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Kawasaki disease (KD) is a form of acute systemic vasculitis syndrome that predominantly occurs in children under the age of 5 years. Its etiology has been postulated due to not only genetic factors but also the presence of foreign antigens or infectious agents. To evaluate possible associations between Kawasaki disease (KD) and COVID-19, we investigated humoral responses of KD patients against S-protein variants with SARS-CoV-2 variant protein microarrays. In this study, plasma from a cohort of KD (N = 90) and non-KD control (non-KD) (N = 69) subjects in categories of unvaccinated–uninfected (pre-pandemic), SARS-CoV-2 infected (10–100 days after infection), and 1-dose, 2-dose, and 3-dose BNT162b2 vaccinated (10–100 days after vaccination) was collected. The principal outcomes were non-KD–KD differences for each category in terms of anti-human/anti-His for binding antibodies and neutralizing percentage for surrogate neutralizing antibodies. Binding antibodies against spikes were lower in the KD subjects with 1-dose of BNT162b2, and mean differences were significant for the P.1 S-protein (non-KD–KD, 3401; 95% CI, 289.0 to 6512; P = 0.0252), B.1.617.2 S-protein (non-KD–KD, 4652; 95% CI, 215.8 to 9087; P = 0.0351) and B.1.617.3 S-protein (non-KD–KD, 4874; 95% CI, 31.41 to 9716; P = 0.0477). Neutralizing antibodies against spikes were higher in the KD subjects with 1-dose of BNT162b2, and mean percentage differences were significant for the 1-dose BNT162b2 B.1.617.3 S-protein (non-KD–KD, −22.89%; 95% CI, −45.08 to −0.6965; P = 0.0399), B.1.1.529 S-protein (non-KD–KD, −25.96%; 95% CI, −50.53 to −1.376; P = 0.0333), BA.2.12.1 S-protein (non-KD–KD, −27.83%; 95% CI, −52.55 to −3.115; P = 0.0195), BA.4 S-protein (non-KD–KD, −28.47%; 95% CI, −53.59 to −3.342; P = 0.0184), and BA.5 S-protein (non-KD–KD, −30.42%; 95% CI, −54.98 to −5.869; P = 0.0077). In conclusion, we have found that KD patients have a comparable immunization response to healthy individuals to SARS-CoV-2 infection and COVID-19 immunization. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection. Author summary: Dengue virus (DENV) can alter cell responses to benefit viral replication. However, most cellular proteins, especially those enhancing viral replication, remains unknown, and their roles in DENV pathogenesis are elusive. Here, we show that integrin-linked kinase (ILK) enhanced DENV infection. ILK binds DENV NS1 and NS3 to induce SOCS3 expression and abrogate STAT1/2-mediated expression of interferon-stimulated genes via the Akt-Erk- NF-κB pathway. Knockdown or inhibiting ILK enhances SOCS3 expression and reduces DENV yields in cells. Furthermore, inhibiting ILK in DENV-infected mice significantly decreased viral loads in the mouse brain and mortality. In conclusion, we identified ILK as a potential therapeutic target for DENV infection. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) which infects about 390 million people per year in tropical and subtropical areas manifests various disease symptoms, ranging from fever to life-threatening hemorrhage and even shock. To date, there is still no effective treatment for DENV disease, but only supportive care. DENV nonstructural protein 1 (NS1) has been shown to play a key role in disease pathogenesis. Recent studies have shown that anti-DENV NS1 antibody can provide disease protection by blocking the DENV-induced disruption of endothelial integrity. We previously demonstrated that anti-NS1 monoclonal antibody (mAb) protected mice from all four serotypes of DENV challenge. Here, we generated humanized anti-NS1 mAbs and transferred them to mice after DENV infection. The results showed that DENV-induced prolonged bleeding time and skin hemorrhage were reduced, even several days after DENV challenge. Mechanistic studies showed the ability of humanized anti-NS1 mAbs to inhibit NS1-induced vascular hyperpermeability and to elicit Fcγ-dependent complement-mediated cytolysis as well as antibody-dependent cellular cytotoxicity of cells infected with four serotypes of DENV. These results highlight humanized anti-NS1 mAb as a potential therapeutic agent in DENV infection. Author summary: DENV comprising four serotypes has a complicated pathogenesis and remains an unresolved global health problem. To date, supportive therapy is the mainstay for treatment of dengue patients. Despite a licensed Sanofi vaccine and ongoing clinical trials, more effective vaccines and/or licensed therapeutic drugs are required. Therapeutic mAbs are a potential tool to treat many epidemic diseases because of their high target specificity. Humanized anti-NS1 mAbs can recognize the NS1 from all four serotypes of DENV without danger of inducing ADE. In the DENV infection mouse model, we demonstrate that humanized NS1 mAbs have therapeutic benefits such as reducing DENV-induced prolonged bleeding time and skin hemorrhage. In vitro mechanistic studies showed a reduction of NS1-induced vascular permeability and an increase in cytolysis of DENV-infected cells. Our results showed that humanized anti-NS1 mAbs show strong potential for development toward clinical use. [ABSTRACT FROM AUTHOR]

