All ETDs from UAB

Advisory Committee Chair

Carlos J Orihuela

Advisory Committee Members

Andre Ballesteros-Tato

Craig L Maynard

Michael J Gray

William E Swords

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Necroptosis, a programmed form of lytic cell death, is initiated by various viral and bacterial pathogens through irreparable ion dysregulation and energy depletion. This cellular damage results in the activation of the cellular kinases RIPK1 and RIPK3, consecutively, and the activation and membrane targeting of MLKL, the latter responsible for lysis. Here we have demonstrated that necroptosis of airway epithelial cells is key in the development of the adaptive immune response to asymptomatic colonization by Streptococcus pneumoniae (Spn). Briefly, necroptotic deficient animals or wildtype animals colonized with Spn lacking the necroptosis-triggering pneumolysin toxin, failed to recruit CD11c+ leukocytes to the sites were Spn were present, had dampened pathogen-specific serum IgG responses, were delayed in bacterial clearance, and were more susceptible to subsequent lethal re-challenge. Further, we examined the role of necroptosis in the generation of an adaptive immune response to influenza A (Flu), a viral pathogen also shown to induce necroptosis of airway epithelial cells. Infection of wildtype and necroptosis deficient (i.e. MLKL KO and RIPK3 KO) mice with Flu strain A/Puerto Rico/8/1934 indicated an MLKL-independent role for RIPK3 activation in the immune response to Flu. RIPK3 KO mice experienced the most severe weight loss, and significantly increased Flu specific CD8 T cell lung infiltrate at day 15 post-infection. In vitro analyses and analysis of airway lavage from these Flu infected mice indicated that NFκB-dependent release of IL-8 in the absence of RIPK3 was responsible for the increased pathology. These results collectively suggest fundamental differences in the role for necroptosis in the development of adaptive immunity against viral versus bacterial pathogens. Future studies are focused on determining the contribution of necroptosis to the intracellular signaling in response to respiratory bacterial and viral pathogens.

Share

COinS