Insights into Virus-Induced Immune Mediated Liver Pathology.

In the context of chronic viral infections, the hepatic microenvironment dictates the outcome of the disease by influencing propagation of virus and regulation of cytotoxic CD8+ T cell response. Nevertheless, such regulation could be beneficial as it resolves the disease or could be detrimental as it causes liver pathological consequences. Liver pathology is a hallmark of chronic viral infection in both human and murine models. Such models show viral infection of hepatocytes and subsequent direct hepatic damage. Other compelling studies showed that liver injury was a consequence of overshooting CD8+ T cells response in experimental mice, so-called immune-mediated liver pathology. This review highlights the viral-induced immune mediated aspects of liver pathology based on the lymphocytic choriomeningitis virus (LCMV) and Hepatitis virus settings.

Arenavirus Therapy in Combination with Checkpoint Blockade as an Effective Way for Better Tumour Clearance.

Viruses have been widely used to treat cancer for many years and they achieved tremendous success in clinical trials with outstanding results, which has led to the foundation of companies that develop recombinant viruses for a better tumor treatment. Even though there has been a great progress in the field of viral tumor immunotherapy, until now only one virus, the oncolytic virus talimogene laherparepvec (TVEC), a genetically modified herpes simplex virus type 1 (T-VEC), has been approved by the FDA for cancer treatment. Although oncolytic viruses showed progress in certain cancer types and patient populations but they have yet shown limited efficacy when it comes to solid tumors. Only recently it was demonstrated that the immune stimulatory aspect of oncolytic viruses can strongly contribute to their anti-tumoral activity. One specific example in this context are arenaviruses, which have been shown to be non-cytopathic in nature lead to the massive immune activation within the tumor resulting in strong anti-tumoral activity. This strong immune activation might be also linked to their noncytopathic features, as their immune stimulatory potential is not self-limiting as is the case for oncolytic viruses due to their fast eradication by anti-viral immune effects. Because of this strong immune activation, arenaviruses appear superior to oncolytic viruses when it comes to potent and long-lasting anti-tumor effects in a broad variety of tumor types. Currently one of the most promising therapeutics which has turned to be very much beneficial for the treatment of different cancer types is represented by antibodies targeting checkpoint inhibitors such as PD-1/PD-L-1. In this review, we will summarize anti-tumoral effects of arenaviruses, and will discuss their potential to be combined with checkpoint inhibitors for a more efficient tumor treatment, which further emphasizes that arenavirus therapy as a viroimmunotherapy can be an efficient tool for the better clearance of tumors.

NK cell-intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection.

During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.

Combined gas exchange characteristics, chlorophyll fluorescence and response curves as selection traits for temperature tolerance in maize genotypes.

Maize is a low-temperature (LT)-sensitive plant and its physiological responses towards LT of temperate regions developed is an adaptive trait. To further our understanding about the response of maize to LT at the physiological and photosynthesis level, we conducted Infrared Gas Analysis (IRGA using LICOR6400-XT in 45-day-old grown two maize genotypes, one from temperate region (Gurez-Kashmir Himalayas), viz., Gurez local (Gz local), and another from tropics (Gujarat), viz., GM6. This study was carried out to evaluate the underlying physiological mechanisms in the two differentially temperature-tolerant maize genotypes. Net photosynthetic rate (A/PN), 18.253 in Gz local and 25.587 (µmol CO2 m-2 s-1) in GM6; leaf conductance (gs), 0.0102 in Gz local and 0.0566 (mmol H2O m-2 s-1) in GM6; transpiration rate (E), 0.5371 in Gz local and 2.9409 (mmol H2O m-2 s-1) in GM6; and water use efficiency (WUE), 33.9852 in Gz local and 8.7224 (µmol CO2 mmol H2O-1) in GM6, were recorded under ambient conditions. Also, photochemical efficiency of photosystem II (PSII) (Fv/Fm), 0.675 in Gz local and 0.705 in GM6; maximum photochemical efficiency (Fv'/Fm'), 0.310234 in Gz local and 0.401391 in GM6; photochemical quenching (qP), 0.2375 in Gz local and 0.2609 in GM6; non-photochemical quenching (NPQ), 2.0036 in Gz local and 1.1686 in GM6; effective yield of PSII (ФPSII), 0.0789 in Gz local and 0.099 in GM6; and electron transport rate (ETR), 55.3152 in Gz local and 68.112 in GM6, were also evaluated in addition to various response curves, like light intensities and temperature. We observed that light response curves show the saturation light intensity requirement of 1600 µmol for both the genotypes, whereas temperature response curves showed the optimum temperature requirement for Gz local as 20 °C and for GM6 it was found to be 35 °C. The results obtained for each individual parameter and other correlational studies indicate that IRGA forms a promising route for quick and reliable screening of various stress-tolerant valuable genotypes, forming the first study of its kind.