Autophagy is not only an intracellular recycling degradation system that maintains cellular homeostasis but is also a component of innate immunity that contributes to host defense against viral infection. The viral components as well as viral particles trapped in autophagosomes can be delivered to lysosomes for degradation. Abundant evidence indicates that dengue virus (DENV) has evolved the potent ability to hijack or subvert autophagy process for escaping host immunity and promoting viral replication. Moreover, autophagy is often required to deliver viral components to pattern recognition receptors signaling for interferon (IFN)‐mediated viral elimination. Hence, this review summarizes DENV‐induced autophagy, which exhibits dual effects on proviral activity of promoting replication and antiviral activity to eliminating viral particles. [ABSTRACT FROM AUTHOR]

Background. Dengue virus (DENV) infection is the most common arboviral disease that affects tropical and subtropical regions. Based on the clinical hallmarks, the different severities of patients range from mild dengue fever (MDF) to severe dengue diseases (SDDs) and include dengue hemorrhagic fever or dengue shock syndrome. These are commonly associated with cytokine release syndrome (CRS). The types and levels of cytokines/chemokines, which are suppressed or enhanced, are varied, indicating CRS's pathogenic and host defensive effects. Principal Finding. In this study, we created an integrated and precise multiplex panel of cytokine/chemokine assays based on our literature analysis to monitor dengue CRS. A 24-plex panel of cytokines/chemokines was evaluated to measure the plasma levels of targeting factors in dengue patients with an MDF and SDD diagnosis without or with comorbidities. As identified in sixteen kinds of cytokines/chemokines, ten were significantly (P < 0.05) (10/16) increased, one was significantly (P < 0.01) (1/16) decreased, and five were potentially (5/16) altered in all dengue patients (n = 30) in the acute phase of disease onset. Compared to MDF, the levels of IL-8 (CXCL-8) and IL-18 in SDD were markedly (P < 0.05) increased, accompanied by positively increased IL-6 and TNF-α and decreased IFN-γ and RANTES. With comorbidities, SDD significantly (P < 0.01) portrayed elevated IL-18 accompanied by increased IL-6 and decreased IFN-α2 and IL-12. In addition, decreased platelets were significantly (P < 0.05) associated with increased IL-18. Significance. These results demonstrate an efficient panel of dengue cytokine/chemokine assays used to explore the possible level of CRS during the acute phase of disease onset; also, we are the first to report the increase of IL-18 in severe dengue with comorbidity compared to severe dengue without comorbidity and mild dengue. [ABSTRACT FROM AUTHOR]

A shift in dengue cases toward the adult population, accompanied by an increased risk of severe cases of dengue in the elderly, has created an important emerging issue in the past decade. To understand the level of past DENV infection among older adults after a large dengue outbreak occurred in southern Taiwan in 2015, we screened 1498 and 2603 serum samples from healthy residents aged ≥ 40 years in Kaohsiung City and Tainan City, respectively, to assess the seroprevalence of anti-DENV IgG in 2016. Seropositive samples were verified to exclude cross-reaction from Japanese encephalitis virus (JEV), using DENV/JEV-NS1 indirect IgG ELISA. We further identified viral serotypes and secondary DENV infections among positive samples in the two cities. The overall age-standardized seroprevalence of DENV-IgG among participants was 25.77% in Kaohsiung and 11.40% in Tainan, and the seroprevalence was significantly higher in older age groups of both cities. Although the percentages of secondary DENV infection in Kaohsiung and Tainan were very similar (43.09% and 44.76%, respectively), DENV-1 and DENV-2 spanned a wider age range in Kaohsiung, whereas DENV-2 was dominant in Tainan. As very few studies have obtained the serostatus of DENV infection in older adults and the elderly, this study highlights the need for further investigation into antibody status, as well as the safety and efficacy of dengue vaccination in these older populations. Author summary: The dengue virus (DENV) has rapidly spread out in tropical and sub-tropical regions. To measure the level of past DENV infections in the older population, we conducted a post-outbreak serosurvey in 2016 among a total of 4,101 older and elderly adults in Kaohsiung and Tainan cities in southern Taiwan. Our results showed district- and city-level differences in the overall seroprevalence of anti-DENV IgG antibody, increased seroprevalence with age, heterogeneous distributions of DENV serotypes, and similar percentages of secondary DENV infection in both metropolises, closely matching past histories of dengue outbreaks. This study demonstrates the importance of monitoring individuals' antibody status among the older and elderly population and highlights the need to investigate the safety and efficacy of dengue vaccination in these populations in the future. [ABSTRACT FROM AUTHOR]

