Sepsis causes more deaths in U.S. hospitals annually than prostate cancer, breast cancer, and AIDS combined. Elderly patients are a particularly high-risk group, with an incidence rate of ~60% of all septic cases. The elderly are also extremely vulnerable to the consequences of sepsis, showing 100-fold higher mortality than younger patients. Some of these deaths occur acutely after sepsis, but ~70% of these patients survive the initial infection, and succumb to opportunistic infections during the chronic phase of sepsis. The chronic stage of sepsis is important and is characterized by immunosuppression, but little is known about the mechanisms of sepsis-induced immunosuppression. CD4 T cells, essential for coordinating immune responses to a range of pathogens, are severely depleted during the acute stage of sepsis, and gradually recover throughout the immunosuppressive phase of sepsis. Our recent publication included data showing certain Ag-specific CD4 T cell populations do not recover, despite quantitative restoration of total CD4 T cells. We suspect that the prolonged loss of Ag-specific CD4 T cells introduces ?gaps? within the T cell repertoire leading to overall decreased adaptive immune system function. Among the immunological settings where CD4 T cell function is vital, this proposal will define the mechanisms responsible for the impairment of CD4 T cell-dependent B cell responses using the CLP model followed by secondary immunization or heterologous pathogen infection. Accordingly, our central hypothesis holds that alterations in the number and function of both follicular helper CD4 T (Tfh) cells and B cells after sublethal CLP-induced sepsis is responsible for suppressed humoral immunity and reduced protection against pathogens encountered within the context of localized or systemic secondary infections. The following specific aims will test our hypothesis:
Aim 1) Define the sepsis-induced defects in Ag-specific CD4 T cells and B cells that restrict the generation of a productive CD4 T cell-dependent B cell response;
Aim 2) Investigate the ability of therapies designed to restore DC or B cell number and function to revitalize humoral immunity after sepsis;
and Aim 3) Determine the impact of sepsis on the maintenance and function of pre- existing memory CD4 T cells and B cells. Ultimately, this proposal will increase our understanding of why septic patients are more susceptible to secondary infections. Our use of the CLP model of polymicrobial sepsis, our ability to identify and study the function of endogenous Ag-specific CD4 T cells and B cells, and our experience measuring the adaptive immune response to infectious pathogens put us in the perfect position to define the mechanism(s) driving sepsis-induced suppression of CD4 T cell-dependent B cell immunity.

Public Health Relevance

Sepsis strikes 750,000 Americans every year, predominantly affecting the elderly; most of these patients will survive the acute stage of sepsis only to end up back in the ICU, weeks later, with hospital-acquired infections. Our goals are to study the mechanisms responsible for the impairment of CD4 T cell- dependent B cell responses during sepsis, and to test novel therapies to reverse it. This proposal will enhance our understanding of why septic patients are highly susceptible to secondary infections, and will determine the impact of therapies to enhance CD4 T cell and B cell function after sepsis and increased patient survival.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX001324-06A1
Application #
9444808
Study Section
Surgery (SURG)
Project Start
2012-10-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Minneapolis VA Medical Center
Department
Type
DUNS #
071774624
City
Minneapolis
State
MN
Country
United States
Zip Code
55417
Cabrera-Perez, Javier; Badovinac, Vladimir P; Griffith, Thomas S (2017) Enteric immunity, the gut microbiome, and sepsis: Rethinking the germ theory of disease. Exp Biol Med (Maywood) 242:127-139
Cabrera-Perez, Javier; Babcock, Jeffrey C; Dileepan, Thamotharampillai et al. (2016) Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis. J Immunol 197:1692-8
Danahy, Derek B; Strother, Robert K; Badovinac, Vladimir P et al. (2016) Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity. Crit Rev Immunol 36:57-74
Strother, Robert K; Danahy, Derek B; Kotov, Dmitri I et al. (2016) Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo. J Immunol 197:4301-4311
Cabrera-Perez, Javier; Condotta, Stephanie A; James, Britnie R et al. (2015) Alterations in antigen-specific naive CD4 T cell precursors after sepsis impairs their responsiveness to pathogen challenge. J Immunol 194:1609-20
Condotta, Stephanie A; Khan, Shaniya H; Rai, Deepa et al. (2015) Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion. J Immunol 195:116-25
Cabrera-Perez, Javier; Condotta, Stephanie A; Badovinac, Vladimir P et al. (2014) Impact of sepsis on CD4 T cell immunity. J Leukoc Biol 96:767-77
Markwart, Robby; Condotta, Stephanie A; Requardt, Robert P et al. (2014) Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function. PLoS One 9:e115094
Duong, Sean; Condotta, Stephanie A; Rai, Deepa et al. (2014) Polymicrobial sepsis alters antigen-dependent and -independent memory CD8 T cell functions. J Immunol 192:3618-25
Condotta, Stephanie A; Cabrera-Perez, Javier; Badovinac, Vladimir P et al. (2013) T-cell-mediated immunity and the role of TRAIL in sepsis-induced immunosuppression. Crit Rev Immunol 33:23-40

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