Lethal Virus Infection Research Articles

Lipid-nanoparticle-encapsulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral infection

It is well established that memory CD8 Tcells protect susceptible strains of mice from mousepox, a lethal viral disease caused by ectromelia virus (ECTV), the murine counterpart to human variola virus. While mRNA vaccines induce protective antibody (Ab) responses, it is unknown whether they also induce protective memory CD8 Tcells. We now show that immunization with different doses of unmodified or N(1)-methylpseudouridine-modified mRNA (modified mRNA) in lipid nanoparticles (LNP) encoding the ECTV gene EVM158 induced similarly strong CD8 Tcell responses to the epitope TSYKFESV, albeit unmodified mRNA-LNP had adverse effects at the inoculation site. A single immunization with 10μg modified mRNA-LNP protected most susceptible mice from mousepox, and booster vaccination increased the memory CD8 Tcell pool, providing full protection. Moreover, modified mRNA-LNP encoding TSYKFESV appended to green fluorescent protein (GFP) protected against wild-type ECTV infection while lymphocytic choriomeningitis virus glycoprotein (GP) modified mRNA-LNP protected against ECTV expressing GP epitopes. Thus, modified mRNA-LNP can be used to create protective CD8 Tcell-based vaccines against viral infections.

STAT1 gain of function mutation impairs immune response to viral infections

Abstract Regulation of T cells by interferons and other cytokines, which act via STAT family transcription factors, is critical for host defense. Patients with STAT1 gain-of-function (GOF) mutations exhibit heightened STAT1 activation after cytokine stimulation and develop lifelong ailments, including chronic infections, autoimmunity, and cancer. A characteristic feature of this disorder is chronic mucocutaneous candidiasis (CMC), related to exagerated type 1/IFNγ bias that antagonizes a type 3/Th17 response required for fungal clearance. However, this type 1/IFNγ bias does not explain why almost 40% of reported patients exhibit chronic and sometimes lethal viral infections. This observation is unexpected, as cells with STAT1-GOF mutations exhibit increased expression of interferon stimulated genes following IFNα/β and IFNγ stimulation and patients show more IFNγ-producing CD4 T cells. This paradox emphasizes the critical need to understand basic principles of cytokine signaling, specifically how a STAT1-GOF mutation alters cytokine output. Using a novel conditional knock-in mouse expressing a common GOF STAT1 mutation, T385M, we found that this model recapitulates observations in patients (i.e. elevated STAT1 activation, increased total STAT1 protein, susceptibility to CMC), as well as a strong type 1/interferon bias at steady state. Despite this type 1 bias, STAT1-GOF exhibit impaired NK and CD8 T cell response to systemic viral infections. These results reveal that STAT1 activity must be tuned for proper immune response to viral infections.

Psychological and Mental Health Issues During the SARS-CoV-2 Global Pandemic: A Critical Analysis

Introduction: With the outbreak of the SARS-CoV-2 in Wuhan, China in December, 2019, presently over 200 countries have been facing gruesome health effects of the deadly virus, with cases and casualties on the rise. So far, no concrete medicinal drug or vaccine has been developed to check the lethal viral infection, henceforth authorities have emphasized on practicing social distancing and imposed strict lockdowns forcing people to confine in their homes. Material and Methods: This review was aimed to analyze the effects on mental health and well being during the pandemic. The studies cited in the review were sourced from journals, books and digital media reports. The research papers indexed in databases such as PUBMED, SCOPUS, INDEX COPERNICUS, CHEMICAL AND BIOLOGICAL ABSTRACTS, MEDLINE, EMBASE, EBSCO, DOAJ and THOMSON REUTERS were reviewed and have been included in the review. Results: The coronavirus mayhem has not only posed a threat to human health, but also jolted different aspects of society, including mental and psychological health. Loss of freedom, boredom, fear and angst are some of the mild psychological effects, whereas a rise in domestic violence and suicidal tendencies is the more serious consequence reported from different parts of the world during the lockdown period. Conclusion: This article is a comprehensive analysis of the effects on mental and psychological well being during this critical time. Strategic measures to be adopted by individuals and administration to cope up with the situation are also suggested as it should be an immediate priority to address the overall distress caused by the pandemic in public.