In recent decades, the global incidence of dengue has increased. Affected countries have responded with more effective surveillance strategies to detect outbreaks early, monitor the trends, and implement prevention and control measures. We have applied newly developed machine learning approaches to identify laboratory-confirmed dengue cases from 4,894 emergency department patients with dengue-like illness (DLI) who received laboratory tests. Among them, 60.11% (2942 cases) were confirmed to have dengue. Using just four input variables [age, body temperature, white blood cells counts (WBCs) and platelets], not only the state-of-the-art deep neural network (DNN) prediction models but also the conventional decision tree (DT) and logistic regression (LR) models delivered performances with receiver operating characteristic (ROC) curves areas under curves (AUCs) of the ranging from 83.75% to 85.87% [for DT, DNN and LR: 84.60% ± 0.03%, 85.87% ± 0.54%, 83.75% ± 0.17%, respectively]. Subgroup analyses found all the models were very sensitive particularly in the pre-epidemic period. Pre-peak sensitivities (<35 weeks) were 92.6%, 92.9%, and 93.1% in DT, DNN, and LR respectively. Adjusted odds ratios examined with LR for low WBCs [≤ 3.2 (x103/μL)], fever (≥38°C), low platelet counts [< 100 (x103/μL)], and elderly (≥ 65 years) were 5.17 [95% confidence interval (CI): 3.96–6.76], 3.17 [95%CI: 2.74–3.66], 3.10 [95%CI: 2.44–3.94], and 1.77 [95%CI: 1.50–2.10], respectively. Our prediction models can readily be used in resource-poor countries where viral/serologic tests are inconvenient and can also be applied for real-time syndromic surveillance to monitor trends of dengue cases and even be integrated with mosquito/environment surveillance for early warning and immediate prevention/control measures. In other words, a local community hospital/clinic with an instrument of complete blood counts (including platelets) can provide a sentinel screening during outbreaks. In conclusion, the machine learning approach can facilitate medical and public health efforts to minimize the health threat of dengue epidemics. However, laboratory confirmation remains the primary goal of surveillance and outbreak investigation. Author summary: Identifying dengue cases early is crucial but challenging for healthcare professionals. This challenge is increased during large epidemics and is a particular problem in non-endemic areas with limited experienced staff. To improve dengue diagnosis, we investigated how to exploit machine learning (ML)-based prediction models and identified four key variables [age, fever, white blood cell counts (WBCs), and platelet counts], which are compatible with clinical and epidemiological knowledge. With these variables, the ML prediction models [decision tree (DT), deep neural network (DNN)] and the logistic regression model developed for identifying laboratory-confirmed dengue cases produced areas under curve (AUCs) of the receiver operating characteristic (ROC) curves ranging from 83.75% to 85.87%. This implies that the prediction models may serve as a pivotal component of an integrated dengue surveillance system and they required only a single complete blood count (CBC) examination. The sensitivities, positive prediction values, and accuracies for major risk factors in the two machine learning models were close to those of the regression models. For future applications, the DNN models with superior performance can be employed at epidemic sites with adequate computer facilities, while the DT and regression models with interpretable prediction logic can be employed at sites with limited or no computer facilities. Artificial intelligence and clinical parameters identified from this study may aid when laboratories are overwhelmed, but should never replace laboratory confirmation. [ABSTRACT FROM AUTHOR]

