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The Role of Innate Immune Recognition in Chronic Viral Infection

  • Author(s): Clingan, Jonathan Michael
  • Advisor(s): Matloubian, Mehrdad
  • et al.
Abstract

The role of innate immune recognition and the importance of these responses for control of acute virus infections are well documented. However, how these pathways contribute to control of chronic virus infections, and to what extent persistent stimulation of innate immunity is necessary, are less well understood. In the studies described herein, we utilized the lymphocytic choriomeningitis virus (LCMV) infection model, where infection with various strains can lead to either acute or persistent infection in mice.

First, we used mice deficient in signaling through either the cytosolic RIG-I-like receptor (RLR) pathway, or the endosomal Toll-like receptor (TLR) nucleic-acid sensing pathways to demonstrate that the RLR pathway was required for normal clearance of acute LCMV infection, whereas the TLR pathway was necessary for clearance of chronic infection. The RLR pathway was the primary means of type I IFN production, which was necessary for early virus control and activation of CD8+ T cell responses. In contrast, the TLR pathway was required for optimal antibody responses, particularly during chronic infection.

Upon investigation of the mechanism by which TLR signaling was required for antibody responses, we used bone marrow chimeric mice to demonstrate a B cell intrinsic role for TLR7 signaling in antibody, germinal center (GC) B cell and plasma cell responses. GC B cells in TLR7-deficient mice exhibited decreased proliferation and an altered GC response, leading to defective plasma cell formation.

We further examined a role for prolonged pDC activation in the control of LCMV infection. Using IFN-β reporter mice, we found that pDCs underwent rapid activation-dependent cell death following virus infection, pDCs were not activated during chronic infection, and were refractory to further stimulus following acute infection. This state was not dependent on prior cell-intrinsic activation or presence of pDCs during the early immune response.

These data together imply that different innate immune recognition pathways impact adaptive immune responses during chronic infection through various means. It is likely that the importance of these pathways for viral clearance is determined by the nature of infection and cell types involved.

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