Identification of COVID - 19 from Chest CT Images using a Deep Neural Network with SVM Classification

Coronavirus is a quickly spreading viral illness that taints people; however, creatures are likewise to be contaminated because of this infection. The day-by-day life of people, their wellbeing, and the economy of a nation are influenced because of this lethal viral infection. A clinical investigation of COVID-19 contaminated patients has demonstrated that these kinds of patients are generally tainted from lung disease in the wake of interacting with this sickness. Chest X-beams (i.e., radiography) and chest CT are a more viable imaging strategy for diagnosing jump related issues. All things considered, a significant chest X-beam is a cheaper cycle in contrast with chest CT. Yet chest CT has more degree of accuracy. Profound learning is the best method of AI, which gives valuable examination to contemplate a lot of chest CT pictures that fundamentally affect the screening of COVID-19. This type has taken the Physician Assistant (PA) perspective on chest CT filters for Coronavirus influenced patients just as solid patients. After tidying up the pictures and applying information increase, the proposed system utilized profound learning-based SVM models and analyzed their exhibition.

Kırım Kongo Kanamalı Ateşi Virüsü Glikoprotein Gc’yi Hedef Alan Bir DNA Aşısının Bağışıklık ve Koruyuculuk Sağlama Özelliklerinin Değerlendirilmesi

Aim: Crimean Congo Hemorrhagic Fever (CCHF) is a lethal, endemic infectious disease in human. For the preventive measures of the disease, there is currently no safe and efficient vaccine, widely for human use. Vaccine development for CCHF virus is an actively researched subject. In this study, we aimed to investigate the immunizing and protective potentials of the CCHF virus surface glycoprotein Gc that is delivered as a single antigen via a DNA based vaccine vector. Material and Methods: A DNA based vaccine targeting the immunogenic envelope glycoprotein Gc of a CCHF virus isolate with Turkey origin (Ank2) was generated and its immunogenicity and protective capability against lethal challenge in IFNα/βR-/- receptor knock out mice was assessed. Results: The developed vaccine candidate (pGc) elicited a considerable amount of neutralizing antibody responses in the vaccinated mice. The vaccine candidate significantly induced both antiviral Th1 and B cell activating Th2 immune responses deduced from the cytokine production profiles in the vaccinated mice. However, despite the immune responses elicited post-immunization, the vaccine failed to confer protection against lethal CCHF virus infection. Conclusion: To the best of our knowledge, this is the first report of a DNA vaccine candidate generated against CCHF virus based on the glycoprotein Gc. The pGc vaccine candidate exhibited antigen-specific immunity in IFN/α/βR-/- mice, but was unable to produce a protection upon lethal challenge with the homologous CCHF virus. Once we comprehensively understand the immune correlates of protection, we will be more eligible to significantly improve the efficacy of vaccines.

Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing.

Natural killer (NK) cell activation depends on the signaling balance of activating and inhibitory receptors. CD94 forms inhibitory receptors with NKG2A and activating receptors with NKG2E or NKG2C. We previously demonstrated that CD94-NKG2 on NK cells and its ligand Qa-1b are important for the resistance of C57BL/6 mice to lethal ectromelia virus (ECTV) infection. We now show that NKG2C or NKG2E deficiency does not increase susceptibility to lethal ECTV infection, but overexpression of Qa-1b in infected cells does. We also demonstrate that Qa-1b is down-regulated in infected and up-regulated in bystander inflammatory monocytes and B cells. Moreover, NK cells activated by ECTV infection kill Qa-1b-deficient cells in vitro and in vivo. Thus, during viral infection, recognition of Qa-1b by activating CD94/NKG2 receptors is not critical. Instead, the levels of Qa-1b expression are down-regulated in infected cells but increased in some bystander immune cells to respectively promote or inhibit their killing by activated NK cells.