Dengue fever is an important epidemic disease with a high prevalence in tropical and subtropical countries. We aimed to investigate the effects of a treatment integrating traditional Chinese (TCM) and Western medicines on dengue inpatients with warning signs (i.e., group B) according to the World Health Organization dengue classification in this retrospective cohort study of medical records. Inpatients who were treated with conventional Western therapies in the absence or presence of TCM were assigned to the control and treatment groups, respectively. Data were compared using an analysis of variance, general linear analysis, and chi-square test. The most common clinical symptoms and signs of dengue fever were fever and muscle ache. The treatment group patients were significantly more likely to present general weakness and poor appetite than the control group patients. Patients in the treatment group were more likely to experience stomachache than those in the control group. Moreover, comparisons of the changes in hemoglobin and alanine aminotransferase levels over time revealed significant differences between the patient groups. Zhu Ye Shi Gao Tang, Gui Pi Tang, Paeonia suffruticosa, and Clerodendrum cyrtophyllum were the most commonly administered TCM formula and single herbs in this study. Patients in the treatment group experienced a resolution of symptoms, signs, and laboratory data and were discharged smoothly, without deterioration to death or critical care. Our findings suggest that the integration of TCM and Western medicine may yield an appropriate treatment for dengue fever. [ABSTRACT FROM AUTHOR]

Dear Editor, Actinomyces are nonsporulating Gram-positive bacilli, facultatively anaerobic bacteria, with negative fast stain, found in the normal flora of the oropharynx, gastrointestinal tract, or urogenital tract. Meanwhile, the pathology of surgical specimen that came out later showed Gram-positive bacilli with sulfur granules, suggesting Actinomyces infection (Fig. [Extracted from the article]

Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA-1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, the HPA-1, metalloproteinase 9 (MMP-9) and syndecan 1 (CD138) serum levels were all increased in dengue patients, and only NS1 and MIF showed a positive correlation with the CD138 level in severe patients. To further characterize and clarify the relationship between MIF and CD138, we used recombinant NS1 to stimulate human cells in vitro and challenge mice in vivo. Our tabulated results suggested that NS1 stimulation could induce human endothelial cells to secrete HPA-1 and immune cells to secrete MMP-9, resulting in endothelial glycocalyx degradation and hyperpermeability. Moreover, HPA-1, MMP-9, and CD138 secretion after NS1 stimulation was blocked by MIF inhibitors or antibodies both in vitro and in mice. Taken together, these results suggest that MIF directly engages in dengue NS1-induced glycocalyx degradation and that targeting MIF may represent a possible therapeutic approach for preventing dengue-induced vascular leakage. [ABSTRACT FROM AUTHOR]

Background: Human adenovirus 7 (HAdV-7) was responsible for a significant number of fatalities during the 2011 community outbreak in Taiwan. The mechanisms underlying the pathogenesis of severe adenovirus infections in non-immunocompromised individuals remain unclear. Adenovirus pneumonia was associated with pleural effusion in a number of patients from the 2011 outbreak suggesting that similar to bacterial pneumonia, patients diagnosed with adenovirus pneumonia who have pleural effusion are more severely and systemically infected, and may have a more protracted disease course. We hypothesized that the host immunological response determines the severity of adenoviral infection.Methods: This retrospective case series study included patients diagnosed with severe lower respiratory tract infections at the National Cheng Kung University Hospital in southern Taiwan between December 2010 and October 2011. The main inclusion criteria were 1) presence of multifocal patchy infiltrates, lobar consolidation or reticular interstitial opacities in chest X-rays, and 2) presence of adenovirus isolated from respiratory specimens. All patients had adenovirus isolated from respiratory specimens, and were negative for other viruses. Pleural effusion was confirmed in all patients using chest echography. Clinical features and laboratory data were compared in patients with (n = 12) and without (n = 15) parapneumonic effusion.Results: Presence of parapneumonic effusion was significantly associated with a longer febrile duration, more complicated clinical management, and a greater risk of extrapulmonary involvement, notably hepatitis. Patients without pleural effusion had significantly higher numbers of WBCs, platelets, and absolute segment cell counts (ASCs) compared to patients with pleural effusion (all p < 0.05). Patients without pleural effusion had significantly higher counts of CD4+, CD8+, and CD20+ T cells (all p < 0.05) compared to patients with pleural effusion.Conclusion: Our data indicated that presence of parapneumonic effusion in adenoviral pneumonia was associated with longer febrile duration, more complicated clinical management, a greater risk of hepatitis, and suppression of host cellular immunity. Further prospective, large-scale studies are needed to validate our results. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV71) infection causes a myriad of diseases from mild hand-foot-and-mouth disease or herpangina to fatal brain stem encephalitis complicated with pulmonary edema. Several severe EV71 endemics have occurred in Asia-Pacific region, including Taiwan, and have become a serious threat to children’s health. EV71 infection is initiated by the attachment of the virion to the target cell surface. Although this process relies primarily upon interaction between viruses and cell surface receptors, soluble factors may also influence the binding of EV71 to host cells.Galectin-1 has been reported to participate in several virus infections, but is not addressed in EV71. In this study, we found that the serum levels of galectin-1 in EV71-infected children were higher than those in non-infected people. In EV71 infected cells, galectin-1 was found to be associated with the EV71 VP1 and VP3 via carbohydrate residues and subsequently released and bound to another cell surface along with the virus. EV71 propagated from galectin-1 knockdown SK-N-SH cells exhibited lower infectivity in cultured cells and less pathogenicity in mice than the virus propagated from parental cells. In addition, this galectin-1-free EV71 virus was sensitive to high temperature and lost its viability after long-term storage, which could be restored following supplement of recombinant galectin-1. Taken together, our findings uncover a new role of galectin-1 in facilitating EV71 virus infection. [ABSTRACT FROM AUTHOR]

