughout the host and establish latency in distal sites. Dissemination is mediated by infected B cells that traffic hematogenously from draining lymph nodes to peripheral lymphoid organs, such as the spleen. B cells serve as the major reservoir for viral latency, and it is hypothesized that periodic reactivation from latently infected B cells contributes to maintaining long-term chronic infection. While fundamentally important to an understanding of GHV biology, aspects of B cell infection in latency establishment and maintenance are incompletely defined, especially roles for lytic replication and reactivation in this cell type. To address this knowledge gap and overcome limitations of replicationdefective viruses, we generated a recombinant murine gammaherpesvirus 68 (MHV68) in which ORF50, the gene that encodes the essential immediate-early replication and transcription activator protein (RTA), was flanked by loxP sites to enable conditional ablation of lytic replication by ORF50 deletion in cells that express Cre recombinase. Following infection of mice that encode Cre in B cells with this virus, splenomegaly and viral reactivation from splenocytes were significantly reduced; however, the number of latently infected splenocytes was equivalent to WT MHV68. Despite ORF50 deletion, MHV68 latency was maintained over time in spleens of mice at levels approximating WT, reactivation-competent MHV68. Treatment of infected mice with lipopolysaccharide (LPS), which promotes B cell activation and MHV68 reactivation ex vivo, yielded equivalent increases in the number of latently infected cells for both ORF50-deleted and WT MHV68, even when mice were simultaneously treated with the antiviral drug cidofovir to prevent reactivation. Together, these data demonstrate that productive viral replication in B cells is not required for MHV68 latency establishment and support the hypothesis that B cell proliferation facilitates latency maintenance in vivo in the absence of reactivation. IMPORTANCE Gammaherpesviruses establish lifelong chronic infections in cells of the immune system and place infected hosts at risk for developing lymphomas and other diseases. It is hypothesized that gammaherpesviruses must initiate acute infection in these cells to establish and maintain long-term infection, but this has not been directly tested. We report here the use of a viral genetic system that allows for cell-type-specific deletion of a viral gene that is essential for replication and reactivation. We employ this system in an in vivo model to reveal that viral replication is not required to initiate or maintain infection within B cells. [ABSTRACT FROM AUTHOR]

Plasmodium multigene families are thought to play important roles in the pathogenesis of malaria. Plasmodium interspersed repeat (pir) genes comprise the largest multigene family in many Plasmodium species. However, their expression pattern and localisation remain to be elucidated. Understanding protein subcellular localisation is fundamental to reveal the functional importance and cell-cell interactions of the PIR proteins. Here, we use the rodent malaria parasite , Plasmodium chabaudi chabaudi , as a model to investigate the localisation pattern of this gene family. We found that most PIR proteins are co-expressed in clusters during acute and chronic infection; members of the S7 clade are predominantly expressed during the acute-phase, whereas members of the L1 clade dominate the chronic-phase of infection. Using peptide antisera specific for S7 or L1 PIRS, we show that these PIRs have different localisations within the infected red blood cells. S7 PIRs are exported into the infected red blood cell cytoplasm where they are co-localised with parasite-induced host cell modifications termed Maurer's clefts, whereas L1 PIRs are localised on or close to the parasitophorous vacuolar membrane. This localisation pattern changes following mosquito transmission and during progression from acute- to chronic-phase of infection. The presence of PIRs in Maurer's clefts, as seen for Plasmodium falciparum RIFIN and STEVOR proteins, might suggest trafficking of the PIRs on the surface of the infected erythrocytes. However, neither S7 nor L1 PIR proteins detected by the peptide antisera are localised on the surface of infected red blood cells, suggesting that they are unlikely to be targets of surface variant-specific antibodies or to be directly involved in adhesion of infected red blood cells to host cells, as described for Plasmodium falciparum VAR proteins. The differences in subcellular localisation of the two major clades of Plasmodium chabaudi PIRs across the blood cycle, and the apparent lack of expression on the red cell surface strongly suggest that the function(s) of this gene family may differ from those of other multigene families of Plasmodium , such as the var genes of Plasmodium falciparum. [ABSTRACT FROM AUTHOR]

Disease progression is slower in HIV-2, as compared with HIV-1 infection, in accordance with low or undetectable plasma viremia at viral setpoint. However, it is unclear why most HIV-2 infected individuals are still at risk of developing AIDS. To explore if specific host responses are linked to HIV disease severity, we have compared blood gene expression profiles between HIV seronegative and HIV-1, HIV-2 or dually HIV-1/HIV-2 infected individuals. In this study the gene encoding Interferon alpha-inducible protein 27 (IFI27) was found to be the most differentially expressed. Detailed expression analysis revealed significantly higher IFI27 expression in HIV infected individuals compared with seronegative individuals, irrespectively of HIV type. Moreover, IFI27 expression was higher in HIV-1 than in HIV-2 infected individuals. Multiple linear regression analysis, adjusting for age and sex, showed also that plasma viral load was the strongest predictor of IFI27 expression, followed by CD4% and HIV type. In line with this, IFI27 expression was found to be higher in HIV-2 viremic, compared with HIV-2 aviremic individuals. Still, HIV-2 aviremic individuals displayed elevated IFI27 expression compared with seronegative individuals. Furthermore, in HIV-2 infected individuals, IFI27 expression was also correlated with plasma markers previously linked to inflammation and disease progression in HIV infection. Taken together, our findings suggest that sustained elevation of type I interferon signaling, here reflected by elevated IFI27 expression in the chronic infection phase, is a key pathogenic feature of both HIV-1 and HIV-2. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors have become new research hot spots in the treatment of non-small-cell lung cancer (NSCLC), but the efficacy and safety of immunotherapy for patients with chronic infection are still unclear because existing clinical trials often exclude those patients. Materials and Methods: We identified 78 locally advanced or advanced NSCLC patients with chronic infection treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results: Objective responses were observed in 19 out of 78 (24.36%) patients, and the disease control rate was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI: 3.71–9.27). PFS was 1.44 months (95% CI: 0.00–4.34) for monotherapy versus 7.34 months (95% CI: 4.50–10.18) for combination therapy (p = 0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, p = 0.001; PFS: 7.67 vs. 5.57 months, p = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs. 4.62, p = 0.027). The incidence of AEs of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 AEs. The incidence of leukopenia in any grade of AEs was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%), and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients and remained unchanged in 65.0% (39/60) patients. Conclusions: The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic infection, but still has the potential to increase the incidence of hepatitis. [ABSTRACT FROM AUTHOR]