Effect of Favipiravir on some epidemic infections: A mini review

Favipiravir is a modern antiviral drug that can be used in developing viral pandemics, such as the Ebola virus, H1N1 flu, Lassa fever, and haemorrhagic fever outbreaks in Argentina in 2009. A. Chain conclusion Favipiravir is transformed to favipiravir-RTP and inserted into the RNA strand that is elongating. Then, since favipiravir acts as a chain terminator, chain elongation slows down at incorporation site of favipiravir and does not continue. The proofreading enzyme cannot repair this complex of RNA-favipiravir and it will be discarded as excessive RNA, which causes the extinction of the viral genome. Mutagenesis with lethal consequences Ribavirin is used in the RNA elongating process until completion. The single strand of RNA with several ribavirin incorporation sites incorporates ribavirin or acts as mRNA for the production of viral proteins. Due to incorporation of ribavirin onto viral RNA, a mismatching of the base pairs (transition mutation) will occur. Translation of this mutated RNA will then cause mutations in the sequence of amino acid residues of the protein, result in impaired of protein function. Viral proteins that have lost their function are unable to replicate or generate infectious viral particles, and the virus is no longer infectious. As a result, lethal mutagenesis ends viral infection in a different way than chain termination. Favipiravir’s clinical trial against Ebola virus-infected patients has not yet been formally approved, and further research is required. Favipiravir, on the other hand, poses a risk of embryo toxicity and teratogenicity. As a result, the Japanese Ministry of Health, Welfare and Labor have been approved this medication with recommendations for more clinical use until August 15, 2014, when they approved the use of favipiravir due to the Ebola virus epidemic in West Africa. The aim of this review is to investigate the potential impact of favipiravir on infections espectially RNA-virus infections, according to previous published investigations, and thus to encourage rapid approval of this interesting antivirus in emergencies.

Sociodemographic Predictors of Outcomes in COVID-19: Examining the Impact of Ethnic Disparities in Northern Nevada.

Background On March 11, 2020, the World Health Organization declared coronavirus disease-19 (COVID-19) a pandemic. Nearly five million individuals have since been diagnosed with this increasingly common and potentially lethal viral infection. Emerging evidence suggests a disproportionate burden of illness and death among minority communities. We aimed to evaluate the effect of ethnicity on outcomes among patients diagnosed with COVID-19 in Northern Nevada.Methods The electronic health records of 172 patients diagnosed with COVID-19 were obtained from a 946-bed tertiary referral center serving Northern Nevada. Demographic and clinical characteristics were compared by ethnic group (Hispanic versus non-Hispanic). Logistic regression was used to determine predictors of mortality. Results Among 172 patients who were diagnosed with COVID-19 between March 12 and May 8, 2020, 87 (50.6%) identified as Hispanic and 81 (47.1%) as non-Hispanic. Hispanic individuals were significantly more likely to be uninsured and to live in low-income communities as compared to their non-Hispanic counterparts (27.6% versus 8.2% and 52.9% versus 30.6%, respectively). Hispanic patients were also less likely than non-Hispanics to have a primary care provider (42.5% versus 61.2%). However, mortality was significantly higher among the non-Hispanic population (15.3% versus 5.8%). Conclusion The COVID-19 pandemic has disproportionately affected Hispanic individuals in Northern Nevada, who account for only 25.7% of the population but over half of the confirmed cases. The underlying causes of ethnic disparities in COVID-19 incidence remain to be established, but further investigation may lead to more effective community- and systems-based interventions.

Protection against neonatal respiratory viral infection via maternal treatment during pregnancy with the benign immune training agent OM-85.

