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Controlling Bacterial Super-infection During Influenza

Rich, Helen (2020) Controlling Bacterial Super-infection During Influenza. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Bacterial super-infection during influenza increases morbidity and mortality from the viral infection. Current therapies for influenza and bacterial super-infection are limited and inadequate, and rising multi-drug resistance in bacteria underscores the need for new therapies. Administration of an engineered antimicrobial peptide, WLBU2, reduced methicillin-resistant Staphylococcus aureus burden during pulmonary bacterial infection, but failed to reduce S. aureus burden during influenza super-infection. Immunopathology is a strong driver of mortality in bacterial super-infection during influenza, so I investigated the underlying dysfunction in antibacterial immunity caused by preceding influenza. Type I interferon induced in response to influenza infection had been previously shown to be a broad suppressor of antibacterial immunity. Type III interferons had been described much more recently, and were shown to be produced in response to influenza at even higher levels than type I interferon. Thus, I interrogated the role of type III interferon in the pathogenesis of bacterial super-infection during influenza. To do this, I compared super-infection outcomes between wild-type mice and mice lacking IFNλ3, one of the two murine type III interferons. However, total IFNλ was not markedly reduced in these mice, so I instead decided to test the effect of IFNλ treatment during influenza on outcomes of bacterial super-infection, as it had been recently published that IFNλ treatment ameliorated morbidity and mortality from influenza. It had also been recently shown that mice lacking the type III interferon receptor had increased burden in S. aureus super-infection during influenza, which mimicked data from mice lacking the type I interferon receptor. Adenoviral overexpression of IFNλ3 one day prior to bacterial super-infection induced neutrophil dysregulation, with lower binding and uptake of both S. aureus and Streptococcus pneumoniae in the lungs of mice during influenza super-infection with each of these bacteria. These results suggest that, while new therapeutics for bacterial super-infection during influenza need to be discovered, neither IFNλ nor WLBU2 should be considered. WLBU2 may be effective for bacterial pneumonia alone, but IFNλ should not be used as a treatment for influenza due to the high risk of mortality and morbidity from bacterial super-infection.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSarkar, Saumendrasaumen@pitt.edusaumen0000-0002-2850-6121
Committee MemberBomberger, Jenniferjbomb@pitt.edujbomb0000-0003-4767-6238
Committee MemberGaffen, Sarahsig65@pitt.edusig650000-0001-8511-2041
Committee MemberWilliams, Johnjvw@chp.edujvw0000-0001-8377-5175
Thesis AdvisorAlcorn, JohnJohn.Alcorn@chp.edujfa9
Date: 8 January 2020
Date Type: Publication
Defense Date: 11 June 2019
Approval Date: 8 January 2020
Submission Date: 16 December 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 112
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: immunology, microbiology
Date Deposited: 09 Jan 2020 03:04
Last Modified: 09 Jan 2020 03:04

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