Genetic recombination is a major evolutionary mechanism among RNA viruses, and it is common in coronaviruses, including those infecting humans. A few SARS-CoV-2 recombinants have been reported to date whose genome harbored combinations of mutations from different mutants or variants, but only a single patient's sample was analyzed, and the virus was not isolated. Here, we report the gradual emergence of a hybrid genome of B.1.160 and Alpha variants in a lymphoma patient chronically infected for 14 months, and we isolated the recombinant virus. The hybrid genome was obtained by next-generation sequencing, and the recombination sites were confirmed by PCR. This consisted of a parental B.1.160 backbone interspersed with two fragments, including the spike gene, from an Alpha variant. An analysis of seven sequential samples from the patient decoded the recombination steps, including the initial infection with a B.1.160 variant, then a concurrent infection with this variant and an Alpha variant, the generation of hybrid genomes, and eventually the emergence of a predominant recombinant virus isolated at the end of the patient's follow-up. This case exemplifies the recombination process of SARS-CoV-2 in real life, and it calls for intensifying the genomic surveillance in patients coinfected with different SARS-CoV-2 variants, and more generally with several RNA viruses, as this may lead to the appearance of new viruses. [ABSTRACT FROM AUTHOR]

In‐depth reviewing of all medical records and clinical databases concluded a 7‐year shorter lifespan among Greenlanders infected with hepatitis B virus (HBV) compared with non‐infected. Mortality did not associate with liver disease or any other specific disease entity. A possible mechanism for the reduced lifespan is subclinical inflammation that may be augmented by chronic viral infection. We hypothesized that chronic HBV infection contributes to this process causing a reduced life span. We added measurement of two markers of inflammation to the 10‐year follow‐up on our study of HBV among 50‐ through 69‐years‐old subjects in Greenland. The markers were YKL40 related to liver disease and hsCRP as a global marker of inflammation. Survival was evaluated using Cox regression with time until death entered as dependent variable and age, sex, smoking, alcohol intake, BMI, the presence of HBsAg and one marker of inflammation as explanatory variables. Forty‐eight percent of participants with chronic HBV infection were alive after 10 years compared with 65% of participants without infection (p = 0.003). Survival associated with age (p < 0.001), BMI (p = 0.003) and both YKL40 and hsCRP (both, p < 0.001). Harbouring HBV influenced 10‐year survival in the Cox regression after adjusting for age, sex, BMI, smoking, alcohol intake and inflammation. In conclusion, chronic low‐grade inflammation and being infected with HBV were independent markers of mortality in otherwise healthy subjects. Thus, the 7‐year shorter lifespan among Greenlanders with chronic HBV infection seems related to the long‐lasting infection. Our findings call for caution in perceiving a chronic infection as benign. [ABSTRACT FROM AUTHOR]

Adverse Childhood Events (ACE), Post-Traumatic Stress Disorder (PTSD), and infectious encephalopathies are associated with immune-mediated diseases. Data supporting this are reviewed, and an integrated hypothesis is provided. All three can be associated with intrusive symptoms and temporal lobe pathology. ACE and PTSD are accompanied by an impaired mental capacity to differentiate external danger vs. safety. Infectious encephalopathies are accompanied by a failure of adaptive immunity and an impaired immune capacity to differentiate internal danger vs. safety. All three conditions are associated with impairments to differentiate danger vs. safety and adapt effectively. There are reciprocal interactions between ACE, PTSD, and infectious encephalopathies with accompanying persistent immune activation. This is associated with immune dysregulation, chronic hyperarousal, activation of the stress response, and impairments of the fear recognition and response neural circuits, hypothalamic–pituitary–adrenal axis, amygdala, and hippocampus. The pathophysiological processes can result in a broad spectrum of chronic neuropsychiatric and somatic symptoms and diseases. Understanding the psychodynamic, neurological, neuroimmune, inflammatory and autoimmune components of this interactive process expands the effective treatment opportunities. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is the most common blood-borne chronic infection in the United States. Chronic lymphocytic sialadenitis and sicca syndrome have been reported in chronic HCV infection. Up to 55% of these patients may have xerostomia; the mechanisms of the xerostomia and salivary gland (SG) hypofunction remain controversial. The objectives of this project are to establish if xerostomia associates with SG and HCV infection and to characterize the structural changes in SG and saliva composition. Eighteen HCV-infected patients with xerostomia were evaluated for SG dysfunction; 6 of these patients (patients 1–6) were further evaluated for SG histopathological changes and changes in saliva composition. The techniques used include clinical and laboratory assessment, SG ultrasonography, histological evaluation, sialochemical and proteomics analysis, and RNA in situ hybridization. All the HCV patients had low saliva flow, chronic sialadenitis, and SG fibrosis and lacked Sjögren syndrome (SS) characteristic autoantibodies. Further evaluation of a subgroup of 6 HCV patients (patients 1–6) demonstrated diffuse lymphocytic infiltrates that are predominantly CD8+ T cells with a significant increase in the number of inflammatory cells. Alcian Blue/periodic acid–Schiff staining showed significant changes in the ratio and intensity of the acinar secretory units of the HCV patients' minor SG. The submandibular glands showed significant ultrasonographic abnormalities in the parenchyma relative to the parotid glands. Significant changes were also observed in the concentration of sodium and mucin 5b. Although no significant correlation was observed between the lymphocytic infiltrates and the years of HCV chronic infection, a positive correlation was observed between HCV RNA–positive epithelial cells and the years of HCV infection. Consistent with the low saliva flow and xerostomia, patients showed changes in several markers of SG acinar and ductal function. Changes in the composition of the saliva suggest that HCV infection can cause xerostomia by mechanisms distinct from SS. [ABSTRACT FROM AUTHOR]