Interferon in the CNS.

While the role of interferon during systemic disease is well known and its immune modulating functions and its role in antiviral activity were extensively studied, the role of IFN-I in the brain is less clear. Here we summarize the most important literature on IFN in homeostasis of the CNS and induction of an IFN response during viral infection in the brain. Furthermore, we present work on the roles of IFN in the developing brain as well as during inflammation in the brain. Lastly, we aim to enlighten the functions of IFN on the blood-brain barrier as well as circulation and in cognitive and psychological functions and degeneration. In short, CNS astrocytes produce IFN-ß, which is of high relevance for homeostasis in the brain. IFN-ß regulates phagocytic removal of myelin debris by microglia. IFN-I limits the permeability of the blood-brain barrier. Disruption of the blood-brain barrier facilitates entrance of peripheral lymphocytes and inflammation. Viral infections during vulnerable phases of embryonic development cause severe fetal pathology and debilitating impairments to human infants. The roles of IFN in these scenarios are diverse and include deficits due to overproduction of IFN during the developmental stage of the brain as seems to be the case in pseudo-TORCH2.

Physiological and biochemical plasticity of Lepidium latifolium as 'sleeper weed' in Western Himalayas.

To understand the spread of native populations of Lepidium latifolium growing in different altitudes in Ladakh region of Western Himalayas, photosynthetic and fluorescence characteristics were evaluated in relation to their micro-environment. Three sites representing sparsely populated (SPS), moderately populated (MPS) and densely populated site (DPS) were selected. Results showed that the DPS had higher photosynthetic accumulation than MPS and SPS. The higher transpiration rate at DPS despite lower vapor pressure deficit and higher relative humidity suggest the regulation of its leaf temperature by evaporative cooling. Intrinsic soil parameters such as water holding capacity and nutrient availability also play crucial role in higher biomass here. The quantum efficiency of PSII photochemistry (Fv/Fm, non-photochemical quenching (NPQ), ΦPSII) and light curve at various PPFDs suggests better light harvesting potential and light compensation point at DPS than the other two sites. Concomitantly, plants at SPS had significantly higher lipid peroxidation, suggesting a stressful environment, and higher induction of antioxidative enzymes. Metabolic content of reduced glutathione also suggests an efficient mechanism in DPS and MPS than SPS. High light intensities at MPS are managed by specialized contrive of carotenoid pigments and PsbS gene product. Large pool of violaxanthin and lutein plays an important role in this response. It is suggested that L. latifolium is present as 'sleeper weed' that has inherent biochemical plasticity involving multiple processes in Western Himalayas. Its potential spread is linked to site-specific micro-environment, whereby, it prefers flat valley bottoms with alluvial fills having high water availability, and has little or no altitudinal effect.

Inhaled nitric oxide in acute pulmonary embolism: a systematic review.

