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BackgroundP21-activated kinase 4 (PAK4) is a serine/threonine protein kinase that is mostly expressed in tumor and stroma cells. PAK4 activates tumor WNT/β-catenin pathway and regulates cellular morphology, motility, EMT, cell proliferation and survival. Recent studies also showed that PAK4 can actively exclude T cells from tumors, suggesting that therapeutic inhibition of PAK4 can increase T cell infiltration in tumor microenvironment and overcome resistance to checkpoint inhibitor immunotherapy.1MethodsWe generated PAK4 knockout (KO) clones in human and mouse tumor cells to validate its biology in vitro and in vivo. We also performed pharmacological evaluation of PAK4 inhibition using Pfizer compounds (referred to as 'PAK4i compounds' below) for their potential tumor-intrinsic and immune-regulatory roles.ResultsNanostring, qPCR and RNASeq analysis showed that PAK4 depletion led to increase of cytokine expression in tumor, including conventional dendritic cell (cDC)- recruiting chemokine CCL4, and type I IFN / ISG pathway genes that are associated with MHC upregulation such as CXCL10. In addition, PAK4 KO sensitizes B16F10 tumors to anti-PD-1 treatment and increases infiltration of cDC and T cells in the tumor microenvironment.We also showed that small molecule PAK4i compounds induced more potent cancer cell growth inhibition over treated normal PBMCs. PAK4i compounds also increased immune-activating and decreased immune exclusion genes in B16F10 cells and tumor explants in vitro. Although PAK4 target engagement is demonstrated by CETSA assay, the compound potency on modulating PAK4 downstream Wnt/ β-catenin pathway is low, suggesting that the aforementioned phenotypic changes induced by PAK4i compounds may be partially attributed to other off-target effects.ConclusionsCollectively, our data suggests that genetic depletion or pharmacological inhibition of PAK4 may induce immune-activating cytokine production in tumor cells, revert immune cell exclusion in tumor microenvironment, and synergize with checkpoint blockade therapies. However, further optimization on these PAK4i compounds is needed to improve its specificity on modulating PAK4 enzyme activities.ReferenceAbril-Rodriguez G, Torrejon DY, Liu W, Zaretsky JM, Nowicki TS, Tsoi J, Puig-Saus C, Baselga-Carretero I, Medina E, Quist MJ, Garcia AJ, Senapedis W, Baloglu E, Kalbasi A, Cheung-Lau G, Berent-Maoz B, Comin-Anduix B, Hu-Lieskovan S, CWang CY, Grasso CS & Ribas A. PAK4 inhibition improves PD-1 blockade immunotherapy. Nat Cancer 2020;1:46–58.Ethics ApprovalAll animal studies were conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee of Pfizer. Approved protocol # LAJ-2019-01347

Automatic detection of sign language from hand gesture images is crucial nowadays. Accurate detection and classification of sign language can help people with hearing and speech disorder. In this paper, a deep multi-layered convolution neural network is proposed for this purpose. In the proposed approach, 32 convolution filters with 3 x3 kernel, LeakyReLU activation function and 2 x2 max pooling operation have been performed in the deep multi-layered CNN structure. SoftMax activation function has been used in the output layer. The proposed approach has been evaluated on a database containing both static (54000 images and 36 classes) and dynamic (49613 images and 23 classes) hand gesture images. Experimental results demonstrate the efficacy of the proposed methodology in sign language detection task.

Severe Acute Respiratory Syndrome Corona virus 2 (SARS-COV-2) also known as COVID-19 has been emerged as a pandemic throughout the globe recently. Therefore, accurate diagnosis of COVID-19 is necessary to fight against this pandemic situation. In this context, chest X-ray (CXR) scans play an important role in the diagnosis of the corona virus. In this paper, an intelligent detection and classification technique of COVID-19 has been proposed to assist doctors in their diagnostic prediction. A deep multi-layered convolution neural network (CNN) has been proposed to detect COVID-19 accurately from CXR scans. The proposed methodology has experimented on a combination of multiple open source publicly available datasets. Experimental results demonstrate the efficacy of the proposed methodology in COVID-19 detection from CXR images.