The Plasmodium falciparum protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. However, the extent to which VAR2CSA genetic diversity contributes to immune evasion and virulence remains poorly understood. The deep sequencing of the var2csa DBL3X domain in placental blood from forty-nine primigravid and multigravid women living in malaria-endemic western Kenya revealed numerous unique sequences within individuals in association with chronic PM but not gravidity. Additional analysis unveiled four distinct sequence types that were variably present in mixed proportions amongst the study population. An analysis of the abundance of each of these sequence types revealed that one was inversely related to infant gestational age, another was inversely related to placental parasitemia, and a third was associated with chronic PM. The categorization of women according to the type to which their dominant sequence belonged resulted in the segregation of types as a function of gravidity: two types predominated in multigravidae whereas the other two predominated in primigravidae. The univariate logistic regression analysis of sequence type dominance further revealed that gravidity, maternal age, placental parasitemia, and hemozoin burden (within maternal leukocytes), reported a lack of antimalarial drug use, and infant gestational age and birth weight influenced the odds of membership in one or more of these sequence predominance groups. Cumulatively, these results show that unique var2csa sequences differentially appear in women with different PM exposure histories and segregate to types independently associated with maternal factors, infection parameters, and birth outcomes. The association of some var2csa sequence types with indicators of pathogenesis should motivate vaccine efforts to further identify and target VAR2CSA epitopes associated with maternal morbidity and poor birth outcomes. [ABSTRACT FROM AUTHOR]

Abstract Introduction Toxocara canis can produce or exacerbate asthma, and the detection of anti‐T. canis immunoglobulin G (IgG) does not discriminate between recent infection or active larva migrans. In this study, we searched for T. canis third‐stage larval antigens (L3TES) and anti‐T. canis antibodies in children with different severities of asthma, controlled or uncontrolled. Methods A total of 145 patients with asthma who were previously diagnosed using the Global Initiative for Asthma guidelines were included. The asthma control was evaluated with the Asthma Control Questionnaire (ACQ). Enzyme‐linked immunosorbent assay was performed for the detection of L3TES; IgG was detected using sera preadsorbed with Ascaris antigens (native kit), and a commercial kit (IgG) was used as the gold standard. Results L3TES was found in 2 patients (1.37%). One had L3TES and anti‐T. canis IgG, suggesting active larva migrans. In the other patient, only L3TES was detected, likely because an infection had begun. The seroprevalence with the commercial kit and native kit was 6.2% and 17.93%, respectively. There was no significant association among asthma severity, ACQ and T. canis seroprevalence (p > .05). Conclusion It is possible to detect L3TES in patients with asthma. Two complementary techniques that can determine the infection status with T. canis and rule out cross‐reactions involve the detection of L3TES and IgG using sera preadsorbed with Ascaris antigen. There was no significant association among asthma severity, ACQ and T. canis seroprevalence.

Abstract Background Factors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions. Methods Two sets of study populations were included: 490 China AIDS Clinical Trial (CACT) participants (Training cohort, followed up for 144 to 288 weeks) and 117 outpatients from Peking Union Medical College Hospital (PUMCH) (Validation cohort, followed up for more than 96 weeks). All patients were chronically HIV-1-infected and achieved successful HIV-1 plasma RNA suppression within week 48. Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, 144 and 288 weeks after combined antiretroviral therapy (cART) initiation were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART. Results The total HIV-1 DNA rapidly decreased from baseline [median = 3.00 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (median = 2.55 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 plasma RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (

Abstract Background Chronic infections played a detrimental role on health outcomes in the aged population, and had complex associations with lymphocyte subsets distribution. Our study aimed to explore the predictive roles of chronic infections, lymphopenia, and lymphocyte subsets on unexpected admission and mortality in the institutionalized oldest-old during 3 year follow-up period. Results There were 163 participants enrolled prospectively with median age of 87.3 years (IQR: 83.1–90.2), male of 88.3%, and being followed for 156.4 weeks (IQR: 136.9–156.4 weeks). The unexpected admission and mortality rates were 55.2 and 24.5% respectively. The Cox proportional hazards models demonstrated the 3rd quartile of cytomegalovirus IgG (OR: 3.26, 95% CI: 1.55–6.84), lymphopenia (OR: 2.85, 95% CI: 1.2–6.74), and 1st quartile of CD19+ B cell count (OR: 2.84, 95% CI: 1.29–6.25) predicted elevated risks of unexpected admission after adjusting for potential confounders; while the 3rd quartile of CD3+ T cell indicated a reduced risk of mortality (OR: 0.19, 95% CI: 0.05–0.71). Negative association between CMV IgG and CD19+ B cell count suggested that CMV infection might lead to B cell depletion via decreasing memory B cells repertoire. Conclusions CMV infection, lymphopenia, and CD19+ B cell depletion might predict greater risk of unexpected admission, while more CD3+ T cell would suggest a reduced risk of mortality among the oldest-old population. A non-linear or U-shaped relationship was supposed between health outcomes and CMV infection, CD3+ T cell, or CD19+ B cell counts. Further prospective studies with more participants included would be needed to elucidate above findings.

The following article presents results of the complex research on postulation of immunohistochemical features of the ovaries’ structure in case of fetuses with a gestational term of 21-28 weeks from mothers with HILGT comparing to ones in case of fetuses from mothers with a physiological pregnancy. The materials of the research are: 25 fetuses from mothers with HILGT as well as 25 fetuses from mothers with physiological pregnancy. All fetuses had died antenatally and inranatally, as a result of violation of uteroplacental and umbilical-uterine circulation. Research methods: macroscopic, organometric, histological, immunohistochemical, morphometric, statistical. The organometric method revealed a clear decrease of main indexes of the fetuses’ ovaries from mothers with a complicated pregnancy comparing to ones in case of organs of fetuses from healthy mothers. Morphometric method revealed a clear decrease of a relative volume of cortical substance as well as a clear increase of a relative volume of brain substance in the gonads of fetuses from the main group; as well as it showed a clear decrease of an index of follicular tissue’ relative volume, likewise a clear increase of an index of interstitial component relative volume.The staining by picrofuxin by van Gieson method revealed a massive growth of the connective tissue in all strucutral components of organs of fetuses from mothers with HILGT relatively to gonads of fetuses from healthy mothers. Using of MCAT to main types of collagens allowed to reveal a violation of maturation of main types of collagens in the structure of connective tissue of fetal gonads in the main group. In the follicular component of the fetuses’ ovaries in the main group are appearing mature, cystic-artretic and growing forms of follicles. Immunohistochemical method revealed an increased number of an apoptotically altered eggs in the ovaries of fetuses from mothers with HILGT comparing to one in organs of fetuses from mothers with physiological pregnancy. The peroxidase method revealed an increased endotheline-producing activity of the vascular component as arterial, like a venous type; likewise a clear decrease of the hormone-producing activity in the ovaries of fetuses from mothers with HILGT comparing to such indexes in fetal organs of fetuses from mothers with physiological pregnancy. The complex of changes in the ovaries of fetuses with a 21-28 weeks of gestational term, which was described, was formed under the influence of the chronic hypoxia, prolonged antigenic stimulation as well as hormonal violations in the mother-placenta-fetus system, which is a leading link of the infectious pathology’ pathogenesis. The aforementioned complex of the structural and functional changes in the ovaries of fetuses from mothers with HILGT in a gestational term of 21-28 weeks indicates violations in implementation and formation of the fetal gonads, as well as it could further lead to disorders of the germinal function in the female organism.