Acute pulmonary embolism (PE) is usually a complication secondary to migration of a deep venous clot or thrombi to lungs, but other significant etiologies include air, amniotic fluid, fat, and bone marrow. Regardless of the underlying etiology, little progress has been made in finding an effective pharmacologic intervention for this serious complication. Among the wide spectrum of PE, massive PE is associated with considerable morbidity and mortality, primarily due to severely elevated pulmonary vascular resistance leading to right ventricular failure, hypoxemia, and cardiogenic shock. We currently have limited therapeutic options at our disposal. Inhaled nitric oxide (iNO) has been proposed as a potential therapeutic agent in cases of acute PE in which hemodynamic compromise secondary to increased pulmonary vascular resistance is present, based on iNO's selective dilation of the pulmonary vasculature and antiplatelet activity. A systematic search of studies using the PubMed database was undertaken in order to assess the available literature. Although there are currently no published randomized controlled trials on the subject, except a recently publish phase I trial involving eight patients, several case reports and case series describe and document the use of iNO in acute PE. The majority of published reports have documented improvements in oxygenation and hemodynamic variables, often within minutes of administration of iNO. These reports, when taken together, raise the possibility that iNO may be a potential therapeutic agent in acute PE. However, based on the current literature, it is not possible to conclude definitively whether iNO is safe and effective. These case reports underscore the need for randomized controlled trials to establish the safety and efficacy of iNO in the treatment of massive acute PE. The purpose of this article is to review the current literature in the use of iNO in the setting of PE given how acute PE causes acute onset of pulmonary hypertension.

To evaluate the analgesic effectiveness of bilateral erector spinae plane block versus thoracic epidural analgesia in open cardiac surgeries approached through midline sternotomy.

BACKGROUND: The efficacy of the erector spinae plane (ESP) block in mitigating postoperative pain has been shown for a range of thoracic and abdominal procedures. However, there is a paucity of literature investigating its impact on postoperative analgesia as well as its influence on weaning and subsequent recovery in comparison to thoracic epidural analgesia (TEA) in median sternotomy-based approach for open-cardiac surgeries and hence the study. METHODS: Irrespective of gender or age, 74 adult patients scheduled to undergo open cardiac surgery were enrolled and randomly allocated into two groups: the Group TEA (thoracic epidural block) and the Group ESP (bilateral Erector Spinae Plane block). The following variables were analysed prospectively and compared among the groups with regard to pain control, as determined by the VAS Scale both at rest (VASR) and during spirometry (VASS), time to extubation, quantity and frequency of rescue analgesia delivered, day of first ambulation, length of stay in the intensive care unit (ICU), and any adverse cardiac events (ACE), respiratory events (ARE), or other events, if pertinent. RESULTS: Clinical and demographic variables were similar in both groups. Both groups had overall good pain control, as determined by the VAS scale both at rest (VASR) and with spirometry (VASS) with Group ESP demonstrating superior pain regulation compared to Group TEA during the post-extubation period at 6, 9, and 12 h, respectively (P > 0.05). Although statistically insignificant, the postoperative mean rescue analgesic doses utilised in both groups were comparable, but there was a higher frequency requirement in Group TEA. The hemodynamic and respiratory profiles were comparable, except for a few arrhythmias in Group TEA. With comparable results, early recovery, fast-track extubation, and intensive care unit (ICU) stay were achieved. CONCLUSIONS: The ESP block has been found to have optimal analgesic effects during open cardiac surgery, resulting in a decreased need for additional analgesic doses and eliminating the possibility of a coagulation emergency. Consequently, it presents itself as a safer alternative to the potentially invasive thoracic epidural analgesia (TEA).

Enhanced potency of immunotherapy against B-cell precursor acute lymphoblastic leukemia by combination of an Fc-engineered CD19 antibody and CD47 blockade.

