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Antiviral Immune Defense Mechanisms

Research Summary

Akiko Iwasaki is interested in understanding the cellular and molecular mechanisms of innate virus recognition and in elucidating innate signals that lead to the generation of protective immunity. Understanding how to generate memory lymphocytes at the site of infection that protect the host against viral infections provides key clues to designing effective vaccines.

The goal of the immune system is to detect and eliminate harmful pathogens while maintaining a homeostatic relationship with beneficial microbes. Pathogens come in many forms—parasites, fungi, bacteria, and viruses—that must be flagged by the immune system as being harmful. The first line of defense is provided by the innate immune system, which comprises cells that detect pathogens through distinct pathogen-associated molecular patterns (PAMPs).  PAMPs are found only in microbes but not in the host and are recognized by innate microbial sensors, collectively known as pattern recognition receptors (PRRs). PRRs consist of several families, each of which recognizes unique PAMPs associated with infections. Stimulating PRRs results in transcriptional activation of genes involved in innate defense as well as those that activate antigen-presenting cells for successful priming of "adaptive" T and B cell responses. Direct stimulation of antigen-presenting cells by PAMPs is required to elicit T cell immunity.  Despite these advances, we know very little about how immune responses are generated during the course of a natural infection. Because most pathogens enter the human host through mucosal surfaces, understanding the rules that govern immunity at these sites is critical for the development of efficacious vaccines.

Our research is focused on understanding how viral infections are recognized by innate immune cells, how signals downstream of the recognition event are translated into the generation of adaptive immunity, how commensal bacteria and endogenous viruses regulate our response to external ones, and what constitutes protective immunity at the site of pathogen encounter.

Figure:  TLR9 mislocalizes in the absence of AP-3.

Innate Recognition of Viral Infections
Unlike other pathogens, all components of replicating viruses are synthesized by the host cell using host cell machinery. PAMPs for viruses were less obvious, because, unlike bacteria or fungi that are coated with specialized cell walls, no unique cell walls are found in viruses.  Instead, we found that viruses are detected through their nucleic acids, which are recognized by Toll-like receptor (TLR) family members TLR9 (dsDNA) and TLR7 (ssRNA) within the endosomes. The endosomal recognition helps to distinguish viral from host nucleic acids.  We also found that viruses that enter cytosol upstream of the endosomal compartment are still detected by TLRs, but in this case, viral replication intermediates have to be delivered to the endosomal TLRs by autophagy. Once the viral nucleic acids enter the endosomes, TLR7 and TLR9 induce signals to stimulate cytokine expression. These TLRs are further shuttled into lysosome-related organelles to induce a signal for interferon production. We are interested in how processes, including autophagy, mediate trafficking and signaling of TLRs upon sensing viral nucleic acids.

Innate Programming of Protective Immune Responses
During a natural viral infection, many different types of signals alert the host of the invading pathogen. We are interested in understanding how innate recognition of "signatures" associated with distinct stages of a live viral infection determines the programming of protective immune responses. We propose that signatures generated during a live pathogen infection fall into three fundamental categories that inform the host of the degree of danger: 1) PAMPs physically associated with viruses, such as viral genomic nucleic acids, inform the host of the presence of pathogens; 2) PAMPs generated as a result of replication, such as replication intermediates, alert the host to active propagation of a pathogen; and 3) signatures of viral replication strategies, such as modifications in cellular organelles or membranes or unusual forms of cell death, reveal irreparable cell damage. My laboratory's studies suggest that these distinct signatures provide a rich source of information to the immune system.  How this information is transduced into an appropriate immune outcome is poorly understood, with current knowledge in the field limited primarily to how particular PAMPs connect to particular PRRs.  Hence, our research aims to test and refine the hypothesis that there is an ascending hierarchy in immunogenicity of innate signatures associated with pathogen presence, replication, and cell damage and that the combination of these signals dictates the outcome of an immune response.

Microbiome and Virome Control of Immunity
A major gap in our understanding of immunity to natural infection is whether and how the microbiome and the virome of the host mucosal microenvironment influence susceptibility to viral pathogens. To this end, we demonstrated that commensal bacteria play an important role in generating adaptive immune responses to respiratory influenza virus infection. Although the beneficial and harmful effects of the bacterial microbiome on human health are beginning to be understood, the impact of endogenous, nonpathogenic viruses (the virome) on human health and disease remains an unexplored mystery. Healthy humans are perpetually infected with a number of bacteria and viruses, and every mucosal tissue is colonized by a distinct set of resident bacteria and viruses, which we believe influence innate and adaptive immune responses to incoming pathogenic viruses.  We are exploring the hypothesis that the host genotype and the environment dictate virome composition in various mucosal tissues, which in turn controls resistance to exogenous pathogens.

Protective Immunity in the Genital Mucosa
Vaccines are the single greatest contribution made by the field of immunology to human health, with the vast majority of successful vaccines relying on antibodies. However, vaccines against pathogens that require robust T cell immunity for protection, including HIV-1 and herpes simplex virus 2, have been difficult to develop. This difficulty is due in part to our lack of understanding of the rules that govern successful protection by the cellular arm of the immune system. Even robust, systemic memory T cell responses do not correlate with host protection. Our results strongly suggest that successful T cell–based vaccines against sexually transmitted viruses must establish a local memory T cell pool. To this end, we have developed a novel approach, called "prime and pull," in which we are able to manipulate the immune system to establish protective tissue-resident memory T cells in a safe and effective manner. This new strategy relies on two steps—the first step is to "prime" the host with a vaccine to generate T cell immunity. This is followed by a second step, in which antigen-specific memory T cells are "pulled" into the target tissue using topical application of chemokines. Therefore, a major focus of our work is to elucidate the determinants of immunological protection by T cells at the sites of natural pathogen entry, and to leverage this understanding for the design of effective vaccines against mucosally transmitted viral pathogens.

Grants from the National Institutes of Health provided partial support for some of these projects.

As of May 16, 2014

Scientist Profile

Investigator
Yale University
Immunology, Virology