During chronic infection, memory T cells acquire a unique phenotype and become dependent on different survival signals than those needed for memory T cells generated during an acute infection. The distinction between the role of effector and memory T cells in an environment of persistent antigen remains unclear. Here, in the context of chronic Toxoplasma gondii infection, we demonstrate that a population of CD8 T cells exhibiting a tissue-resident memory (TRM) phenotype accumulates within the brain. We show that this population is distributed throughout the brain in both parenchymal and extraparenchymal spaces. Furthermore, this population is transcriptionally distinct and exhibits a transcriptional signature consistent with the TRM observed in acute viral infections. Finally, we establish that the CD103+ TRM population has an intrinsic capacity to produce both IFN-γ and TNF-α, cytokines critical for parasite control within the central nervous system (CNS). The contribution of this population to pro-inflammatory cytokine production suggests an important role for TRM in protective and ongoing immune responses in the infected CNS. Accession number: GSE95105.

Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection.

Plasmodium multigene families are thought to play important roles in the pathogenesis of malaria. Plasmodium interspersed repeat (pir) genes comprise the largest multigene family in many Plasmodium species. However, their expression pattern and localisation remain to be elucidated. Understanding protein subcellular localisation is fundamental to reveal the functional importance and cell-cell interactions of the PIR proteins. Here, we use the rodent malaria parasite, Plasmodium chabaudi chabaudi, as a model to investigate the localisation pattern of this gene family. We found that most PIR proteins are co-expressed in clusters during acute and chronic infection; members of the S7 clade are predominantly expressed during the acute-phase, whereas members of the L1 clade dominate the chronic-phase of infection. Using peptide antisera specific for S7 or L1 PIRS, we show that these PIRs have different localisations within the infected red blood cells. S7 PIRs are exported into the infected red blood cell cytoplasm where they are co-localised with parasite-induced host cell modifications termed Maurer’s clefts, whereas L1 PIRs are localised on or close to the parasitophorous vacuolar membrane. This localisation pattern changes following mosquito transmission and during progression from acute- to chronic-phase of infection. The presence of PIRs in Maurer’s clefts, as seen for Plasmodium falciparum RIFIN and STEVOR proteins, might suggest trafficking of the PIRs on the surface of the infected erythrocytes. However, neither S7 nor L1 PIR proteins detected by the peptide antisera are localised on the surface of infected red blood cells, suggesting that they are unlikely to be targets of surface variant-specific antibodies or to be directly involved in adhesion of infected red blood cells to host cells, as described for Plasmodium falciparum VAR proteins. The differences in subcellular localisation of the two major clades of Plasmodium chabaudi PIRs across the blood cycle, and the apparent lack of expression on the red cell surface strongly suggest that the function(s) of this gene family may differ from those of other multigene families of Plasmodium, such as the var genes of Plasmodium falciparum.

Disease progression is slower in HIV-2, as compared with HIV-1 infection, in accordance with low or undetectable plasma viremia at viral setpoint. However, it is unclear why most HIV-2 infected individuals are still at risk of developing AIDS. To explore if specific host responses are linked to HIV disease severity, we have compared blood gene expression profiles between HIV seronegative and HIV-1, HIV-2 or dually HIV-1/HIV-2 infected individuals. In this study the gene encoding Interferon alpha-inducible protein 27 (IFI27) was found to be the most differentially expressed. Detailed expression analysis revealed significantly higher IFI27 expression in HIV infected individuals compared with seronegative individuals, irrespectively of HIV type. Moreover, IFI27 expression was higher in HIV-1 than in HIV-2 infected individuals. Multiple linear regression analysis, adjusting for age and sex, showed also that plasma viral load was the strongest predictor of IFI27 expression, followed by CD4% and HIV type. In line with this, IFI27 expression was found to be higher in HIV-2 viremic, compared with HIV-2 aviremic individuals. Still, HIV-2 aviremic individuals displayed elevated IFI27 expression compared with seronegative individuals. Furthermore, in HIV-2 infected individuals, IFI27 expression was also correlated with plasma markers previously linked to inflammation and disease progression in HIV infection. Taken together, our findings suggest that sustained elevation of type I interferon signaling, here reflected by elevated IFI27 expression in the chronic infection phase, is a key pathogenic feature of both HIV-1 and HIV-2.

