title: Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion.
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.
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Condotta
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Shaniya H
authors.initials: SH
authors.lastname: Khan
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Deepa
authors.initials: D
authors.lastname: Rai
authors.affiliation: 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.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
authors.affiliation: 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.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D003289:Convalescence; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000209:etiology / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000150:complications / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D019562:Viral Load; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000906:Antibodies; D015703:Antigens, CD; C490007:Cd244a protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein