Influenza Structure

Structure of the influenza A virus NS1 interferon antagonist protein’s RNA-binding domain. IMAGERY BY: E. NISTAL-VILLAN

Project Overview

Project 1 - Contribution of NS1 to Pathogenicity and Evasion of Innate Immunity

Principal Investigator: Adolfo García-Sastre, PhD
Professor, Department of Microbiology
Fischberg Chair and Professor, Department of Medicine, Division of Infectious Diseases
Co-Director, Emerging Pathogens Institute
Icahn School of Medicine, New York, NY

Co-evolution of pathogens with their hosts has shaped the human immune system. A major component of this system is the innate immune response that has broad specificity against pathogens. The innate immune response not only represents the first barrier against infection, but also provides the appropriate signals required for the optimal development of the subsequent adaptive cell-mediated and humoral (antibody) immune responses. The type I interferon (IFNalpha/beta) response constitutes a critical element of the innate immune system in the battle against viral pathogens. Secretion of IFNalpha/beta induces a cellular antiviral program involving more than one hundred genes.

Interferon antagonists. Despite the multi-layered immune defenses, viruses continue to successfully infect their hosts and cause disease. The success of viruses is explained, at least in part, by the evolution of viral genes that evade the host immune response. Viral-encoded IFNalpha/beta antagonists, proteins that block the type I interferon (IFN) response, appear to be present in most if not all animal viruses. This is the major role of the influenza NS1 protein. Influenza NS1 is the most abundant non-structural viral protein expressed in infected cells and possesses multiple antiviral functions. Through the development of reverse genetics techniques to manipulate the influenza A virus genome, we have been able to generate NS1 mutant viruses, including a recombinant influenza A virus lacking the NS1 gene. The NS1 knock-out influenza A virus is replication defective in most cells and hosts, except for those lacking a functional IFNalpha/beta system. Remarkably, the NS1 knock-out virus was highly attenuated in mice, but replicated and caused disease in mice lacking a key transactivator molecule (STAT1) needed for the IFNa/? response. Thus, the NS1 protein is required during influenza A virus infection to overcome the host's IFNalpha/beta response, and thus NS1 allows evasion of innate and adaptive immune responses.

Unraveling NS1. Our research at CRIP is aimed at molecular resolution of the functions of NS1 in pathogenicity. It is likely that viral strains from different animal hosts have NS1 genes adapted to antagonize the IFNalpha/beta system of their specific host species. We hypothesize that influenza virus strains adapted to specific hosts (avian, swine, equine, or human) will have differential abilities to inhibit the IFN system in cells derived from different host species, and that viral strains with strong IFN antagonistic properties in multiple hosts will be more likely to replicate in multiple hosts. The NS1 of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in South East Asia might be responsible for an enhanced pro-inflammatory cytokine response (especially TNF-alpha) induced by these viruses in human macrophages. High levels of pro-inflammatory cytokines are likely to play an important role in the unusual lethality of these viruses in humans. In addition, we are studying how the NS1 gene may be responsible for differential IFN induction/sensitivity phenotypes among different strains, and that adaptation to a new host will require the acquisition of specific NS1 mutations.

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