Abstract Background Biomarker discovery remains a major challenge for predictive medicine, in particular, in the context of chronic diseases. This is true for the widespread protozoan Toxoplasma gondii which establishes long-lasting parasitism in metazoans, humans included. This microbe successively unfolds distinct genetic programs that direct the transition from high to low replicative potential inside host cells. As a slow-replicating cell, the T. gondii bradyzoite developmental stage persists enclosed in a cyst compartment within tissues including the nervous system, being held by a sustained immune equilibrium which accounts for the prolonged clinically silent phase of parasitism. Serological surveys indicate that nearly one third of the human population has been exposed to T. gondii and possibly host bradyzoites. Because any disruption of the immune balance drives the reverse transition from bradyzoite to fast replicating tachyzoite and uncontrolled growth of the latter, these people are at risk for life-threatening disease. While serological tests for discriminating recent from past infection are available, there is yet no immunogenic biomarker used in the serological test to allow ascertaining the presence of persistent bradyzoites. Results Capitalizing on genetically engineered parasites induced to produce mature bradyzoites in vitro, we have identified the BCLA/MAG2 protein being restricted to the bradyzoite and the cyst envelope. Using laboratory mice as relevant T. gondii host models, we demonstrated that BCLA/MAG2 drives the generation of antibodies that recognize bradyzoite and the enveloping cyst structure. We have designed an ELISA assay based on a bacterially produced BCLA recombinant polypeptide, which was validated using a large collection of sera from mice of different genetic backgrounds and infected with bcla+ or bcla-null cystogenic and non-cystogenic T. gondii strains. To refine the design of the ELISA assay, we applied high-resolution BCLA epitope mapping and identified a specific combination of peptides and accordingly set up a selective and sensitive ELISA assay which allowed the detection of anti-BCLA/MAG2 antibodies in the sera of human patients with various forms of toxoplasmosis. Conclusions We brought proof of principle that anti-BCLA/MAG2 antibodies serve as specific and sensitive serological markers in the perspective of a combinatorial strategy for detection of persistent T. gondii parasitism.

The relevance of the following article is prescribed by the growing number of perinatal mortality and morbidity among newborns due to the mother’s chronic infection of the lower genital tract (HILGT). It is commonly known, that HILGT contributes to the delay of the fetal development likewise is often manifested by the violation of internal organs and systems implementation. One of the most acute topic is the the fetus’ reproductive system in ther early gestation terms. However, the immunohistochemical features of the fetuses’ uterus structure with the gestational term of 21-28 weeks from mothers with HILGT on the current stage of the medical science develpment have not been described yet. The aim of the current research is to identify immunohistochemical features of the fetuses’ uterus structure with the term of gestation of 21-28 weeks from mothers, whose pregnancy is complicated by HILGT. Material of the research: 25 fetuses from mothers, whose course of pregnancy was physiological (group of comparison) as well as 25 fetuses from mothers, whose pregnancy was complicated by HILGT (main group). All fetuses had died intranatally, as a result of acute uterine placental and placental-fetal circulation. Research methods: organometric, histological, immunohistochemical, morphometric, statistical. The research results and their discussion: the organometric parameters of the fetuses’ uterus from the main group were clearily decreased in comparison to such parameters in case of the group of comparison. The decrease of the parameter of the uterine wall thickness of fetuses from mothers with the complicated pregnancy prescribes thinning of the main structural components. Namely: endometrium, myometrium and perimetrium. In case of endometrium of fetuses’ uterus a decrease of number of glands and the lack of their functional activity was noticed. It characterizes this layer as structurally immature.At the same time, in case of fetal organs of fetuses from mothers with complicated pregnancies, we could notice an increase in the number of apoptotically altered cells. Comparing to the structure of layers of uterine walls in case of fetuses from mothers with physiological pregnancy, in the uterus of fetuses from mothers with complicated pregnancy our attention is attracted by a massive growth of the connective tissue. In the myometrium it contributes to the disruption of the muscle fibers strusture likewise to its absence in some areas. By the immunohistochemical method it was possible to reveal a prevalence of the collagen of the III type in the structure of connective tissue likewise in the walls of blood vessels. It is connected primarily with disruption of the collagen’ maturation. The vascular component of the uterine wall in case of fetuses from mothers with HILGT differs from ones in case of fetuses from mothers with physiological pregnancy. This difference is grounded on the increase of endothelin-producing activity by vessels of both arterial and venous types. By processing preparations by monoclonal antibodies to estrogen, it has been postulated, that the intensity of the reaction as well as number of cells in the fetuses’ organs of the main group are clearily decreased comparing to ones in cases of fetuses from the group of comparison. The disorders of the fetuses’ uterus in case of fetuses from mothers with HILGT, that were provided in the current article, are prescribed by chronic hypoxia, endocrine disorders as well as influences of the infectious agents, that are taking place in case of such pathology. The characteristic features of the fetuses’ uterus structure in case of fetuses from mothers, whose pregnancy is complicated by HILGT, indicate gross violation in the organ’s implementation on the early stages of the fetal organogenesis, likewise they could be a leading link of pathogenesis of primary infertility’ development in the future ontogenesis.

Mycoplasma synoviae causes infectious synovitis and respiratory tract infections in chickens and is responsible for significant economic losses in the poultry industry. Effective attachment and colonisation of the trachea is critical for the persistence of the organism and progression of the disease it causes. The respiratory tract infection is usually sub-clinical, but concurrent infection with infectious bronchitis virus (IBV) is known to enhance the pathogenicity of M. synoviae. This study aimed to explore differentially expressed genes in the tracheal mucosa, and their functional categories, during chronic infection with M. synoviae , using a M. synoviae -IBV infection model. The transcriptional profiles of the trachea were assessed 2 weeks after infection using RNA sequencing. In chickens infected with M. synoviae or IBV, only 1 or 8 genes were differentially expressed compared to uninfected chickens, respectively. In contrast, the M. synoviae -IBV infected chickens had 621 upregulated and 206 downregulated genes compared to uninfected chickens. Upregulated genes and their functional categories were suggestive of uncontrolled lymphoid cell proliferation and an ongoing pro-inflammatory response. Genes associated with anti-inflammatory effects, pathogen removal, apoptosis, regulation of the immune response, airway homoeostasis, cell adhesion and tissue regeneration were downregulated. Overall, transcriptional changes in the trachea, 2 weeks after infection with M. synoviae and IBV, indicate immune dysregulation, robust inflammation and a lack of cytotoxic damage during chronic infection. This model provides insights into the pathogenesis of chronic infection with M. synoviae. • Mycoplasma synoviae causes respiratory tract infections in chickens. • The tracheal response to infection with M. synoviae was assessed at 2 weeks post infection. • Transcriptional changes were indicative of uncontrolled lymphoid cell proliferation and robust inflammation. • This analysis provides insights into the pathogenesis of chronic infection with M. synoviae. [ABSTRACT FROM AUTHOR]

The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx—nuclear-, cytoplasmic- or mitochondria-associated—this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.