Background/Purpose: Emerging non-7-valent pneumococcal conjugate vaccine (PCV7) serotypes have replaced PCV7 serotypes in childhood invasive pneumococcal disease (IPD). This study was designed to describe the IPD caused by non-PCV7 serotypes under partial PCV7 immunization in Taiwan. Methods: All children <18 years of age diagnosed with IPD at National Cheng Kung University Hospital from 1998 to 2010 were enrolled. Clinical and laboratory information was collected. Pneumococcal isolates were tested for antimicrobial susceptibility and interpreted using Clinical Laboratory Standard Institute guidelines (2008). Serotypes were determined using the capsular swelling method. Results: One hundred and five patients with IPD were identified, including 75 PCV7 and 30 non-PCV7 isolates. Pneumonia (63.3%) was the leading clinical manifestation of non-PCV7 IPDs and 78.9% of pneumonia cases were associated with necrotizing pneumonia or empyema. Children with non-PCV7 IPDs had longer febrile days, required longer intensive care unit stays, and had a higher C-reactive protein level than those with PCV7 IPDs (p < 0.05). Serotype 3 is the most common non-PCV7 serotype (46.7%) and possesses the highest potential for pulmonary complications (p < 0.05, odds ratio: 0.114; 95% confidence interval, 0.013 – 0.973). Conclusion: The changing epidemiology of IPDs following the introduction of PCV7 has been noted. Expanded serotype coverage of the vaccine is warranted. [Copyright &y& Elsevier]

Background/Purpose: Primary physicians and nurses serve as the first-line health care providers of dengue virus infection diagnosis, notification, and treatment. Knowledge, attitude, and practice (KAP) among primary healthcare professionals (HCPs) regarding dengue diseases may pace alarm and improve the outcome of dengue control. Methods: A cross-sectional survey using a structured quiz in 264 HCPs (response rate, 76%) was conducted in Tainan City in southern Taiwan. The quiz consisted of 10 questions regarding the control measures, notification, and clinical practices of dengue diseases. Scores of KAP and demographic characteristics of HCPs were analyzed. Results: One hundred thirty-four physicians and 130 nurses comprise the 264 HCP responders. Forty-three physicians (32%) and 80 nurses (61.5%) were practicing in medical centers, and they scored higher than nonmedical center peers on quizzes on notification (1.18 vs. 0.93 points, p < 0.01) but lower on control measures (3.52 vs. 3.22 points, p < 0.01). Fifty-seven physicians (42.5%) were experienced in reporting suspected dengue cases, and 13.1% of nurses had reported dengue cases. Three-fourths of HCPs failed to respond to the timing of dengue case notification, whereas nurses scored higher than physicians (0.34 vs. 0.16, p < 0.01). In addition, 57.2% of the HCPs failed to respond correctly to the timing of typical skin rashes occurring in the patients with dengue. More than half of the HCPs considered Taiwan an endemic area of dengue diseases. Conclusion: This pilot study showed a lack of acquaintance with notification timing and important clinical features of dengue among HCPs in southern Taiwan. Future continued medical/nursing education should place more emphasis on these factors to improve dengue control in this demographic area. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is an important public health issue in Taiwan and worldwide. Taiwan has made major progress in combating TB in the past 40 years. However, childhood TB still constitutes a significant challenge in disease control. From January to mid December 2011, 369 new cases of pediatric TB were confirmed. The relatively low case number and variable clinical presentations made it difficult for early detection. Latent TB infections in children also pose further complexity in clinical management. Knowledge of the clinical features of active and latent TB infection is crucial for efficient TB control. [ABSTRACT FROM AUTHOR]

