Disparate Contribution of Endosomal and Cytosolic RNA-Sensing Pathways to Antiviral Immunity
Date of Award
Doctor of Philosophy (PhD)
Innate antiviral defense largely depends on type I interferons (IFN-I). While establishing an antiviral state in uninfected cells and promoting apoptosis of infected cells, IFN-I are crucial in establishing antiviral immunity. Production of IFN-I is mainly triggered by a series of germ-line encoded molecular sensors, known as pathogen recognition receptors (PRRs). PRRs recognize conserved viral components, known as pathogen associated molecular patterns (PAMPs) that largely consist of nucleic acid sequences and viral surface macromolecules. Because viruses vary tremendously in size, structure, genomic composition and tissue tropism, multiple sensors are often required to detect their presence in various tissues and cell types. Here, we ask whether these PRRs are complementary, compensatory or simply redundant in inducing cytotoxic CD8 T cell responses. We also discuss why viral sensors are differentially distributed in distinct cell types and whether a particular cell type dominates the IFN-I response.
Polyinosinic:polycytidylic acid (Poly-I:C), a potent IFN-I inducer, is detected by both Toll-like receptor 3 (TLR3) and Melanoma Differentiation-Associated protein 5 (MDA5) in vivo. Although it is known that TLR3 promotes cross-priming to viral-infected cells, the role of MDA5 in inducing CD8 T cell responses is still unclear. Here we demonstrate that the majority of CD8 T cells primed in mice lacking MDA5 do not survive following immunization with Poly-I:C and antigen and therefore fail to mount a memory response to subsequent antigen challenge. We show that MDA5 and TLR3 mediate substantially distinct yet complementary functions during poly-I:C-mediated activation of antigen-specific CD8 T cell responses.
We next defined the role of MDA5 and other sensors in inducing antiviral CD8 T cell responses during both acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. While IFN-I responses to LCMV are mediated by both MDA5 and TLR7, we found that MDA5 is the key source of IFN-I required for the CD8 T cell responses. In the absence of MDA5, the CD8 T cell responses to acute infection relies on CD4 T cell help; CD8 T cell exhaustion and persistent infection ensue in the absence of both MDA5 and CD4 T cells. Chronic LCMV infection rapidly attenuates the IFN-I response while early administration of exogenous IFN-I rescues CD8 T cells promoting viral clearance. Thus, induction of effective antiviral CD8 T cells depends on the timing and magnitude of the IFN-I response.
The picture emerging from these studies is that disparate viral sensors in different cell types form a dynamic and integrated molecular network that can be exploited for improving the efficacy of vaccines and therapies of infectious and autoimmune diseases.
Chair and Committee
Paul M Allen, Michael S Diamond, Anthony R French, Deborah J Lenschow, Emil R Unanue, Herbert W Virgin
Wang, Yaming, "Disparate Contribution of Endosomal and Cytosolic RNA-Sensing Pathways to Antiviral Immunity" (2013). Arts & Sciences Electronic Theses and Dissertations. 69.