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      IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection

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          Abstract

          West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8 + T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons.

          Author Summary

          Since its introduction into North America in 1999, West Nile virus (WNV) has emerged as a leading cause of viral encephalitic disease in the United States. While low level inflammation is important for clearance of WNV, high levels of inflammation are associated with increased disease. The goal of this study was to identify host signaling pathways that control the balance of inflammation and protective immunity to WNV. Using a mouse model of infection, we identified a central nervous system (CNS)-intrinsic requirement for the NLRP3 inflammasome and IL-1β signaling in limiting WNV associated disease within the CNS. First, IL-1β signaling was essential for regulating the magnitude and kinetics of inflammation within CNS. Secondly, the absence of IL-1β signaling disrupted the quality of the effector T lymphocyte response against the virus. Finally, these dysregulated immune responses were linked to a direct ability for IL-1β signaling to synergize with type I IFN signaling and limit virus replication within cortical neurons, key target cells of WNV infection within the CNS. Together this study identifies the NLRP3 inflammasome and IL-1β signaling as key restriction factors that act to regulate viral load and the quality of inflammatory responses within the CNS to impart protective immunity against WNV infection.

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          Most cited references50

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          An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome.

          Cytoplasmic DNA triggers activation of the innate immune system. Although 'downstream' signaling components have been characterized, the DNA-sensing components remain elusive. Here we present a systematic proteomics screen for proteins that associate with DNA, 'crossed' to a screen for transcripts induced by interferon-beta, which identified AIM2 as a candidate cytoplasmic DNA sensor. AIM2 showed specificity for double-stranded DNA. It also recruited the inflammasome adaptor ASC and localized to ASC 'speckles'. A decrease in AIM2 expression produced by RNA-mediated interference impaired DNA-induced maturation of interleukin 1beta in THP-1 human monocytic cells, which indicated that endogenous AIM2 is required for DNA recognition. Reconstitution of unresponsive HEK293 cells with AIM2, ASC, caspase-1 and interleukin 1beta showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.
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            Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1.

            Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1alpha, IL-1beta, and IL-18. IL-1beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway.
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              Epidemiology and Transmission Dynamics of West Nile Virus Disease

