Persistent virus infections cause disease in hundreds of millions of people and exert constant strain on the global economy due to healthcare costs. While progress has been made towards understanding mechanisms that allow viruses to persist, therapies to control persistent viruses are not optimal due an incomplete understanding of the factors involved in virus persistence. One common theme that accompanies virus persistence is an exhaustive or hypo-responsive state of adaptive immune response. This phenomenon was first described using the staple animal model for studying virus persistence, Lymphocytic Choriomeningitis Virus (LCMV), in its natural mouse host and extended to human persistent infections. Using this model, it was revealed that a balance between positive and negative immune regulatory molecules is essential to purge virus infection. One of the most extensively studied mechanisms contributing to virus persistence has been T cell exhaustion, which is potentiated by negative immune regulatory molecules such as IL-10 and PD-1. Interestingly, the absence of two positive immune regulatory molecules, IL-6 and IL-21, result in the inability to control persistent virus infection. These molecules are known to be important for B cell function. However, studies on whether B cells also control persistent virus infection have been neglected and their role remains unknown. A newly discovered member of the IL-6 family, IL-27, modulates both B and T cell responses during infection. However, few studies have examined how IL-27 affects antiviral immune responses. I began studying how IL-27 deletion affects the outcome of both acute and persistent LCMV infection. I made the observation that IL-27-deficiency resulted in prolonged LCMV clone-13 persistence. Prolonged virus persistence in IL-27-/- mice correlated with defects in both T and B cell responses. Virus specific T cells in IL- 27-/- mice displayed exacerbated T cell exhaustion following clone-13 infection. Moreover, I discovered that IL- 27-/- mice made elevated levels of IgG1 with minimal production of IgG2a, compared to predominant production of IgG2a in IL-27+/+ hosts. I further demonstrated that development of plasma B cells (the major antibody producers) and anti-LCMV IgG production is required to control clone-13 infection, indicating that antibody likely plays an important role in controlling persistent virus infection. This grant proposal aims to elucidate the mechanisms by which IL-27-deficiency leads to prolonged LCMV persistence.
The aims are focused on understanding how IL-27 contributes to altered antiviral T and B cell responses and whether IL-27 signaling on T or B cells is essential to purge persistent LCMV infection. The absence of IgG2a production during persistent virus infection in IL-27-deficient mice suggests that IL-27- dependent induction of IgG2a may be essential to control persistent virus infection. The possibility that a specific antibody isotype may be essential to purge persistent virus infection i novel and will be investigated within this proposal.

Public Health Relevance

Viral infections represent a significant public health problem across the globe with hundreds of millions of people currently infected. The balance between immune stimulatory and suppressive molecules dictates whether a virus is cleared acutely or persists. Here we identify IL-27 as a novel immune stimulatory cytokine essential for controlling persistent virus infection and propose to dissect the mechanism(s) by which IL-27 contributes to the control of Arenavirus infection, with an emphasis on the role of IgG2a antibody.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI118862-01A1
Application #
9103446
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2016-01-15
Project End
2020-12-31
Budget Start
2016-01-15
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$481,250
Indirect Cost
$231,250
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Teijaro, John R (2016) Too much of a good thing: Sustained type 1 interferon signaling limits humoral responses to secondary viral infection. Eur J Immunol 46:300-2
Teijaro, John R (2016) Type I interferons in viral control and immune regulation. Curr Opin Virol 16:31-40
Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M et al. (2016) Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection. J Immunol 197:1017-22