Classification of retinal diseases using Optical Coherence Tomographical (OCT) scans is a crucial task. Accurate detection and classification of these diseases is necessary for patient’s survival. Presently, the analysis of retinal diseases are carried out by doctors by examining the OCT images regularly. However the manual diagnosis procedure is tedious. Therefore, in this paper, an automatic detection and classification technique of retinal diseases has been proposed to assist doctors in their diagnosis. A deep multilayered convolutional neural network (CNN) has been used to detect and classify the retinal abnormalities using OCT scans. The proposed technique has been applied on an open source retinal OCT dataset containing 59,142 images and 96.5% blind test accuracy has been achieved.

May-Thurner syndrome (MTS) is a clinical condition where the left common iliac vein gets compressed by the overlying right common iliac artery anterior to the fifth lumbar vertebra and the sacral promontory. It results in vessel wall injury and predisposition to thrombosis. We present a case of a 21-year-old African-American man with no significant past medical history who came to the emergency department with left lower limb swelling associated with shortness of breath, and was eventually diagnosed to have extensive left lower extremity deep vein thrombosis (DVT) along with acute bilateral extensive pulmonary embolism (PE) as a consequence to MTS. MTS should be considered in the differential when young patients present with unprovoked or recurrent left-sided DVT. Diagnosis of this anatomical variant is critical as it may need long-term anticoagulation and consideration of pharmaco-mechanical intervention such as mechanical thrombectomy and venoplasty with or without stenting.

BackgroundHematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy.MethodsHuman primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo.ResultsCompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease.ConclusionCompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.

Injudicious use of over-the-counter calcium supplements has resulted in increased incidences of hypercalcaemia and related complications. We present a case of acute pancreatitis in a chronic hypocalcaemic patient of DiGeorge’s syndrome. The patient came into the ED with sepsis syndrome, right upper quadrant and epigastric pain and no obvious source of infection. Lab results and imaging were indicative of acute pancreatitis. There was severe renal dysfunction. The patient needed haemodialysis and had a prolonged stay in intensive care. The medical history was negative for biliary duct pathology or alcohol use. The patient had vomiting and diarrhoea in the nursing home for about a week, but she continued to receive her regular medications that included the calcium supplements and thiazide diuretics. It is likely that a complex interplay between calcium supplementation, dehydration and thiazide diuretics resulted in the development of acute pancreatitis and severe renal dysfunction in a chronic hypocalcaemic patient.

Functional exhaustion of CD8 + T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-γ), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8 + T cells (an important source of IFN-γ) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8 + T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8 + T cells. While the transfer of immune CD8 + T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8 + T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8 + T cells fail to become long-lived, one of the cardinal features of memory CD8 + T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8 + T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis.

Although the highest numbers of studies linking an infectious agent with schizophrenia has involved the parasite Toxoplasma gondii, the mechanistic underpinnings of this correlation has remained unaddressed. Incidentally, CD8 T cells, which play a pivotal role in mediating long-term immunity to Toxoplasma, are downregulated in schizophrenia patients. Recent studies have demonstrated that CD8 response is also impaired during chronic toxoplasmosis in murine models. In light of these new findings, in this article, we discuss the potential role of CD8 T cells in causing altered mental status in Toxoplasma seropositive schizophrenia patients.

The aim of this comprehensive review article is to emphasize on the possible exploration of a new therapeutic approach in the management of heart failure (HF) and other cardiovascular diseases: the renin-angiotensin-aldosterone system-neprilysin combination inhibitors, also called angiotensin receptor neprilysin inhibitor, valsartan/sacubitril (LCZ696). Sacubitril is an inhibitor of neutral endopeptidase (NEP) which degrades vasoactive peptides such as atrial natriuretic peptide and brain natriuretic peptide. Valsartan is an angiotensin receptor blocker which is usually used in hypertension. Although HF has been a global health burden, for decades there has been lack of novel therapeutic options as many trials failed due to potential side effects. With the published results of the landmark trial Prospective comparison of ARNI with ACEI to Determine the Impact on Global Mortality and morbidity in HF (PARADIGM-HF), a new direction in the treatment of HF is anticipated. This trial showed that LCZ696 was able to reduce the primary composite end point of cardiovascular death or HF hospitalization, and similar reduction was observed for cardiovascular death. This review article also highlights the results of 4 published trials of LCZ696 in both HTN and HF. After the results of PARADIGM-HF trial, the major challenge will be outcome in regular clinical practice, as subjects in the trial were mostly stable New York Heart Association class II patients with no comorbidities. In addition, many trials are simultaneously in progress regarding the use of LCZ696 in patients with diabetes, renal failure, and hepatic impairment. To conclude, sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HF, but it will need meticulous attention when used in real outpatient practice.