ObjectivesIncomplete maturation of immune regulatory functions at birth is antecedent to the heightened risk for severe respiratory infections during infancy. Our forerunner animal model studies demonstrated that maternal treatment with the microbial‐derived immune training agent OM‐85 during pregnancy promotes accelerated postnatal maturation of mechanisms that regulate inflammatory processes in the offspring airways. Here, we aimed to provide proof of concept for a novel solution to reduce the burden and potential long‐term sequelae of severe early‐life respiratory viral infection through maternal oral treatment during pregnancy with OM‐85, already in widespread human clinical use.MethodsIn this study, we performed flow cytometry and targeted gene expression (RT‐qPCR) analysis on lungs from neonatal offspring whose mothers received oral OM‐85 treatment during pregnancy. We next determined whether neonatal offspring from OM‐85 treated mothers demonstrate enhanced protection against lethal lower respiratory infection with mouse‐adapted rhinovirus (vMC0), and associated lung immune changes.ResultsOffspring from mothers treated with OM‐85 during pregnancy display accelerated postnatal seeding of lung myeloid populations demonstrating upregulation of function‐associated markers. Offspring from OM‐85 mothers additionally exhibit enhanced expression of TLR4/7 and the IL‐1β/NLRP3 inflammasome complex within the lung. These treatment effects were associated with enhanced capacity to clear an otherwise lethal respiratory viral infection during the neonatal period, with concomitant regulation of viral‐induced IFN response intensity.ConclusionThese results demonstrate that maternal OM‐85 treatment protects offspring against lethal neonatal respiratory viral infection by accelerating development of innate immune mechanisms crucial for maintenance of local immune homeostasis in the face of pathogen challenge.

Prevalence of Hepatitis B virus Infection Among Cataract Patients in South-East Nigeria

Background: Hepatitis B Virus (HBV) is a public health issue especially in sub-Saharan Africa. This is because attention has not been given to this potentially lethal viral infection especially in cataract patients which will need extraordinary safety measures. Cataracts remain the commonest cause of blindness in Nigeria and globally. We are yet to know the prevalence of HBV when co-existing cataract among patients in Nigeria.

Covid-19 pathogenesis in prostatic cancer and TMPRSS2-ERG regulatory genetic pathway.

Members of Coronaviridae family have been the source of respiratory illnesses. The outbreak of SARS-CoV-2 that produced a severe lung disease in afflicted patients in China and other countries was the reason for the incredible attention paid toward this viral infection. It is known that SARS-CoV-2 is dependent on TMPRSS2 activity for entrance and subsequent infection of the host cells and TMPRSS2 is a host cell molecule that is important for the spread of viruses such as coronaviruses.Different factors can increase the risk of prostate cancer, including older age, a family history of the disease. Androgen receptor (AR) initiates a transcriptional cascade which plays a serious role in both normal and malignant prostate tissues. TMPRSS2 protein is highly expressed in prostate secretory epithelial cells, and its expression is dependent on androgen signals. One of the molecular signs of prostate cancer is TMPRSS2-ERG gene fusion. In TMPRSS2-ERG-positive prostate cancers different patterns of changed gene expression can be detected. The possible molecular relation between fusion positive prostate cancer patients and the increased risk of lethal respiratory viral infections especially SARS-CoV-2 can candidate TMPRSS2 as an attractive drug target. The studies show that some molecules such as nicotinamide, PARP1, ETS and IL-1R can be studied deeper in order to control SARS-CoV-2 infection especially in prostate cancer patients.This review attempts to investigate the possible relation between the gene expression pattern that is produced through TMPRSS2-ERG fusion positive prostate cancer and the possible influence of these fluctuations on the pathogenesis and development of viral infections such as SARS-CoV-2.

On the role of viruses in nature and what this means for the COVID-19 pandemic.

On the role of viruses in nature and what this means for the COVID-19 pandemic.

Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains1. The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells1–4. Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fcγ receptor FcγRIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8+ T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.

Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication.

Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance.

Transcriptomic and Epigenomic Dynamics of Honey Bees in Response to Lethal Viral Infection.