A case of juvenile red tilapia (Oreochromis sp.) showing body deformity due to spinal curvature was investigated. Approximately 20% of the crop (4,000 fish/crop) was affected. Bacterial isolation from the kidney and tissue surrounding the spinal lesion of the affected fish was negative. Histopathology revealed granulomatous inflammation and Gram‐positive cocci in connective tissues around the bone and notochord. PCR assay confirmed the presence of S. agalactiae in the spinal tissue lesion. Spinal deformity in red tilapia observed in our study may be associated with the inflammatory process and granuloma that compress the skeleton structure. The present study highlights chronic streptococcosis in tilapia culture that may be unnoticed. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii bradyzoites establish chronic infections within their host cells. Recent studies have demonstrated that several parasite effector proteins are translocated to host cells during the bradyzoite stage of chronic infection. To understand the interaction between host cells and bradyzoites at the transcriptomic landscape level, we utilized single-cell RNA-sequencing (scRNA-Seq) to characterize the bradyzoite-induced host cell response. Distinct gene expression profiles were observed in infected host, cells with low parasite mapped reads, and mock (non-exposed) control cells. Gene set enrichment analysis showed that c-Myc and NF-κB signaling and energy metabolic pathways were upregulated by infection. Type I and II interferon response pathways were upregulated in cells with low parasite mapped reads compared to the non-exposed host control cells, and this upregulation effect was reversed in infected cells. Differences were observed in the host cells depending on the differentiation status of the parasites, as determined by BAG1 and SAG1 expression. NF-κB, inflammatory response pathways, and IFN-γ response pathways were downregulated in host cells containing T. gondii BAG1+/SAG1−, whereas this downregulation effect was reversed in case of T. gondii BAG1−/SAG1+. We also identified two distinct host cell subsets that contained T. gondii BAG1+/SAG1−, one of which displayed distinct transcriptomes with upregulated c-Myc expression. Overall, these data clearly demonstrate that host cell transcriptional alteration by bradyzoite infection is different from that of tachyzoite infection, indicating fine-tuning of the host immune response. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) is a sexually transmitted virus with a wide range of terminal complications. As such, female sex workers (FSWs) are an important group in the epidemiology of the virus. This study was aimed at evaluating the seroprevalence of HBV markers and the exposure rate of the virus among FSWs in Enugu State, Nigeria. A cross-sectional study was carried out among brothel-based FSWs, involving 200 participants recruited using a consecutive sampling method. Blood specimens were collected and tested for HBV markers using chromatographic immunoassay rapid test kits. Additional information was obtained through the administration of a well-structured pre-tested questionnaire. Data were entered into Statistical Package for Social Sciences (SPSS) version 20.0 and analyzed using the Descriptive Statistics and Chi-Square test in SPSS. Out of the 200 sampled individuals, 82(41%) tested positive for at least one seromarker, with 44(22%) showing evidence of natural infection and 38(19%) indicating a vaccine response. Hepatitis B core antibody (total anti-HBc) was present in 42(21%) of the participants, while 8(4%) had hepatitis B surface antigen (HBsAg), which is indicative of current infection. This study revealed intermediate prevalence, a high exposure rate and a low vaccination rate among the study population. There is a need for more effective intervention strategies among FSWs in the study area. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is the predominant cause of chronic biofilm infections that form in the lungs of people with cystic fibrosis (CF). These infections are highly resistant to antibiotics and persist for years in the respiratory tract. One of the main research challenges is that current laboratory models do not accurately replicate key aspects of a P. aeruginosa biofilm infection, highlighted by previous RNA-sequencing studies. We compared the P. aeruginosa PA14 transcriptome in an ex vivo pig lung (EVPL) model of CF and a well-studied synthetic cystic fibrosis sputum medium (SCFM). P. aeruginosa was grown in the EVPL model for 1, 2, and 7 days, and in vitro in SCFM for 1 and 2 days. The RNA was extracted and sequenced at each time point. Our findings demonstrate that expression of antimicrobial resistance genes was cued by growth in the EVPL model, highlighting the importance of growth environment in determining accurate resistance profiles. The EVPL model created two distinct growth environments: tissue-associated biofilm and the SCFM surrounding tissue, each cuing a transcriptome distinct from that seen in SCFM in vitro. The expression of quorum sensing associated genes in the EVPL tissue-associated biofilm at 48 h relative to in vitro SCFM was similar to CF sputum versus in vitro conditions. Hence, the EVPL model can replicate key aspects of in vivo biofilm infection that are missing from other current models. It provides a more accurate P. aeruginosa growth environment for determining antimicrobial resistance that quickly drives P. aeruginosa into a chronic-like infection phenotype. Pseudomonas aeruginosa lung infections that affect people with cystic fibrosis are resistant to most available antimicrobial treatments. The lack of a laboratory model that captures all key aspects of these infections hinders not only research progression but also clinical diagnostics. We used transcriptome analysis to demonstrate how a model using pig lungs can more accurately replicate key characteristics of P. aeruginosa lung infection, including mechanisms of antibiotic resistance and infection establishment. Therefore, this model may be used in the future to further understand infection dynamics to develop novel treatments and more accurate treatment plans. This could improve clinical outcomes as well as quality of life for individuals affected by these infections. [ABSTRACT FROM AUTHOR]

Biofilms over the years have been implicated to play a major role in the development of various diseases particularly Otorhinolaryngology. It is one of the topics with great interest within the field of medicine. A thorough review of the literature reveals the association of various infectious conditions of ENT practice is associated with biofilm-producing bacteria. Infections associated with biofilms are usually chronic due to the resilience of bacteria, to the innate and acquired immune system of the host and antibiotic therapy. This review article is written to evaluate and understand various aspects of biofilm-related infections in ENT.

Target cells contagion has sparked the necessity of a multiple target cell model with chronic infection and intracellular delay (MTC-CI-ID). This paper seeks to advance a viral dynamical model with multiple target cells and corroborate the global stability of their steady states. Hence, the affiliation of the virus with two classes of target cells, CD4 + Tcells and macrophage. The time delay amidst viral entry and the output of virions were intimated and the basic reproductive number was procured, as the long term behavior of the model and less than unity. The contagious free equilibrium E0 was unveiled as locally and globally asymptotically stable. The conditions of an infected CD4 + Tcell and macrophage on viral production were engaged. It was ascertained that CD4 + Tcell accounts for larger amounts of virions in the blood as per macrophage cells. Hence, varying time delay has no impact on peak viral levels, but only shelves the viral peaking time. The adopted model has unrestrained bearing on HIV-1 therapy.