Protozoan parasites cause severe morbidity and mortality in humans worldwide, especially in developing countries where access to chemotherapeutic agents is limited. Although parasites initially evoke a robust immune response, subsequent immunity fails to clear infection, ultimately leading to the chronic stage. This enigmatic situation was initially addressed in chronic viral models, where T cells lose their function, a phenomenon referred to as 'exhaustion'. However, recent studies demonstrate that this paradigm can be extended to protozoan diseases as well, although with notable differences. These studies have revealed that T cell responses generated against Toxoplasma gondii, Plasmodium sp., and Leishmania sp. can become dysfunctional. This review discusses T cell exhaustion in parasitic infection, mechanisms of development, and a possible role in disease outcome.

The increasing demand and popularity of bariatric surgery are not only due to the ever-increasing obesity epidemic but to tackle obesity-related comorbidities like diabetes and hypertension. However, bariatric surgery is not free of complications. One rare complication is intussusception, jejuno-jejunal intussusception being the most common. Intussusception has been defined both in pregnant and in non-pregnant women as well as men. We describe the case of a 40-year-old woman in the first trimester of pregnancy came to the hospital with worsening abdominal pain, was found to have intussusception of small bowel involving the jejunum, along with ischaemic perforation and necrosis of the fundus of the stomach. Postsurgery, the patient had a complete recovery and eventually, she successfully delivered an intact, viable fetus.

Khan et al. demonstrate that in chronic toxoplasmosis, CD4 T cell–intrinsic expression of Blimp-1 results in progressive exhaustion, which in turn contributes to CD8 T cell exhaustion and poor pathogen control., CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

Advanced age is associated with immune system deficits that result in an increased susceptibility to infectious diseases; however, specific mediators of age-dependent immune dysfunction have not been fully elucidated. Here we demonstrated that aged mice exhibit poor effector CD8+ T cell polyfunctionality, primarily due to CD8+ T cell-extrinsic deficits, and that reduced CD8+ T cell polyfunctionality correlates with increased susceptibility to pathogenic diseases. In aged animals challenged with the parasite Encephalitozoon cuniculi, effector CD8+ T cell survival and polyfunctionality were suppressed by highly elevated TGF-β1. Furthermore, TGF-β depletion reduced effector CD8+ T cell apoptosis in both young and aged mice and enhanced effector CD8+ T cell polyfunctionality in aged mice. Surprisingly, intrinsic blockade of TGF-β signaling in CD8+ T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-β1 promote apoptosis of CD8+ effector T cells and high TGF-β1 levels associated with age result in both CD8+ T cell apoptosis and an altered transcriptional profile, which correlates with loss of polyfunctionality. Furthermore, elevated TGF-β levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-β represents an evolutionarily conserved negative regulator of the immune response in aging organisms.