              West Nile virus (WNV) was first detected in the Western Hemisphere in 1999 during an outbreak of encephalitis in New York City. Over the next 5 years, the virus spread across the continental United States as well as north into Canada, and southward into the Caribbean Islands and Latin America (1). This article highlights new information about the epidemiology and transmission dynamics of human WNV disease obtained over the past 5 years of intensified research. Epidemiology WNV is transmitted primarily by the bite of infected mosquitoes that acquire the virus by feeding on infected birds. The intensity of transmission to humans is dependent on abundance and feeding patterns of infected mosquitoes and on local ecology and behavior that influence human exposure to mosquitoes. Although up to 55% of affected populations became infected during epidemics in Africa, more recent outbreaks in Europe and North America have yielded much lower attack rates (1,2). In the area of most intense WNV transmission in Queens, New York, in 1999, ≈2.6% of residents were infected (most of these were asymptomatic infections), and similarly low prevalence of infection has been seen in other areas of the United States (3,4). WNV outbreaks in Europe and the Middle East since 1995 appear to have caused infection in 1,000 potentially WNV-viremic blood donations were identified, and the corresponding blood components were sequestered. Nevertheless, 6 WNV cases due to transfusion were documented in 2003, and at least 1 was documented in 2004, indicating that infectious blood components with low concentrations of WNV may escape current screening tests (19). One instance of possible WNV transmission through dialysis has been reported (20). WNV transmission through organ transplantation was also first described during the 2002 epidemic (15). Chronically immunosuppressed organ transplant patients appear to have an increased risk for severe WNV disease, even after mosquito-acquired infection (16). During 2002, the estimated risk of neuroinvasive WNV disease in solid organ transplant patients in Toronto, Canada, was approximately 40 times greater than in the general population (16). Whether other immunosuppressed or immunocompromised patients are at increased risk for severe WNV disease is uncertain, but severe WNV disease has been described among immunocompromised patients. WNV infection has been occupationally acquired by laboratory workers through percutaneous inoculation and possibly through aerosol exposure (21,22). An outbreak of WNV disease among turkey handlers at a turkey farm raised the possibility of aerosol exposure (17). Dynamics of Transmission: Vectors WNV is transmitted primarily by Culex mosquitoes, but other genera may also be vectors (23). In Europe and Africa, the principal vectors are Cx. pipiens, Cx. univittatus, and Cx. antennatus, and in India, species of the Cx. vishnui complex (6,24). In Australia, Kunjin virus is transmitted primarily by Cx. annulirostris (11). In North America, WNV has been found in 59 different mosquito species with diverse ecology and behavior; however, 40%. Field studies during and after WNV outbreaks in several areas of the United States have confirmed that house sparrows were abundant and frequently infected with WNV, characteristics that would allow them to serve as important amplifying hosts (23,25,37). The importance of birds in dispersing WNV remains speculative. Local movements of resident, nonmigratory birds and long-range travel of migratory birds may both contribute to the spread of WNV (38,39). Although WNV was isolated from rodents in Nigeria and a bat in India, most mammals do not appear to generate viremia levels of sufficient titer to contribute to transmission (24,40–42). Three reptilian and 1 amphibian species (red-ear slider, garter snake, green iguana, and North American bullfrog) were found to be incompetent as amplifying hosts of a North American WNV strain, and no signs of illness developed in these animals (43). Viremia levels of sufficient titer to infect mosquitoes were found after experimental infection of young alligators (Alligator mississippiensis) (44). In Russia, the lake frog (Rana ridibunda) appears to be a competent reservoir (45). Nonmosquitoborne WNV transmission has been observed or strongly suspected among farmed alligators, domestic turkeys in Wisconsin, and domestic geese in Canada (17,46,47). Transmission through close contact has been confirmed in both birds and alligators in laboratory conditions but has yet to be documented in wild vertebrate populations (23,36,44). Control of WNV Transmission Avoiding human exposure to WNV-infected mosquitoes remains the cornerstone for preventing WNV disease. Source reduction, application of larvicides, and targeted spraying of pesticides to kill adult mosquitoes can reduce the abundance of mosquitoes, but demonstrating their impact on the incidence of human WNV disease is challenging because of the difficulty in accounting for all determinants of mosquito abundance and human exposure. One study indicated that clustering of human WNV disease in Chicago varied between mosquito abatement districts, suggesting that mosquito control may have some impact on transmission to humans (14). Persons in WNV-endemic areas should wear insect repellent on skin and clothes when exposed to mosquitoes and avoid being outdoors during dusk to dawn when mosquito vectors of WNV are abundant. Of insect repellents recommended for use on skin, those containing N,N-diethyl-m-toluamide (DEET), picaridin (KBR-3023), or oil of lemon eucalyptus (p-menthane-3,8 diol) provide long-lasting protection (48). Both DEET and permethrin provide effective protection against mosquitoes when applied to clothing. Persons' willingness to use DEET as a repellent appears to be influenced primarily by their level of concern about being bitten by mosquitoes and by their concern that DEET may be harmful to health, despite its good safety record (49). To prevent transmission of WNV through blood transfusion, blood donations in WNV-endemic areas should be screened by using nucleic acid amplification tests. Screening of organ donors for WNV infection has not been universally implemented because of concern about rejecting essential organs after false-positive screening results (50). Pregnant women should avoid exposure to mosquito bites to reduce the risk for intrauterine WNV transmission. Future Directions WNV disease will likely continue to be a public health concern for the foreseeable future; the virus has become established in a broad range of ecologic settings and is transmitted by a relatively large number of mosquito species. WNV will also likely continue to spread into Central and South America, but the public health implications of this spread remain uncertain. Observations thus far in North America indicate that circulation of other flaviviruses, such as dengue, viral mutation, and differing ecologic conditions may yield different clinical manifestations and transmission dynamics. Over the next few years, research efforts might well be focused in several areas. Research into new methods to reduce human exposure to mosquitoes is crucial and can help prevent other mosquitoborne illnesses. This should include development of new methods to reduce mosquito abundance, development of new repellents, and behavioral research to enhance the use of existing effective repellents and other personal protective measures against mosquito bites. A better understanding of the dynamics of nonmosquitoborne transmission is essential to prevent disease among infants of infected mothers and recipients of blood transfusions and transplanted organs. Currently available prevention strategies such as the dissemination of knowledge and products for personal protection from mosquito exposure and the application of existing techniques for reducing mosquito abundance in communities at risk of WNV transmission need to be vigorously implemented. National and international surveillance for WNV transmission will be important to monitor spread of the virus and the effect of control strategies. Finally, further research into the ecologic determinants of WNV transmission, including climatic factors and dynamics of reservoir and vector populations, could help in determining geographic areas of higher risk for WNV disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                November 2012
                November 2012
                29 November 2012
                : 8
                : 11
                : e1003039
                Affiliations
                [1 ]Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America
                [2 ]Blood Systems Research Institute, San Francisco, California, United States of America
                [3 ]Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
                [4 ]Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
                [5 ]Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
                [6 ]Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
                Yale University School of Medicine, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HJR MG MCL PJN MPB. Performed the experiments: HJR MCL GB MMB KS AN MSS PMT. Analyzed the data: HJR MCL PMT. Wrote the paper: HJR MG.

                Article
                PPATHOGENS-D-12-00953
                10.1371/journal.ppat.1003039
                3510243
                23209411
                e79a9ae4-2930-4fdc-83ad-b2a4a23c60e6
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 April 2012
                : 3 October 2012
                Page count
                Pages: 16
                Funding
                This study was supported by the National Institutes of Health grants U54 AI081680 and U19 AI083019 (MG). Human patient studies were supported by National Institutes of Health/National Heart Lung and Blood Institute RC2HL101632. HJR is supported by National Institutes of Health grant F32A1096759. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immunity
                Inflammation
                Microbiology
                Virology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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