Every year, sepsis causes more deaths in U.S. hospitals 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. This patient population is very 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 opportunistic pathogens, are severely depleted during the acute stage of sepsis, and gradually recover throughout the immunosuppressive phase of sepsis. Our preliminary data indicates that 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. Thus, we will examine novel strategies aimed at enhancing CD4 T cell recovery and function during the immunosuppressive stage of sepsis. Cytokines, such as IL-2 and IL-7, show great promise in the treatment of sepsis immunosuppression, but they can be detrimental to septic patients because of non-specific, systemic toxicity. One way to minimize unintended toxicity while maximizing potency of a cytokine therapy is to use cytokine:?-cytokine mAb conjugates (cytokine complexes). The impact of IL-2 or IL-7 complexes in terms of CD4 T cell reconstitution, repertoire diversity, and pathogen clearance in sepsis survivors has not been thoroughly studied. Accordingly, our central hypothesis holds that sepsis-induced lymphopenia results in long-lasting changes in the composition and/or function of Ag-specific CD4 T cell populations, which ultimately are responsible for the reduced CD4 T cell response to pathogen-derived Ag encountered within the context of localized or systemic secondary infections. The following specific aims will test our hypothesis:
Aim 1) Define the sepsis-induced intrinsic and extrinsic factors affecting the function of Ag-specific CD4 T cells;
Aim 2) Investigate the abilityof cytokine complexes to improve CD4 T cell recovery and function after sepsis;
and Aim 3) Evaluate the extent to which CD4 T cell recovery and function is controlled by commensal bacteria-derived Ag released during a septic episode. Ultimately, this application will increase our understanding of why septic patients are more susceptible to secondary infections. Our combined experience with the two-hit CLP sepsis model (CLP followed by a secondary heterologous infection) and peptide:MHC II tetramer approaches to study endogenous Ag-specific CD4 T cells positions us perfectly to accomplish the proposed experiments.

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 a previously unappreciated mechanism of CD4 T cell impairment during sepsis, and to test novel therapies to reverse it. This application will enhance our understanding of why septic patients succumb to opportunistic infections, and will determine the impact of cytokine therapies in the enhancement of CD4 T cell immunity, and patient survival, after sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115462-04
Application #
9737967
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Zhao, Xiaoli
Project Start
2016-09-15
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Urology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Jensen, Isaac J; Sjaastad, Frances V; Griffith, Thomas S et al. (2018) Sepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity. J Immunol 200:1543-1553
Hirsova, Petra; Weng, Peggy; Salim, Warda et al. (2017) TRAIL Deletion Prevents Liver, but Not Adipose Tissue, Inflammation during Murine Diet-Induced Obesity. Hepatol Commun 1:648-662
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
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