Herbal medicines have been perceived as natural, safe, and economically and socio-culturally acceptable remedies to many illnesses. Complementary and alternative medicine (CAM) includes herbal medicine and yoga as well as homeopathy, chiropractic care, and acupuncture. Herbal products are an important component of complementary and alternative medicine.1 In the United States, complementary and alternative medicine is an approximately $9 billion dollar market, approximately three per cent of national ambulatory healthcare expenditures.2 However, due to intrinsic pharmacokinetic and dynamic interactions, variability in herbal product compositions, unsupervised self-administration, and lack of adequate knowledge about the ingredients and their pharmacological properties, there is a serious risk of potentially adverse herb-drug interactions. Worldwide prevalence of the use of CAM A cross-sectional study comprising 463 patients suffering from chronic pain and receiving primary care at 12 US academic health centres showed widespread prevalence of CAM.1 Users of CAM may use conventional and complementary medicines simultaneously, and this raises concerns about herb-drug interactions.2 Physicians may be uncertain about the effects of concomitant use of herbs and allopathic medicines. A study of prescription and use of CAM among physicians and patients in a tertiary hospital in India showed that although doctors use herbal medicines more than patients (58 per cent compared to 38 per cent), they seldom enquired about herbal supplement usage among their patients.3 The same study showed that only 15 per cent of the doctors taking herbal supplements were aware of the sources of information about those products. A national survey among university hospitals in Sweden showed a lack of adequate knowledge about herbal supplements and other CAM modalities among registered healthcare providers in surgical care.4 In the United States, herbal medicine and yoga became popular as CAM between 1997 and 2002.5 However, the surge stabilised and the prevalence rates slightly declined from 18.9 per cent in 2002 to 17.9 per cent in 2007 and 2012 as evidenced by population health interview surveys conducted in those respective years.6 A 2007 survey revealed that approximately 33 per cent of US adults who used herbal supplements disclosed it to their physicians.7 Patients largely self-medicated without informing their doctors.7 Figures were even worse (19 per cent) in an Indian setting.3 Physicians’ perspective and knowledge about herbs and other CAM modalities Physicians are largely divided on the use of herbal medicine and other CAM modalities.8 American physicians are generally sceptical about the use of herbs and supplements.8 A systematic review of CAM studies has shown that both physician and patient attributes are integral for adequate physician-patient communication about the use of herbal products and other CAM modalities.9,10 Despite personal reservations, physicians need to be aware of patients’ CAM usage in order to practice clinical medicine effectively. This has been shown to be particularly true when treating patients belonging to minority groups. One study showed the rate of non-disclosure of herbal medications was higher among racial and ethnic minority groups and among non-citizens. Impairments in language, diverse cultural factors, and economic reasons have limited the access of such subpopulations to conventional medical care.11 Increasing physician awareness about CAM and herbal products We believe that steps must be taken to improve knowledge, attitudes, and perceptions about herbal medications amongst primary care and general physicians, as well as to improve physician-patient communication. Ways to integrate herbal and alternative medicine into mainstream conventional medicine include more pharmacokinetic research, conducting studies involving pharmacogenomics (the study of how genes can affect an individual's response to drugs) and adverse drug events, offering continuing medical education (CME) credits for alternative medicine courses, and encouraging active collaboration between conventional medical providers and CAM providers.12 Ways to strengthen effective physician-patient communication should include emphasis on communication and interpersonal skills, cultural sensitivity issues, cost effectiveness, understanding the faith and practice of the community, and most importantly, awareness regarding different CAM therapies. Clinical implications of herb-drug interactions Herbs can increase or decrease a prescription drug’s expected activity, leading to either unwanted adverse effects or therapeutic failure. Active ingredients in the herbs can alter remarkably the pharmacokinetic and pharmacodynamic properties of a drug. For example, Co-enzyme Q10, a widely used food