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Type III interferons are expressed in tuberculosis granulomas and can enhance anti-mycobacterial activity of macrophages

TALUKDAR, PRIYANKA (2023) Type III interferons are expressed in tuberculosis granulomas and can enhance anti-mycobacterial activity of macrophages. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Humans and non-human primates express four subtypes of type 3 interferons (IFNλs; IFNλ1-IFNλ4). Unlike type I interferons, which have been extensively investigated in tuberculosis (TB), the role of IFNλs and their effects on immunity in TB remain unknown. Here we examined expression of IFNλ1 and IFNλ4 in Mycobacterium tuberculosis infected cynomolgus macaque granulomas and investigated the effects of IFNλ1, IFNλ4 and IFNα signaling on macaque macrophages. We identified differential IFNλ1 and IFNλ4 expression in granuloma macrophages and neutrophils, including IFNλ4 localization in the nuclei of epithelioid and alveolar macrophages. Further, we found that macrophages from granulomas from long term M. tuberculosis infection have a higher concentration of IFNλ1 as compared to those from acute infections. To measure IFNλ1 and IFNλ4’s effect on macrophage gene expression and compare these cytokines against type 1 interferons (IFN1), we performed transcriptional profiling and analysis on cytokine-stimulated macrophages to identify differentially regulated pathways. We found that IFN1 upregulated the greatest number of interferon stimulated genes (ISGs), followed by IFNλ1, whereas IFNλ4 stimulation had minimal effect on gene expression. Pro-inflammatory genes including IL-1β, IL-8, NFKB1, and NFKB2 were upregulated by IFNλ1 while they were downregulated by IFN1. To determine the effect of IFNλ signaling on anti-mycobacterial macrophage responses, we used a reporter Mtb strain to determine how IFNλ1 and IFNλ4 affect the viability of M. tuberculosis. There was a reduction in mycobacterial transcriptional activity, as indicated by reduced GFP expression, when macrophages were activated with IFNλ1 prior to infection. Furthermore, we identified that pre-treatment with IFNλ1 enhanced acidification of macrophage phagolysosomes. Our data suggest that IFNλs have non-redundant properties with type 1 interferons that may promote macrophage activation, inflammation, and antibacterial activity in TB.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHartman, Amyhartman2@pitt.eduhartman2
Thesis AdvisorMattila, Joshuajmattila@pitt.edujmattila
Committee MemberFlynn, JoAnnejoanne@pitt.edujoanne
Committee MemberBarratt-Boyes, Simonsmbb@pitt.edusmbb
Date: 3 January 2023
Date Type: Publication
Defense Date: 24 October 2022
Approval Date: 3 January 2023
Submission Date: 7 December 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 213
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Tuberculosis, Interferon lambda, granuloma, macrophages, non-human primate
Date Deposited: 03 Jan 2023 15:44
Last Modified: 03 Jan 2023 15:44


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