Non-typhoidal and Typhoidal Salmonella are bacterial pathogens source of worldwide and major disease burden. Virulent determinants of specific serovars belonging to non-typhoidal Salmonella have been extensively studied in different models, yet the pathogenesis of this group of bacteria and the development of clinical symptoms globally remains underexplored. Herein, we implemented microbiological and molecular procedures to investigate isolate virulence traits and molecular diversity, likely in association with disease severity. Our results show that selected clinical isolates from a tertiary referring hospital, depending on the richness of the environment and isolate serotypes, exhibited different, and sometimes controversial, virulence properties. The tested strains were susceptible to Ceftriaxone (90%) with decreasing reactivity to Trimethoprim–Sulfamethoxazole (72%), Chloramphenicol (64%), Ampicillin (48%), Gentamicin (44%), and Ciprofloxacin (2%). Disc susceptibility results partially correlated with minimum inhibitory concentration (MIC); however, special attention must be given to antimicrobial treatment, as a rise in multi-resistant isolates to Trimethoprim–Sulfamethoxazole (2/38 µg/mL), Minocycline (8 µg/mL) and Ampicillin (16 µg/mL) has been noticed, with two isolates resistant to Ceftazidime (16 µg/mL). By comparison to previous molecular epidemiology studies, the variation in the gene profiles of endemic pathogens supports the need for continuous and up-to-date microbiological and molecular reports. [ABSTRACT FROM AUTHOR]

Background: Severe dengue virus (DENV) infection involves plasma leakage and vascular collapse, and leads to significant morbidity and death. Serum soluble ST2 (sST2 [interleukin (IL)-1 receptor like-1 protein: IL-1-RL-1]) levels are high in pediatric cases of DENV infection, and the disease progresses. However, the correlation between serum sST2 levels and the outcomes of DENV infection in the elderly (≥65 years) is unclear. We thus explored the mechanisms of serial sST2 level changes involved in the coagulopathy and bloodstream infections of elderly patients in Taiwan's 2015 DENV outbreak. Methods: This retrospective study was done in a tertiary medical center in southern Taiwan during the outbreak. All DENV-infected patients who, between July 1, 2015, and December 31, 2015, provided a written informed consent for at least two blood sample analyses were enrolled and reviewed. The serum levels of sST2 were quantified. ΔsST2 is defined as the "changes of sST2 levels in serially paired samples". Receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) analyses were used to evaluate the prognostic ability of ΔsST2. Results: Forty-three patients with DENV infection were enrolled. Mean patient age was 75.0 ± 12.2 years and the case fatality rate was 44.2% (19/43). Significantly more non-survivors than survivors had increased ST2 level (78.9% vs. 12.5%, p < 0.001). The AUC value for serum ΔsST2 level was 0.857 for predicting DENV fatality. Moreover, patients given frozen fresh plasma (FFP) transfusions were significantly (p = 0.025) more likely to have higher serum ST2 level changes than were those who had not. DENV-infected patients with early bloodstream infections (BSIs) seemed to have higher ST2 levels than those who did not have BSIs. Conclusions: Serum ST2 levels increased in the elderly (≥ 65 years of age) with DENV infection. The changes in serum sST2 levels might be a critical indicator of DENV infection severity for the elderly; sST2 is an important modulator of coagulopathy in severe DENV infections. Author summary: Dengue virus (DENV) infection is a mosquito-borne disease that annually affects at least 50 million people worldwide. The cytokine response during DENV infection is mercurial and abstruse. IL-1 receptor-like-1 (IL-1R-L-1 [aka ST2]) protein is associated with the severity of DENV infection, and elevated cytokine levels are important early predictors of dengue hemorrhagic fever and dengue shock syndrome. ST2, a member of the interleukin-1-receptor/toll-like receptor (TLR) superfamily, is an important biomarker of severe forms of pediatric DENV infection. We first confirmed a similar trend in the elderly cohort. Serial changes of soluble ST2 (sST2) levels were a more reliable predictor for dengue fatality than a single measurement was. Patients given fresh frozen plasma (FFP) transfusions had significantly higher serum ST2 levels than those who had not been given FFP transfusions. SerumsST2 might be necessary for modulating coagulopathy in severe DENV infections. The exact molecular mechanism and the optimal timing for sST2 testing need further investigation. [ABSTRACT FROM AUTHOR]