supplement, interferes with the efflux transporter P-glycoprotein and thus alters the pharmacokinetics of many drugs.13 In contrast to drug-drug interactions, it is difficult to access information about herb-drug interactions. With the exception of some review articles, reliable resources for such information are limited. Table 1 outlines some common herb-drug interactions. Table 1: Common herbal supplements, their usage (in brackets) and potential interactions with prescription drugs18-25 The pharmacological effect of a drug depends on its concentration at its site of action, which in turn depends on its rate of elimination. In many drugs, hepatic microsomal enzymes govern this. Inducers of the CYP450 hepatic microsomal system can result in rapid elimination and reduced bioavailability of certain drugs and may result in therapeutic failure, whereas opposite effects may be encountered when the same enzyme system is inhibited. Drug elimination is reduced and plasma half-life is increased manifold, which can lead to unwanted adverse effects. Common herb-drug Interactions Many herbs have the potential to induce the CYP450 enzyme system. Perhaps the most notable is St. John's Wort (Hypericum perforatum), which reduces the plasma concentration of many drugs such as amitriptyline, digoxin, theophylline, non-steroidal anti-inflammatories (NSAIDs), and oral contraceptive pills.13 St. John's Wort also increases the activity and expression of multidrug transporter P-glycoprotein efflux pumps in the duodenum. This mechanism has been implicated in its interactions with indinavir, digoxin, and cyclosporin. It also increases the metabolism of protease inhibitor indinavir, resulting in therapeutic failure. It has also been implicated for reducing cyclosporine bioavailability, an immunosuppressive agent given in transplant recipient patients.14,15 In conjunction with the use of medicinal herbs at the same time as warfarin, serious adverse effects have been encountered with warfarin due to herb-based inhibition of its metabolising enzymes. These include spontaneous postoperative bleeding, haematomas, haematemesis, melena, subarachnoid haemorrhage, subdural haematomas, and thrombosis. The herbs that can cause such adverse reactions include: Panax ginseng, Hypericum perforatum (St John's Wort), Gingko biloba, Serenoa repens, Angelica sinensis, Vaccinium species, Allium sativum (garlic), Zingiber officinale (ginger), Tanacetum parthenium, Lucium barbarum, Matricaria chamomilla, Boswellia serrate, and Camellia sinensis (tea).15 Zingiber officinale (ginger) is a common herbal medication that is used in motion sickness and inflammation. Ginkgo biloba is another common herbal remedy that is reputed to increase mental alertness. St John's Wort is an herbal remedy for treating depression. Vitamin K, a naturally occurring vitamin, is principally found in green leafy vegetables. It is suggested that Vitamin K intake from the diet should be restricted to 65–80 micrograms in patients who receive warfarin.15 Dietetic advice is recommended. Accordingly, physicians need to be aware of patients’ dietary habits, in addition to any unsupervised intake of herbal medications in order to prevent hazardous side effects. The commonly used dietary supplement liquorice contains glycyrrhizin and glycyrrhetinic acid.16 These are potent inhibitors of 11-βhydroxy steroid dehydrogenase, causing raised cortisol and increased mineralocorticoid activity, leading to hypertension and suppression of the renin-angiotensin aldosterone system. Liquorice also interacts with various medicines such as some antihypertensives and some antiarrhythmics. Furanocoumarins found in grapefruit juice are potent inhibitors of the CYP enzyme system; bergamottin is the most potent of all. Furanocoumarins are found in many Chinese herbs. Flavonoids found in some herbal remedies also can cause significant inhibition of the CYP3A4 system. Similarly, people taking mono amine oxidase inhibitors (MAOIs) as prescription medications should avoid consuming Scotch broom (Cytisus scoparius) (which contains tyramine), as the combination may trigger a hypertensive crisis. Ginger, used by traditional Western and Chinese medicine to treat nausea, inactivates pro-emetic substances in the stomach. The same mechanism can hinder the absorption of certain drugs and neutralise their effect. Ginger can hinder the absorption of drugs by deactivating them in the stomach and therefore reducing their absorption. Herbs of the genus Rehmannia have been shown to antagonise suppressant effect of steroids on the hypothalamic-pituitary-adrenal axis. In such cases, the physician needs to tailor the patients’ dose of steroids. Lower than usual therapeutic dose needs to be administered, otherwise adverse effects relating to increased steroid levels in the blood will increase. 17