ABSTRACT Neospora caninum is the main etiologic agent of neosporosis in domestic animals and its pathogenesis comprises two characteristic phases: acute and chronic. Rodents are used as experimental models to mimic acute and chronic bovine neosporosis. In this study, we inoculated a total of 27 female gerbils, with different doses of N. caninum tachyzoites aiming to induce chronic disease. DNA was extracted from different organs of each animal after spontaneous death or euthanasia. Encephalic tissues were submitted to a highly sensitive real time PCR aiming to detect chronically infected animals. All the other samples were submitted to standard PCR. A total of 11 gerbils died due to acute neosporosis, as confirmed by N. caninum DNA detection in organs. 5x103 tachyzoites/mL of N. caninum was the dosage of antigen that can induce chronic infection in gerbils. In the encephalon sections of some animals that showed clinical signs of persistent infection, we found 70% positive for the anterior encephalon section, suggesting this area as preferential for cyst formation. Therefore, we determined the doses of tachyzoites that cause acute or chronic infection and detection of positive tissues, preferably, systemic organs during acute and encephalon in chronic phases.

Immune checkpoint inhibitors (ICIs) are the key drugs used in patients with non‐small cell lung cancer (NSCLC). However, anti‐PD‐1 therapy might worsen chronic infection by reactivating the immune response to infectious diseases. Here, we describe a case of successful treatment with nivolumab in a patient with NSCLC complicated by pulmonary aspergilloma, which was safely treated by surgical resection before administration of nivolumab. In conclusion, to safely treat patients with locally limited chronic pulmonary aspergillosis (CPA), surgical resection should be considered before ICI therapy.

Toxoplasma gondii bradyzoites establish chronic infections within their host cells. Recent studies have demonstrated that several parasite effector proteins are translocated to host cells during the bradyzoite stage of chronic infection. To understand the interaction between host cells and bradyzoites at the transcriptomic landscape level, we utilized single-cell RNA-sequencing (scRNA-Seq) to characterize the bradyzoite-induced host cell response. Distinct gene expression profiles were observed in infected host, cells with low parasite mapped reads, and mock (non-exposed) control cells. Gene set enrichment analysis showed that c-Myc and NF-κB signaling and energy metabolic pathways were upregulated by infection. Type I and II interferon response pathways were upregulated in cells with low parasite mapped reads compared to the non-exposed host control cells, and this upregulation effect was reversed in infected cells. Differences were observed in the host cells depending on the differentiation status of the parasites, as determined by BAG1 and SAG1 expression. NF-κB, inflammatory response pathways, and IFN-γ response pathways were downregulated in host cells containing T. gondiiBAG1+/SAG1−, whereas this downregulation effect was reversed in case of T. gondiiBAG1−/SAG1+. We also identified two distinct host cell subsets that contained T. gondiiBAG1+/SAG1−, one of which displayed distinct transcriptomes with upregulated c-Myc expression. Overall, these data clearly demonstrate that host cell transcriptional alteration by bradyzoite infection is different from that of tachyzoite infection, indicating fine-tuning of the host immune response.

ABSTRACT Mycobacterium abscessus is the etiological agent of severe pulmonary infections in vulnerable patients, such as those with cystic fibrosis (CF), where it represents a relevant cause of morbidity and mortality. Treatment of pulmonary infections caused by M. abscessus remains extremely difficult, as this species is resistant to most classes of antibiotics, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams. Here, we show that apoptotic body like liposomes loaded with phosphatidylinositol 5-phosphate (ABL/PI5P) enhance the antimycobacterial response, both in macrophages from healthy donors exposed to pharmacological inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) and in macrophages from CF patients, by enhancing phagosome acidification and reactive oxygen species (ROS) production. The treatment with liposomes of wild-type as well as CF mice, intratracheally infected with M. abscessus, resulted in about a 2-log reduction of pulmonary mycobacterial burden and a significant reduction of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF). Finally, the combination treatment with ABL/PI5P and amikacin, to specifically target intracellular and extracellular bacilli, resulted in a further significant reduction of both pulmonary mycobacterial burden and inflammatory response in comparison with the single treatments. These results offer the conceptual basis for a novel therapeutic regimen based on antibiotic and bioactive liposomes, used as a combined host- and pathogen-directed therapeutic strategy, aimed at the control of M. abscessus infection, and of related immunopathogenic responses, for which therapeutic options are still limited. IMPORTANCE Mycobacterium abscessus is an opportunistic pathogen intrinsically resistant to many antibiotics, frequently linked to chronic pulmonary infections, and representing a relevant cause of morbidity and mortality, especially in immunocompromised patients, such as those affected by cystic fibrosis. M. abscessus-caused pulmonary infection treatment is extremely difficult due to its high toxicity and long-lasting regimen with life-impairing side effects and the scarce availability of new antibiotics approved for human use. In this context, there is an urgent need for the development of an alternative therapeutic strategy that aims at improving the current management of patients affected by chronic M. abscessus infections. Our data support the therapeutic value of a combined host- and pathogen-directed therapy as a promising approach, as an alternative to single treatments, to simultaneously target intracellular and extracellular pathogens and improve the clinical management of patients infected with multidrug-resistant pathogens such as M. abscessus.

Abstract Adaptation of opportunistic pathogens to their host environment requires reprogramming of a vast array of genes to facilitate survival in the host. Burkholderia cenocepacia, a Gram‐negative bacterium with a large genome of ∼8 Mb that colonizes environmental niches, is exquisitely adaptable to the hypoxic environment of the cystic fibrosis lung and survives in macrophages. We previously identified an immunoreactive acidic protein encoded on replicon 3, BCAS0292. Deletion of the BCAS0292 gene significantly altered the abundance of 979 proteins by 1.5‐fold or more; 19 proteins became undetectable while 545 proteins showed ≥1.5‐fold reduced abundance, suggesting the BCAS0292 protein is a global regulator. Moreover, the ∆BCAS0292 mutant showed a range of pleiotropic effects: virulence and host‐cell attachment were reduced, antibiotic susceptibility was altered, and biofilm formation enhanced. Its growth and survival were impaired in 6% oxygen. In silico prediction of its three‐dimensional structure revealed BCAS0292 presents a dimeric β‐structure with a negative surface charge. The ΔBCAS0292 mutant displayed altered DNA supercoiling, implicated in global regulation of gene expression. Three proteins were identified in pull‐downs with FLAG‐tagged BCAS0292, including the Histone H1‐like protein, HctB, which is recognized as a global transcriptional regulator. We propose that BCAS0292 protein, which we have named Burkholderia negatively surface‐charged regulatory protein 1 (Bnr1), acts as a DNA‐mimic and binds to DNA‐binding proteins, altering DNA topology and regulating the expression of multiple genes, thereby enabling the adaptation of B. cenocepacia to highly diverse environments.