CD19-directed immunotherapy has become a cornerstone in the therapy of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). CD19-directed cellular and antibody-based therapeutics have entered therapy of primary and relapsed disease and contributed to improved outcomes in relapsed disease and lower therapy toxicity. However, efficacy remains limited in many cases due to a lack of therapy response, short remission phases, or antigen escape. Here, BCP-ALL cell lines, patient-derived xenograft (PDX) samples, human macrophages, and an in vivo transplantation model in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were used to examine the therapeutic potency of a CD19 antibody Fc-engineered for improved effector cell recruitment (CD19-DE) and antibody-dependent cellular phagocytosis (ADCP), in combination with a novel modified CD47 antibody (Hu5F9-IgG2σ). For the in vivo model, only samples refractory to CD19-DE monotherapy were chosen. Hu5F9-IgG2σ enhanced ADCP by CD19-DE in various BCP-ALL cell line models with varying CD19 surface expression and cytogenetic backgrounds, two of which contained the KMT2A-AFF1 fusion. Also, the antibody combination was efficient in inducing ADCP by human macrophages in pediatric PDX samples with and adult samples with and without KMT2A-rearrangement in vitro. In a randomized phase 2-like PDX trial using seven KMT2A-rearranged BCP-ALL samples in NSG mice, the CD19/CD47 antibody combination proved highly efficient. Our findings support that the efficacy of Fc-engineered CD19 antibodies may be substantially enhanced by a combination with CD47 blockade. This suggests that the combination may be a promising therapy option for BCP-ALL, especially in relapsed patients and/or patients refractory to CD19-directed therapy.

Pseudoaneurysm a rare complication of transradial cardiac catheterization: a case report.

Transradial access for cardiac catheterization is a safe and viable approach with significantly lower incidence of major access-related complications compared with the transfemoral approach. As this form of access is getting wider acceptance among interventional cardiologists, awareness of its complications is of vital importance. Asymptomatic radial artery occlusion, non-occlusive radial artery injury and radial artery spasm are commonly reported complication of this approach. Symptomatic radial arterial occlusion, pseudoaneurysm and radial artery perforation are rarely reported complications of transradial approach. Early identification of these uncommon complications and their urgent management is of significant importance. We present the case of an 80-year-old lady who developed pseudoaneurysm a week after transradial cardiac catheterization managed with surgical excision with no long-term sequela.

Biventricular pacing in normal hearts.

For more than half a century, pacemakers have proven to be one of the most successful medical interventions. In an effort to approximate normal cardiac physiology, pacemakers have evolved from simple to highly sophisticated devices. There is a growing demand, not only to improve overall mortality and safety in patients with existing devices, but also to improve patient quality of life. With growing evidence of left ventricular dysfunction and desychronization due to prolonged right ventricle apex (RVA) pacing, alternative ways to avoid excessive RVA pacing have been devised. In the pursuit of providing safe long-term pacing, biventricular pacing is emerging as an attractive option.

Lactic Acidosis in Diabetic Ketoacidosis: A Marker of Severity or Alternate Substrate for Metabolism.

PURPOSE: The lactate level is being increasingly used as a marker of severity of illness and prognosis in multitude of critical conditions. However, its role in diabetic ketoacidosis (DKA) is not well defined. AIM: To determine the prevalence and clinical importance along with the underlying role of metformin in lactic acidosis (LA) in patients admitted with DKA. METHODS: A 2-year prospective and observational study involving 62 consenting in hospital DKA patients. Plasma lactate level on arrival, its clinical significance and relationship with morbidity and mortality in patients with DKA was evaluated. RESULTS: The prevalence of LA (lactate ≥2.5 mmol/l) among the study cohort was found to be 55% with significant LA (≥5 mmol/l) documented in 16%. The median lactate level was 2.55 mmol/l (interquartile range, 1.70-3.20). No significant difference in the severity of LA was seen with metformin use. Lactate correlated positively with initial plasma glucose (IPG) (P = 0.001) and APACHE-II Score (P = 0.002); correlated negatively with systolic blood pressure (P = 0.003), pH (P = 0.002) and severity of DKA (P = 0.001). After controlling for AKI, APACHE II score and blood pressure, lactate continued to correlate positively with IPG (P = 0.002). No mortality or significant morbidity was documented in the entire cohort. CONCLUSIONS: LA has a significant presence in patients with DKA; however, it is not associated with mortality or significant morbidity. Moreover, there was no significant difference in severity of LA with metformin use. Elevated lactate levels may be an adaptation to provide alternate substrate for metabolism in the presence of hypoinsulinemic state. The study results provide rationale for large well-designed studies evaluating in-depth clinical relationship of lactate in DKA.