Dengue is one of the most significant mosquito-borne virus diseases worldwide, particularly in tropical and subtropical regions. This study sought to examine the antiviral activity of resveratrol (RESV), a phytoalexin secreted naturally by plants, against dengue virus (DENV) infection. Our data showed that RESV inhibits the translocation of high mobility group box 1 (HMGB1), a DNA binding protein that normally resides in the nucleus, into the cytoplasm and extracellular milieu. HMGB1 migrates out of the nucleus during DENV infection. This migration is inhibited by RESV treatment and is mediated by induction of Sirt1 which leads to the retention of HMGB1 in the nucleus and consequently helps in the increased production of interferon-stimulated genes (ISGs). Nuclear HMGB1 was found to bind to the promoter region of the ISG and positively regulated the expression of ISG. The enhanced transcription of ISGs by nuclear HMGB1 thus contributes to the antiviral activity of RESV against DENV. To the best of our knowledge, this is the first report to demonstrate that RESV antagonizes DENV replication and that nuclear HMGB1 plays a role in regulating ISG production. [ABSTRACT FROM AUTHOR]

Microbial volatile organic compounds (mVCs) are formed in the metabolism of microorganisms and widely distributed in nature and pose threats to human health. However, the air pollution by microorganisms is a situation which is poorly understood. In this study, the cytotoxicity of E. aerogenes VCs was evaluated in the model organism Saccharomyces cerevisiae. E. aerogenes VCs inhibited the survival of yeast and triggered the formation of intracellular reactive oxygen species (ROS). The hypersensitive of MAP kinase mpk1 / slt2 and 19S regulatory assembly chaperone adc17 mutants to the E. aerogenes VCs indicated cell wall integrity (CWI) pathway together with stress-inducible proteasome assembly regulation are essentially involved in mVCs tolerance mechanism. Furthermore, exposure to the mVCs resulted in the transcriptional upregulation of the CWI pathway, the regulatory particle assembly chaperones, and genes involved in proteasome regulations. Our research suggested that the ROS/MAPK signaling and proteasome regulatory pathway play pivotal roles in the integration and fine-tuning of the mVCs stress response. This study provides a molecular framework for future study of the effects of mVCs on more complex organisms, such as humans. Image 1 • MVCs impose toxicity to yeast by oxdative stress. • Mpk1/Slt2 protects yeast cell from mVCs toxicity. • The exposure of mVCs affects CWI pathway in yeast. • Proteasome homeostasis is required for mVCs stress tolerance in yeast. [ABSTRACT FROM AUTHOR]

There is an urgent need for a safe and effective vaccine against dengue virus (DENV) which infects about 390 million humans per year. In the present study we combined modifications of two DENV proteins, the nonstructural protein 1 (NS1) and the envelope (E) protein, to produce a DENV vaccine candidate with enhanced features. One of these modified proteins was a C-terminal-deleted fragment of NS1 called ΔC NS1 which we have shown previously to be protective without the potentially harmful effects of cross-reactive epitopes common to surface antigens on platelets and endothelial cells. The other modified protein was an envelope protein domain III (cEDIII) containing a consensus amino acid sequence among the four serotypes of DENV, which induces neutralizing antibody against all four DENV serotypes. The cEDIII and ΔC NS1 were expressed as a fusion protein cEDIII-ΔC NS1 and its protective effects against DENV were evaluated in a mouse model. C3H/HeN mice were immunized three times with cEDIII-ΔC NS1 fusion protein mixed with alum as adjuvant. Sera collected from cEDIII-ΔC NS1-immunized mice neutralized four serotypes of DENV and also caused complement-mediated cytolysis of HMEC-1 cells infected with each of the four different DENV serotypes. Mice immunized with cEDIII-ΔC NS1 and challenged with DENV showed reduced serum virus titer, soluble NS1 and bleeding time, compared with mice infected with DENV alone. The results reveal that antibodies induced by cEDIII-ΔC NS1 not only show anti-viral efficacy by in vitro assays but also provide protective effects against DENV infection in a mouse model. The cEDIII-ΔC NS1 thus represents a novel, effective DENV vaccine candidate. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has led to millions of fatalities globally. Kidney transplant (KT) patients, given their comorbidities and under immunosuppressant drugs, are identified as a high-risk group. Though vaccination remains pivotal for pandemic control, some studies indicate that KT exhibits diminished immune reactions to SARS-CoV-2 vaccines. Therefore, evaluating the vaccine responses in KT, especially the humoral responses against emergent variants is crucial. Methods: We developed a multiplexed SARS-CoV-2 variant protein microarray, incorporating the extracellular domain (ECD) and the receptor binding domain (RBD) of the spike proteins from the variants. This was employed to investigate the collective humoral responses after administering two doses of mRNA-1273 and AZD1222 vaccines in KT under immunosuppressive drugs and in healthy controls. Results: After two doses of either mRNA-1273 or AZD1222, the KT generally showed lower surrogate neutralizing and total antibodies against spike ECD in multiple variants compared to healthy controls. Although two doses of mRNA-1273 induced 1.5-2 fold more surrogate neutralizing and total antibodies than AZD1222 in healthy controls, the KT subjects with two doses of mRNA-1273 generally exhibited higher surrogate neutralizing but similar total antibodies against spike ECD in multiple variants. There were moderate to high correlations between the surrogate neutralizing and total antibodies against spike ECDs. Conclusion: This study offers pivotal insights into the relative vulnerability of KT concerning humoral immunity and the evolving mutations of SARS-CoV-2. Such findings are useful for evaluating vaccine responses and recommending vaccine episodes for KT.

