Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion

Stephanie A Condotta; Shaniya H Khan; Deepa Rai; Thomas S Griffith; Vladimir P Badovinac

doi:10.4049/jimmunol.1402473

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Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion

Journal article

Peer reviewed

Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion

Stephanie A Condotta, Shaniya H Khan, Deepa Rai, Thomas S Griffith and Vladimir P Badovinac

The Journal of immunology (1950), Vol.195(1), pp.116-125

07/01/2015

DOI: 10.4049/jimmunol.1402473

PMCID: PMC4475506

PMID: 25980007

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Abstract

Patients who survive sepsis display suppressed immune functions, often manifested as an increased susceptibility to secondary infections. Recently, using a cecal-ligation and puncture (CLP) model of sepsis, we showed that sepsis induces substantial and long-lasting changes in the available naive CD8(+) T cell repertoire affecting the capacity of the host to respond to newly encountered acute infections. However, the extent to which sepsis changes the host susceptibility to chronic infection and affects CD8(+) T cell responses is currently unknown. In this study, we demonstrate that inbred and outbred mice recovering from a septic event are more susceptible to lymphocytic choriomeningitis virus (LCMV) clone-13 infection exhibited by mortality and viral burden. Primary virus-specific CD8(+) T cells in LCMV clone-13-infected septic mice displayed exacerbated CD8(+) T cell exhaustion illustrated by increased inhibitory molecule expression (e.g., programmed cell death 1, lymphocyte-activation gene 3, and 2B4) and diminished Ag-driven cytokine production (e.g., IFN-γ, TNF-α) compared with similarly infected sham-treated mice. Importantly, therapeutic inhibitory molecule dual blockade (anti-PD-L1 and anti-lymphocyte-activation gene 3) increased the number of circulating LCMV-specific CD8(+) T cells, and improved CD8(+) T cell function and pathogen control in chronically infected septic mice. Together, these results illustrate that polymicrobial sepsis compromises the overall health of the host leading to increased vulnerability to chronic infection and exacerbated CD8(+) T cell exhaustion. Collectively, our findings suggest that septic survivors may be more susceptible and at greater risk for developing exhaustible CD8(+) T cells upon encountering a subsequent chronic infection.

Lymphocytic choriomeningitis virus - immunology

Antigens, CD - immunology

CD8-Positive T-Lymphocytes - pathology

Humans

Tumor Necrosis Factor-alpha - genetics

Programmed Cell Death 1 Receptor - antagonists & inhibitors

Sepsis - complications

Lymphocytic Choriomeningitis - immunology

Antigens, CD - genetics

Viral Load

Host-Pathogen Interactions - immunology

Lymphocytic Choriomeningitis - mortality

Lymphocytic Choriomeningitis - etiology

Sepsis - pathology

Tumor Necrosis Factor-alpha - immunology

Interferon-gamma - genetics

Receptors, Immunologic - immunology

Sepsis - immunology

Disease Susceptibility

Signal Transduction

Lymphocytic Choriomeningitis - pathology

Mice, Inbred C57BL

Gene Expression Regulation

Mice, Transgenic

Signaling Lymphocytic Activation Molecule Family

Sepsis - mortality

Antibodies - pharmacology

Animals

Convalescence

CD8-Positive T-Lymphocytes - drug effects

Interferon-gamma - immunology

Survival Analysis

Lymphocyte Count

Mice

Primary Cell Culture

Programmed Cell Death 1 Receptor - immunology

CD8-Positive T-Lymphocytes - immunology

Receptors, Immunologic - genetics

Programmed Cell Death 1 Receptor - genetics

Details

Title: Subtitle: Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion
Creators: Stephanie A Condotta - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Shaniya H Khan - Interdisciplinary Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Deepa Rai - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Thomas S Griffith - Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota Medical School, Minneapolis, MN 55455; Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455; Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455; Department of Urology, University of Minnesota Medical School, Minneapolis, MN 55455; and Minneapolis VA Health Care System, Minneapolis, MN 55417
Vladimir P Badovinac - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Interdisciplinary Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242; vladimir-badovinac@uiowa.edu
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.195(1), pp.116-125
DOI: 10.4049/jimmunol.1402473
PMID: 25980007
PMCID: PMC4475506
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: I01 BX001324 / BLRD VA R01 AI114543 / NIAID NIH HHS R01 AI083286 / NIAID NIH HHS T32 AI007485 / NIAID NIH HHS P30CA086862 / NCI NIH HHS AI114543 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 07/01/2015
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984047678502771

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