Chronic viral infections and the co-infections they foster are among the greatest health concerns worldwide. Although their linkage is clear, it is much less clear how one pathogen alters the immune environment to foster another. T cells are critical both to control chronic virus infections and to correctly orchestrate de novo immune responses against co-infecting pathogens. Thus, we surmised that if the immune environment during chronic virus infection altered the ability to appropriately mount T cell responses, that it would jointly and simultaneously affect the chronic infection and susceptibility / severity of secondary infections. The goal of this proposal is to investigate how chronic inflammation and the evolving host:pathogen interactions as viral persistence progresses alters immunity to co-infecting pathogens. To achieve this goal, we have developed a novel mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection and Mycobacterium tuberculosis (Mtb) co-infection. Our preliminary data demonstrate that in the presence of established chronic viral infection, Mtb specific immune responses are delayed, redirected and Mtb replication increased. In the current proposal, we will mechanistically investigate how the modulation of the immune response by the chronic virus spreads to delay acquired Mtb-specific immunity and determine the mechanistic basis through which the altered T cell immunity enhances Mtb disease progression. We will then examine the reciprocal relationship between established Mtb infection and chronic viral co-infection to understand how they comparatively impact the ability to generate and sustain simultaneous immune responses and modulate disease course. The experiments outlined in this proposal will establish important biologic principles and provide a new mechanistic link between the host:pathogen interactions that foster viral persistence with those that enhance susceptibility to and severity of secondary infections. Ultimately, the mechanisms and paradigms we reveal have the potential to lead to new strategies to treat chronic viral infections and the co-infections that plague them.
Chronic viral infections, including HIV, hepatitis C and B viruses, are among the greatest health concerns worldwide. Strategies to enhance immune activity to clear these chronic viral infections or to prevent the most devastating co-infections they promote. have so far been unsuccessful. The proposed experiments will define critical immune dysfunctions during chronic infection and develop novel immune redirecting therapies to eliminate chronic viruses and the co-infections that arise during them.
|Clemente-Casares, Xavier; Hosseinzadeh, Siyavash; Barbu, Iulia et al. (2017) A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis. Immunity 47:974-989.e8|
|Zhen, Anjie; Rezek, Valerie; Youn, Cindy et al. (2017) Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J Clin Invest 127:260-268|
|Cunningham, Cameron R; Champhekar, Ameya; Tullius, Michael V et al. (2016) Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence. PLoS Pathog 12:e1005356|
|Snell, Laura M; Osokine, Ivan; Yamada, Douglas H et al. (2016) Overcoming CD4 Th1 Cell Fate Restrictions to Sustain Antiviral CD8 T Cells and Control Persistent Virus Infection. Cell Rep 16:3286-3296|
|York, Autumn G; Williams, Kevin J; Argus, Joseph P et al. (2015) Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell 163:1716-29|
|Snell, Laura M; Brooks, David G (2015) New insights into type I interferon and the immunopathogenesis of persistent viral infections. Curr Opin Immunol 34:91-8|
|Yamada, Douglas H; Elsaesser, Heidi; Lux, Anja et al. (2015) Suppression of Fc?-receptor-mediated antibody effector function during persistent viral infection. Immunity 42:379-390|
|Walsh, Nicole C; Waters, Lynnea R; Fowler, Jessica A et al. (2015) LKB1 inhibition of NF-?B in B cells prevents T follicular helper cell differentiation and germinal center formation. EMBO Rep 16:753-68|
|Osokine, Ivan; Snell, Laura M; Cunningham, Cameron R et al. (2014) Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection. Proc Natl Acad Sci U S A 111:7409-14|
|Wilson, Elizabeth B; Brooks, David G (2013) Decoding the complexity of type I interferon to treat persistent viral infections. Trends Microbiol 21:634-40|
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