Kidney transplant recipients (KTRs) have been identified as a population at increased risk for severe SARS-CoV-2 infection outcomes. This study focused on understanding the immune response of KTRs post-vaccination, specifically examining both serological and cellular responses to the SARS-CoV-2 vaccine. Thirteen individuals, including seven KTRs and six healthy donors, were evaluated for antibody levels and T cell responses post-vaccination. The study revealed that KTRs had significantly lower serological responses, including reduced anti-receptor binding domain (RBD) binding antibodies and neutralizing antibodies against the Wuhan, Delta, and Omicron BA.2 strains. Additionally, KTRs demonstrated weaker CD8 T cell cytotoxic responses and lower Th1 cytokine secretion, particularly IFN-γ, after stimulation with variant spike peptide pools. These findings highlight the compromised immunity in KTRs post-vaccination and underscore the need for tailored strategies to bolster immune responses in this vulnerable group. Further investigations are warranted into the mechanisms underlying reduced vaccine efficacy in KTRs and potential therapeutic interventions., Importance: Some studies have revealed that KTRs had lower serological response against SARS-CoV-2 than healthy people. Nevertheless, limited studies investigate the cellular response against SARS-CoV-2 in KTRs receiving SARS-CoV-2 vaccines. Here, we found that KTRs have lower serological and cellular responses. Moreover, we found that KTRs had a significantly lower IFN-γ secretion than healthy individuals when their PBMCs were stimulated with SARS-CoV-2 spike peptide pools. Thus, our findings suggested that additional strategies are needed to enhance KTR immunity triggered by the vaccine., Competing Interests: The authors declare no conflict of interest.

In November 2022, 68% of the population received at least one dose of COVID-19 vaccines. Owing to the ongoing mutations, especially for the variants of concern (VOCs), it is important to monitor the humoral immune responses after different vaccination strategies. In this study, we developed a SARS-CoV-2 variant protein microarray that contained the spike proteins from the VOCs, e.g., alpha, beta, gamma, delta, and omicron, to quantify the binding antibody and surrogate neutralizing antibody. Plasmas were collected after two doses of matching AZD1222 (AZx2), two doses of matching mRNA-1273 (Mx2), or mixing AZD1222 and mRNA-1273 (AZ+M). The results showed a significant decrease of surrogate neutralizing antibodies against the receptor-binding domain in all VOCs in AZx2 and Mx2 but not AZ+M. A similar but minor reduction pattern of surrogate neutralizing antibodies against the extracellular domain was observed. While Mx2 exhibited a higher surrogate neutralizing level against all VOCs compared with AZx2, AZ+M showed an even higher surrogate neutralizing level in gamma and omicron compared with Mx2. It is worth noting that the binding antibody displayed a low correlation to the surrogate neutralizing antibody (R-square 0.130-0.382). This study delivers insights into humoral immunities, SARS-CoV-2 mutations, and mixing and matching vaccine strategies, which may provide a more effective vaccine strategy especially in preventing omicron., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)