• There is no gold standard definition of chronic Pseudomonas (Pa) infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and then compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. • We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years ("Green 3/4") resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. • The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency. Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years ("Green 3/4") resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic that has been affecting the entire world and has caused the death of approximately 2.8 million people. Although the duration of viral shedding varies, an average of 7-10 days is accepted. It is still unclear whether prolonged viral shedding means prolonged contagious period and whether COVID-19 will become chronic or not. This article presents a case with hematological malignancy (lymphoma) with the longest polymerase chain reaction positivity that we could find in the literature (110 days in total). [ABSTRACT FROM AUTHOR]

Chronic enterovirus infections can cause significant morbidity, particularly in immunocompromised patients. This study describes a fatal case associated with a chronic untypeable enterovirus infection in an immunocompromised patient admitted to a Dutch university hospital over nine months. We aimed to identify the enterovirus genotype responsible for the infection and to determine potential evolutionary changes. Long-read sequencing was performed using viral targeted sequence capture on four respiratory and one faecal sample. Phylogenetic analysis was performed using a maximum likelihood method, along with a root-to-tip regression and time-scaled phylogenetic analysis to estimate evolutionary changes between sample dates. Intra-host variant detection, using a Fixed Ploidy algorithm, and selection pressure, using a Fixed Effect Likelihood and a Mixed Effects Model of Evolution, were also used to explore the patient samples. Near-complete genomes of enterovirus C104 (EV-C104) were recovered in all respiratory samples but not in the faecal sample. The recovered genomes clustered with a recently reported EV-C104 from Belgium in August 2018. Phylodynamic analysis including ten available EV-C104 genomes, along with the patient sequences, estimated the most recent common ancestor to occur in the middle of 2005 with an overall estimated evolution rate of 2.97 × 10−3 substitutions per year. Although positive selection pressure was identified in the EV-C104 reference sequences, the genomes recovered from the patient samples alone showed an overall negative selection pressure in multiple codon sites along the genome. A chronic infection resulting in respiratory failure from a relatively rare enterovirus was observed in a transplant recipient. We observed an increase in single-nucleotide variations between sample dates from a rapidly declining patient, suggesting mutations are weakly deleterious and have not been purged during selection. This is further supported by the persistence of EV-C104 in the patient, despite the clearance of other viral infections. Next-generation sequencing with viral enrichment could be used to detect and characterise challenging samples when conventional workflows are insufficient. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a serious public health concern that may lead to neurological disorders in affected individuals. The virus can be transmitted from an infected mother to her fetus, via mosquitoes, or sexually. ZIKV infections are associated with increased risk for Guillain-Barré syndrome (GBS) and congenital microcephaly in newborns infected prenatally. Dysregulations of intracellular microRNAs (miRNAs) in infected neurons have been linked to different neurological diseases. To determine the potential role of miRNAs in ZIKV infection we developed a chronically infected neuroblastoma cell line and carried out differential expression analyses of miRNAs with reference to an uninfected neuroblastoma cell line. A total of 3192miRNAs were evaluated and 389 were found to be upregulated < 2-fold and 1291 were downregulated < 2-fold. In particular, we determined that hsa-mir-431-5p, hsa-mir-3687, hsa-mir-4655-5p, hsa-mir-6071, hsa-mir-762, hsa-mir-5787, and hsa-mir-6825-3p were significantly downregulated, ranging from -5711 to -660-fold whereas, has-mir-4315, hsa-mir-5681b, hsa-mir-6511a-3p, hsa-mir-1264, hsa-mir-4418, hsa-mir-4497, hsa-mir-4485-3p, hsa-mir-4715-3p, hsa-mir-4433-3p, hsa-mir-4708-3p, hsa-mir-1973 and hsa-mir-564 were upregulated, ranging from 20-0.8-fold. We carried out target gene alignment of these miRNAs with the ZIKV genome to predict the function of the differentially expressed miRNAs and their potential impact on ZIKV pathogenesis. These miRNAs might prove useful as novel diagnostic or therapeutic markers and targets for further research on ZIKV infection and neuronal injury resulting from ZIKV infectivity in developing fetal brain neurons. [ABSTRACT FROM AUTHOR]

Introduction: Several management strategies exist for the treatment of infected abdominal mesh. Using the American Hernia Society Quality Collaborative, we examined management patterns and 30-day outcomes of infected mesh removal with concomitant incisional hernia repair. Methods: All patients undergoing incisional hernia repair with removal of infected mesh were identified. A complete repair (CR) was defined as fascial closure with mesh; a partial repair (PR) was defined as fascial closure without mesh or no fascial closure with mesh. A two-tailed p value less than or equal to 0.05 was considered statistically significant. Results: A total of 282 patients were identified: 136 patients in CR group and 146 patients in PR group. Patients had similar comorbidities but differed in wound class (class IV: 55% CR vs 83% SR, p < 0.001) and incidence of associated concomitant colorectal procedures (5% CR vs 18% SR, p = 0.015). Sublay placement was used primarily in CR (94%) compared to PR (52% inlay, 48% sublay). When comparing CR to PR, length of stay (median 6, p = 0.69), complications (40% vs 44%, p = 0.44), surgical site infections (16% vs 21%, p = 0.27), surgical site occurrence (30% vs 35%, p = 0.45), and readmission within 30 days (9% vs. 13%) were not statistically different. Conclusions: Analysis of data from a multicenter hernia registry comparing CR and PR during infected mesh removal and concurrent incisional hernia repair has not identified higher rates of short-term complications between groups in the presence of infection. [ABSTRACT FROM AUTHOR]