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Antiviral response drives epithelial metabolic reprogramming to promote secondary bacterial infection

Carreno-Florez, Grace Paola (2024) Antiviral response drives epithelial metabolic reprogramming to promote secondary bacterial infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Increasing evidence shows that viral infections predispose the host to the acquisition of acute or chronic bacterial infections. Viral-bacterial co-infections are often linked to more severe outcomes, leading to prolonged stays in intensive care units and more severe clinical symptoms (1,2). These viral-bacterial co-infections happen at multiple host sites, including the airways (3–19). Unfortunately, the research focused on elucidating the mechanisms that lead viral infection in the airway epithelium to increase the susceptibility to developing secondary bacterial infection is scarce. Several lines of evidence support a role of the antiviral response in increasing the likelihood of secondary bacterial infections (20–23). Previous work in our laboratory has shown that the antiviral response triggered during the infection by respiratory syncytial virus (RSV) predisposes to the development of Pseudomonas aeruginosa chronic infection, specifically in the chronic respiratory disease model Cystic Fibrosis (CF) (22).
Here we will show our new findings on how the antiviral response driven by IFN signaling induces the expression of Interferon-Stimulated Genes (ISGs), a wide array of genes that are meant to inhibit viral infection and are involved in a wide range of cellular processes, including metabolism. We used a lentivirus-based ISG screen to identify ISGs that promote chronic P. aeruginosa infection in an in vitro model of CF bronchial epithelial cells. This ISG screen led us to the identification of 5 hit ISGs, and we further dissected the mechanism by which the hit hexokinase 2 (HK2), stimulates P. aeruginosa biofilm formation. HK2 encodes the first rate-limiting enzyme in glycolysis associated with an extension of glycolysis, known as aerobic glycolysis or Warburg effect (WE), which funnels glucose toward the synthesis of L-lactate. We observed that the increase of L-lactate and its apical secretion enhanced P. aeruginosa biofilm growth. These results suggest that the antiviral interferon response drives reprogramming of the host which supports secondary bacterial infections.
Understanding how viral infections predispose to secondary bacterial infections opens new avenues for treatments based on the host, being a priority in the context of chronic bacterial infections affecting people with chronic lung diseases, for which the efficacy of current treatments is limited.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Carreno-Florez, Grace Paolagrc38@pitt.edugrc380000-0002-0756-6002
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBomberger, Jennifer Mjennifer.m.bomberger@dartmouth.edu0000-0003-4767-6238
Committee ChairRichardson, Anthony Ranthony.richardson@pitt.edu
Committee MemberAlcorn, John Fjohn.alcorn@chp.edu0000-0001-5997-7711
Committee MemberBrodsky, Jeffrey Ljbrodsky@pitt.edu0000-0002-6984-8486
Committee MemberLakdawala, Seemaseema.s.lakdawala@emory.edu0000-0002-7679-2150
Date: 16 September 2024
Date Type: Publication
Defense Date: 21 November 2023
Approval Date: 16 September 2024
Submission Date: 15 February 2024
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 100
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: viral-bacterial co-infection, interferon-stimulated genes, aerobic glycolysis, Warburg effect, Pseudomonas aeruginosa, bacterial infection, L-lactate
Related URLs:
Date Deposited: 16 Sep 2024 19:04
Last Modified: 16 Sep 2024 19:04
URI: http://d-scholarship.pitt.edu/id/eprint/45805

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