IPS-1 Is Essential for the Control of West Nile Virus Infection and Immunity

PLoS Pathogens

Alexander Y. Rudensky¹  Michael S. Diamond¹  Nu Zhang¹  Mehul S. Suthar¹  Daphne Y. Ma¹  Michael J. Bevan¹  Sunil Thomas¹  Jennifer M. Lund¹  Edward A. Clark¹  Murali-Krishna Kaja²  Stephane Daffis³  Michael Gale Jr³ 

[1] Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America;Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America;Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America

关键词: West Nile virus;    Immune response;    Inflammation;    T cells;    Regulatory T cells;    Viral replication;    Cytotoxic T cells;    Central nervous system;   

DOI  :  10.1371/journal.ppat.1000757

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The innate immune response is essential for controlling West Nile virus (WNV) infection but how this response is propagated and regulates adaptive immunity in vivo are not defined. Herein, we show that IPS-1, the central adaptor protein to RIG-I-like receptor (RLR) signaling, is essential for triggering of innate immunity and for effective development and regulation of adaptive immunity against pathogenic WNV. IPS-1−/− mice exhibited increased susceptibility to WNV infection marked by enhanced viral replication and dissemination with early viral entry into the CNS. Infection of cultured bone-marrow (BM) derived dendritic cells (DCs), macrophages (Macs), and primary cortical neurons showed that the IPS-1-dependent RLR signaling was essential for triggering IFN defenses and controlling virus replication in these key target cells of infection. Intriguingly, infected IPS-1−/− mice displayed uncontrolled inflammation that included elevated systemic type I IFN, proinflammatory cytokine and chemokine responses, increased numbers of inflammatory DCs, enhanced humoral responses marked by complete loss of virus neutralization activity, and increased numbers of virus-specific CD8+ T cells and non-specific immune cell proliferation in the periphery and in the CNS. This uncontrolled inflammatory response was associated with a lack of regulatory T cell expansion that normally occurs during acute WNV infection. Thus, the enhanced inflammatory response in the absence of IPS-1 was coupled with a failure to protect against WNV infection. Our data define an innate/adaptive immune interface mediated through IPS-1-dependent RLR signaling that regulates the quantity, quality, and balance of the immune response to WNV infection.

【 授权许可】

CC BY