Honey bees (Apis mellifera L.) suffer from many brood pathogens, including viruses. Despite considerable research, the molecular responses and dynamics of honey bee pupae to viral pathogens remain poorly understood. Israeli Acute Paralysis Virus (IAPV) is emerging as a model virus since its association with severe colony losses. Using worker pupae, we studied the transcriptomic and methylomic consequences of IAPV infection over three distinct time points after inoculation. Contrasts of gene expression and 5 mC DNA methylation profiles between IAPV-infected and control individuals at these time points – corresponding to the pre-replicative (5 h), replicative (20 h), and terminal (48 h) phase of infection – indicate that profound immune responses and distinct manipulation of host molecular processes accompany the lethal progression of this virus. We identify the temporal dynamics of the transcriptomic response to with more genes differentially expressed in the replicative and terminal phases than in the pre-replicative phase. However, the number of differentially methylated regions decreased dramatically from the pre-replicative to the replicative and terminal phase. Several cellular pathways experienced hyper- and hypo-methylation in the pre-replicative phase and later dramatically increased in gene expression at the terminal phase, including the MAPK, Jak-STAT, Hippo, mTOR, TGF-beta signaling pathways, ubiquitin mediated proteolysis, and spliceosome. These affected biological functions suggest that adaptive host responses to combat the virus are mixed with viral manipulations of the host to increase its own reproduction, all of which are involved in anti-viral immune response, cell growth, and proliferation. Comparative genomic analyses with other studies of viral infections of honey bees and fruit flies indicated that similar immune pathways are shared. Our results further suggest that dynamic DNA methylation responds to viral infections quickly, regulating subsequent gene activities. Our study provides new insights of molecular mechanisms involved in epigenetic that can serve as foundation for the long-term goal to develop anti-viral strategies for honey bees, the most important commercial pollinator.

Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection.

Cells contain numerous immune sensors to detect virus infection. The cyclic GMP-AMP (cGAMP) synthase (cGAS) recognizes cytosolic DNA and activates innate immune responses via stimulator of interferon genes (STING), but the impact of DNA sensing pathways on host protective responses has not been fully defined. We demonstrate that cGAS/STING activation is required to resist lethal poxvirus infection. We identified viral Schlafen (vSlfn) as the main STING inhibitor, and ectromelia virus was severely attenuated in the absence of vSlfn. Both vSlfn-mediated virulence and STING inhibitory activity were mapped to the recently discovered poxin cGAMP nuclease domain. Animals were protected from subcutaneous, respiratory, and intravenous infection in the absence of vSlfn, and interferon was the main antiviral protective mechanism controlled by the DNA sensing pathway. Our findings support the idea that manipulation of DNA sensing is an efficient therapeutic strategy in diseases triggered by viral infection or tissue damage-mediated release of self-DNA.

The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection.

Covid-19 has caused worldwide devastation. IFIH1 is a pattern recognition receptor that senses coronavirus RNA and triggers interferon production as a first line of viral immune defense. The role of IFIH1 polymorphism, rs1990760 (C>T; aaA946T) in the epidemiology of viral infection is well studied, and the minor allele T resists viral infection. Knock-in mice with mutated IFIH1 protein (946T) for this allele have enhanced interferon production and protection from lethal viral infection. The minor allele frequency (Tmaf) varies widely from Africans (0.06 to 0.35) to Chinese (0.19 to 0.23) to Caucasians (0.56 to 0.69). During the initial days of infection when the social restrictions were not imposed, I show that the infection rate in Italy was lower as expected from its higher Tmaf (0.56) than that in China (Tmaf for southern China, 0.23). The infection rate in the USA and Spain was intermediate between those two countries despite higher Caucasian overall Tmaf (0.69), perhaps due to a more admixed African population in these countries. These analyses suggest that African-Americans and Chinese with low Tmaf of rs1990760 are more vulnerable to SARS-COV2 infection, apart from other genetic factors or socioeconomic conditions in these population. Taken together, an IFN-beta supplement might aid in preventing COVID-19 infection and help in development of herd immunity.

Malignant Catarrhal Fever in Cattle in the Irkutsk Region.