Replication of Influenza A Virus in Secondary Lymphatic Tissue Contributes to Innate Immune Activation.

The replication of viruses in secondary lymphoid organs guarantees sufficient amounts of pattern-recognition receptor ligands and antigens to activate the innate and adaptive immune system. Viruses with broad cell tropism usually replicate in lymphoid organs; however, whether a virus with a narrow tropism relies on replication in the secondary lymphoid organs to activate the immune system remains not well studied. In this study, we used the artificial intravenous route of infection to determine whether Influenza A virus (IAV) replication can occur in secondary lymphatic organs (SLO) and whether such replication correlates with innate immune activation. Indeed, we found that IAV replicates in secondary lymphatic tissue. IAV replication was dependent on the expression of Sialic acid residues in antigen-presenting cells and on the expression of the interferon-inhibitor UBP43 (Usp18). The replication of IAV correlated with innate immune activation, resulting in IAV eradication. The genetic deletion of Usp18 curbed IAV replication and limited innate immune activation. In conclusion, we found that IAV replicates in SLO, a mechanism which allows innate immune activation.

Protein Signatures of NK Cell-Mediated Melanoma Killing Predict Response to Immunotherapies.

Despite impressive advances in melanoma-directed immunotherapies, resistance is common and many patients still succumb to metastatic disease. In this context, harnessing natural killer (NK) cells, which have thus far been sidelined in the development of melanoma immunotherapy, could provide therapeutic benefits for cancer treatment. To identify molecular determinants of NK cell-mediated melanoma killing (NKmK), we quantified NK-cell cytotoxicity against a panel of genetically diverse melanoma cell lines and observed highly heterogeneous susceptibility. Melanoma protein microarrays revealed a correlation between NKmK and the abundance and activity of a subset of proteins, including several metabolic factors. Oxidative phoshorylation, measured by oxygen consumption rate, negatively correlated with melanoma cell sensitivity toward NKmK, and proteins involved in mitochondrial metabolism and epithelial-mesenchymal transition were confirmed to regulate NKmK. Two- and three-dimensional killing assays and melanoma xenografts established that the PI3K/AKT/mTOR signaling axis controls NKmK via regulation of NK cell-relevant surface proteins. A "protein-killing-signature" based on the protein analysis predicted NKmK of additional melanoma cell lines and the response of patients with melanoma to anti-PD-1 checkpoint therapy. Collectively, these findings identify novel NK cell-related prognostic biomarkers and may contribute to improved and personalized melanoma-directed immunotherapies. SIGNIFICANCE: NK-cell cytotoxicity assays and protein microarrays reveal novel biomarkers of NK cell-mediated melanoma killing and enable development of signatures to predict melanoma patient responsiveness to immunotherapies.

Prevalence of diabetes and prediabetes in tribal population of Kashmir: Lessons for the future.

AIMS: Considering a surge in the incidence of Diabetes mellitus (DM) across all ethnic groups and lack of any representative data from the tribal communities of Jammu and Kashmir, the present study aimed to assess the prevalence of DM and prediabetes in them. METHODS: Subjects were recruited from five districts of Kashmir valley using multistage cluster sampling by probability proportional to size (PPS) technique. Data collection included recording of socio-demographic, medical facts, assessment of anthropometric parameters and biochemical evaluation HbA1c and random blood glucose measurements as per the American Diabetes Association (ADA) criteria were used for diagnosis of DM. RESULTS: A total of 6808 subjects were recruited in this study including 2872 (42%) men and 3936 (58%) women with mean age of 39.60 ± 20.19 years and 35.17 ± 16.70 years, respectively. Around 8.60% subjects were obese, 38.9% were found to be hypertensive, 73% had dyslipidemia and 3.75% had metabolic syndrome. About 1.26% (0.5% males and 0.9% females) had DM and 11.64% had prediabetes based on HbA1c cut offs. Increasing age, body mass index and family history portend significant risk factors while smoking and sedentary lifestyle increased the risk marginally. CONCLUSIONS: Although the prevalence of DM among tribals of Kashmir valley is lower than general population, the higher prediabetes to DM ratio may indicate a future trend of increasing DM prevalence in this disadvantageous subpopulation.

