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Follistatin-like protein 1 deficiency confers protection from Klebsiella pneumoniae pulmonary infection

Dutta, Justin (2019) Follistatin-like protein 1 deficiency confers protection from Klebsiella pneumoniae pulmonary infection. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Klebsiella pneumoniae is the third most common cause of nosocomial infections and leads to tremendous burden on health care spending and infection control, due to multiple drug resistance to the majority of present-day antibiotics. Elucidating the role of diverse innate immunity control mechanisms and signaling pathways in Klebsiella pneumoniae host response is essential in public health importance for developing new therapeutic antibiotic-alternatives. There is currently a gap in the research literature about the role of Follistatin-like protein 1 in infectious diseases. In this study, we establish that innate mechanisms can play a protective role in a Klebsiella pneumoniae pulmonary infection murine model via decreased secreted glycoprotein Follistatin-Like 1 Protein (FSTL1). Using a FSTL1 hypomorphic in vivo mouse model, we discovered that deficiency in FSTL1 production leads to significantly lower Klebsiella pneumoniae infectious burden (p<0.005) in a lung infection model. We additionally assessed gene expression by real-time qPCR that this lower burden was associated with differences in pro-inflammatory cytokine signaling, as expression of il7a, il1b, and csf3 were all significantly upregulated in FSTL1 hypomorphic mice compared to C57B6 wildtype controls. We further identified that FSTL1 hypomorphic mice express significantly higher γδ T cell receptor components, trdc (p<0.001) and trv4 (p<0.005), as well as increased populations of γδ T cells with significantly higher in IL-17A cytokine production (p<0.05) via flow cytometry analysis. These phenotypes were not able to be phenocopied in FSTL1 conditional knockout mice or the FSTL1 neutralizing antibody experimental model, suggesting that FSTL-1 hypomorph mice, uniquely, have increased γδ T-cells populations that likely are essential for control of infection. Our study provides evidence that deficient FSTL1 production in genetic and developmental mouse model can protect against Klebsiella pneumoniae lung infection. If this discovery is translational to the human condition, it could signify further research into FSTL1 protein as a host-oriented broad-spectrum drug target is warranted.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Dutta, Justinj.dutta@pitt.edujsd300000-0002-1740-0639
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMattila, Joshuajmattila@pitt.edu
Committee MemberCampfield, BrianBrian.Campfield@chp.edu
Committee MemberFinegold, Daviddnf@pitt.edu
Centers: Other Centers, Institutes, or Units > Center for Biologic Imaging
Date: 20 June 2019
Date Type: Publication
Defense Date: 24 April 2019
Approval Date: 20 June 2019
Submission Date: 22 April 2019
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 48
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MPH - Master of Public Health
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Follistatin-like protein
Date Deposited: 20 Jun 2019 21:38
Last Modified: 05 Sep 2019 12:43
URI: http://d-scholarship.pitt.edu/id/eprint/35975

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