IntroductionMalignant catarrhal fever (MCF) is a rare, under-explored lethal viral infection of cattle with gammaherpesvirus aetiological agents. Most often, the disease occurs on farms where cattle and sheep are kept together. However, other trigger mechanisms and environmental factors contribute. This study investigates the causation of MCF.Material and MethodsAn outbreak of MCF occurred in June - August 2017 in Kharchev village in Irkutsk Oblast, Russia. In this paper, we provide epidemiological (sanitary status of pastures, watering places, and premises) and weather data during the outbreak, and descriptions of the clinical signs and post-mortem changes in cattle. The virus was detected and isolated from pathological material samples and identified by molecular methods.ResultsExtreme weather conditions, mixed-herd cattle and sheep farming, and unsatisfactory feed quality contributed to the outbreak. A virus related to herpesvirus OvHV2 was isolated and typed (MCF/Irkutsk/2017). Phylogenetic analysis showed its close genetic relationship to isolates from cattle and sheep in Germany, USA, and the Netherlands.ConclusionSporadic outbreaks of MCF caused by biotic and abiotic factors together are typical for the Russian Federation, and the Irkutsk outbreak epitomised this. Temperature anomalies caused pasture depletion, resulting in feed and water deficiency for grazing animals and dehydration and acidosis. Heat stress in animals ultimately led to the occurrence of MCF in the herd.

Nexus between CNS resident microglia and migrating peripheral T cells pave the way for host immunity against neurotropic virus infection

Abstract Neurotropic virus induced neuroinflammation initiates with the activation of brain resident immune cells which causes a heightened release of chemokines/cytokines leading to a compromise in the blood brain barrier integrity. This accentuates the upregulation of regulatory molecules like antiviral Interferon stimulating gene induced tetratricopeptide repeats protein, Ifit2, and augments infiltration of peripheral immune cells. Among the early infiltrating immune cells, a large population is composed of neutrophils and monocyte/macrophages which, along with brain resident microglia, orchestrate the full panoply of innate immune responses. Ifit2 has been shown to be beneficial in protecting mice from lethal neurotropic virus infection by restricting viral replication and amplifying antiviral responses. Using a murine neurotropic coronavirus infection in Ifit2−/− mice, we report that in the absence of Ifit2, viral replication is significantly increased and mice develop severe neuropathy. Despite the enormous viral load, Ifit2-deficient mice are impaired in microglial activation and recruitment of peripheral T cells into the CNS. To further confirm the role of migratory T cells in viral-induced neuroinflammation and neurodegeneration, studies were conducted in CD4−/− mice. Results showed no significant change in acute stage pathogenesis, whereas CD4−/− mice showed accelerated loss of axon-myelin coherence during the chronic stage. Together, studies in Ifit2 and CD4 knockout mice reveal that the interplay between brain resident microglia and migratory helper T cells is important for strengthening host immunity against neurotropic virus infection.

Contribution of STAT1 to innate and adaptive immunity during type I interferon-mediated lethal virus infection.

Signal transducers and activators of transcription (STAT) 1 is critical for cellular responses to type I interferons (IFN-Is), with the capacity to determine the outcome of viral infection. We previously showed that while wildtype (WT) mice develop mild disease and survive infection with lymphocytic choriomeningitis virus (LCMV), LCMV infection of STAT1-deficient mice results in a lethal wasting disease that is dependent on IFN-I and CD4+ cells. IFN-Is are considered to act as a bridge between innate and adaptive immunity. Here, we determined the relative contribution of STAT1 on innate and adaptive immunity during LCMV infection. We show that STAT1 deficiency results in a biphasic disease following LCMV infection. The initial, innate immunity-driven phase of disease was characterized by rapid weight loss, thrombocytopenia, systemic cytokine and chemokine responses and leukocyte infiltration of infected organs. In the absence of an adaptive immune response, this first phase of disease largely resolved resulting in survival of the infected host. However, in the presence of adaptive immunity, the disease progressed into a second phase with continued cytokine and chemokine production, persistent leukocyte extravasation into infected tissues and ultimately, host death. Overall, our findings demonstrate the key contribution of STAT1 in modulating innate and adaptive immunity during type I interferon-mediated lethal virus infection.