Chronic infectious diseases such as HIV, HBV, and HCV, among others, cause severe morbidity and mortality globally. Progressive decline in CD8 functionality, survival, and proliferative potential—a phenomenon referred to as CD8 exhaustion—is believed to be responsible for poor pathogen control in chronic infectious diseases. While the role of negative inhibitory receptors such as PD-1 in augmenting CD8 exhaustion has been extensively studied, the role of positive costimulatory receptors remains poorly understood. In this review, we discuss how one such costimulatory pathway, CD40–CD40L, regulates CD8 dysfunction and rescue. While the significance of this pathway has been extensively investigated in models of autoimmunity, acute infectious diseases, and tumor models, the role played by CD40–CD40L in regulating CD8 exhaustion in chronic infectious diseases is just beginning to be understood. Considering that monotherapy with blocking antibodies targeting inhibitory PD-1-PD-L1 pathway is only partially effective at ameliorating CD8 exhaustion and that humanized CD40 agonist antibodies are currently available, a better understanding of the role of the CD40–CD40L pathway in chronic infectious diseases will pave the way for the development of more robust immunotherapeutic and prophylactic vaccination strategies.

Zika virus (ZIKV) infection is a well-nurtured topic for healthcare personnel nowadays. Central nervous system involvement including microcephaly and ocular involvements has already been reported in neonates of affected pregnant ladies. In this article, we have discussed these effects on the newborns of ZIKV-infected mothers. The proposed pathogenesis, modes of transmission of this infection from mothers to the fetuses, diagnosis of the cases and precaution for the pregnant ladies have also been discussed. We have gathered the recently available data on the risk of ZIKV for expectant mothers from PubMed, https://www.gov.uk/guidance/zika-virus as well as from centers for disease control and prevention websites.

We reported earlier that during chronic toxoplasmosis CD8(+) T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8(+) T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon γ(+)/granzyme B(-) memory but not effector CD8(+) T cells. In summary, the present report underscores the critical role of the PD-1-PD-L1 pathway in mediating attrition of this important CD8(+) T-cell subset and addresses the mechanistic basis of how αPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections.

Toxoplasma gondii infection induces a robust CD8 T-cell immunity that is critical for keeping chronic infection under control. In studies using animal models, it has been demonstrated that the absence of this response can compromise the host ability to keep chronic infection under check. Therapeutic agents that facilitate the induction and maintenance of CD8 T-cell response against the pathogen need to be developed. In the last decade, major strides in understanding the development of effector and memory response, particularly in viral and tumor models, have been made. However, factors involved in the generation of effector or memory response against T. gondii infection have not been extensively investigated. This information will be invaluable in designing immunotherapeutic regimens needed for combating this intracellular pathogen that poses a severe risk for pregnant women and immunocompromised individuals.

In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 T-cell dysfunction during chronic infection. We demonstrate that CD8 + T-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these cells become exhausted, leading to parasite reactivation and mortality. Concomitant with increased CD8 + T-cell apoptosis and decreased effector response, this dysfunction is characterized by a graded elevation in expression of inhibitory receptor PD-1 on these cells in both lymphoid and nonlymphoid tissue. Blockade of the PD-1–PDL-1 pathway reinvigorates this suboptimal CD8 + T-cell response, resulting in control of parasite reactivation and prevention of mortality in chronically infected animals. To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8 + T-cell dysfunction and parasite reactivation.

CD8 T cells are essential for control ofToxoplasma gondiiinfection. Once activated they undergo differentiation into short-lived effector and memory precursor effector cells. As effector cells, CD8 T cells exert immune pressure on the parasite via production of inflammatory cytokines and through their cytolytic activity. Once immune control has been established, the parasite encysts and develops into chronic infection regulated by the memory CD8 T-cell population. Several signals are needed for this process to be initiated and for development of fully differentiated memory CD8 T cells. With newly developed tools including CD8 T-cell tetramers and TCR transgenic mice, dissecting the biology behindT. gondii-specific CD8 T-cell responses can now be more effectively addressed. In this paper, we discuss what is known about the signals required for effectiveT. gondii-specific CD8 T-cell development, their differentiation, and effector function.

IL-7 and IL-15 are believed to be important for homeostatic proliferation of CD8+ memory T cells. However, the simultaneous role played by these two cytokines in the generation of this response during acute phase of infection has not been described. Our results demonstrate that depletion of IL-7 in mice lacking IL-15 gene leads to poor development of both short-lived effectors as well as memory phenotype CD8+ T cells during Toxoplasma gondii infection. CD8+ T cells from these animals lack the ability to produce optimal levels of IFNγ upon antigenic-restimulation and their ability to exhibit cytotoxic response is severely hampered. Moreover, Bcl-2 and KI-67 expression on these cells is down regulated. To the best of our knowledge this synergism between IL-7 and IL-15 in generating a potent CD8+ T cell immunity in an infectious disease model has not been previously reported.