Open tendoachilles injuries due to squatting type of toilet seats: Five-year prospective observational study from a tertiary care center in India.

BACKGROUND: Open traumatic tendoachilles injuries due to toilet seats are least reported. The exact mechanism of such injuries is debatable. None of the studies have reported associated neurovascular injuries and the need for microvascular tissue transfer. METHODS: It is a 5-year prospective observational study from Sep 2013 - Aug 2018 at a tertiary care center on 26 patients who had sustained foot injuries due to squatting type toilet seats. All the patients were managed by thorough wound irrigation and debridement followed by repair of cut tendoachilles, other tendons and neurovascular structures. All the complications and secondary procedures required were recorded. Functional outcome was assessed by Boyden clinical outcome score. Follow up ranged from 1 to 5 years. RESULTS: All the 26 patients reported a particular mechanism of injury. Complete transection of tendoachilles was seen in 23 (88.5%) patients and partial transection in three (11.5%) patients. Microvascular repair of cut posterior tibial artery was undertaken in three and posterior tibial nerve in two cases and microvascular parascapular flap in one case for soft tissue reconstruction. Twenty-three (88.5%) patients had good to excellent Boyden score while three patients (11.5%) had fair to poor score at 1 year. Such severe injuries due to toilet seats have never been reported in literature. CONCLUSIONS: Squatting toilet seats can cause devastating foot injuries involving tendons and neurovascular structures and may require microvascular tissue transfer for definitive wound management. The risk of such injuries will continue unless some modifications are undertaken in the design of the seat.

Map3k14 as a Regulator of Innate and Adaptive Immune Response during Acute Viral Infection.

The replication of virus in secondary lymphoid organs is crucial for the activation of antigen-presenting cells. Balanced viral replication ensures the sufficient availability of antigens and production of cytokines, and both of which are needed for virus-specific immune activation and viral elimination. Host factors that regulate coordinated viral replication are not fully understood. In the study reported here, we identified Map3k14 as an important regulator of enforced viral replication in the spleen while performing genome-wide association studies of various inbred mouse lines in a model of lymphocytic choriomeningitis virus (LCMV) infection. When alymphoplasia mice (aly/aly, Map3k14aly/aly, or Nikaly/aly), which carry a mutation in Map3k14, were infected with LCMV or vesicular stomatitis virus (VSV), they display early reductions in early viral replication in the spleen, reduced innate and adaptive immune activation, and lack of viral control. Histologically, scant B cells and the lack of CD169+ macrophages correlated with reduced immune activation in Map3k14aly/aly mice. The transfer of wildtype B cells into Map3k14aly/aly mice repopulated CD169+ macrophages, restored enforced viral replication, and resulted in enhanced immune activation and faster viral control.

Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells.

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.

Immunotherapeutic Blockade of CD47 Inhibitory Signaling Enhances Innate and Adaptive Immune Responses to Viral Infection.

Paradoxically, early host responses to infection include the upregulation of the antiphagocytic molecule, CD47. This suggests that CD47 blockade could enhance antigen presentation and subsequent immune responses. Indeed, mice treated with anti-CD47 monoclonal antibody following lymphocytic choriomeningitis virus infections show increased activation of both macrophages and dendritic cells (DCs), enhancement of the kinetics and potency of CD8+ T cell responses, and significantly improved virus control. Treatment efficacy is critically dependent on both APCs and CD8+ T cells. In preliminary results from one of two cohorts of humanized mice infected with HIV-1 for 6 weeks, CD47 blockade reduces plasma p24 levels and restores CD4+ T cell counts. The results indicate that CD47 blockade not only enhances the function of innate immune cells but also links to adaptive immune responses through improved APC function. As such, immunotherapy by CD47 blockade may have broad applicability to treat a wide range of infectious diseases.

Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection.

Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor ß (TGF-ß). Lack of Mertk in Mertk-/- mice prevents induction of IL-10 and TGF-ß, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV.