Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Stressed Erythrophagocytosis as a Modifier of the Innate Immune Response to Klebsiella pneumoniae

Olonisakin, Tolani F. (2020) Stressed Erythrophagocytosis as a Modifier of the Innate Immune Response to Klebsiella pneumoniae. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Restricted to University of Pittsburgh users only until 15 June 2022.

Download (9MB) | Request a Copy

Abstract

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent red cells (sRBC). Macrophages are also essential in defense against microbial threats, but pathologic states of heme excess may be immunosuppressive. Here, we uncover a novel mechanism whereby an acute rise in sRBC disposal by macrophages leads to an immunosuppressive phenotype following intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary dissemination and reduced survival in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal is independent of iron acquisition by bacterial siderophores, as K. pneumoniae mutant lacking siderophore function recapitulates findings observed with wildtype strain. Rather, we show that sRBC disposal induces a liver transcriptomic profile notable for suppression of Stat1 and interferon-related responses during K. pneumoniae infection. Excess heme handling by macrophages recapitulates STAT1 suppression during infection that requires synergistic NRF1 and NRF2 activation but is independent of heme oxygenase-1 induction. Whereas iron is dispensable, the porphyrin moiety of heme is sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promote liver dissemination of K. pneumoniae in vivo. Thus, dysfunction in cellular heme metabolism negatively regulates the STAT1 pathway with implications in host defense.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Olonisakin, Tolani F.tfo5@pitt.edutfo5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendy M.wmars@pitt.edu
Thesis AdvisorLee, Janet S.leejs3@upmc.edu
Committee MemberWenzel, Sally E.swenzel@pitt.edu
Committee MemberBullock, Grant C.bullockgc@upmc.edu
Committee MemberSarkar, Saumendra N.saumen@pitt.edu
Date: 15 June 2020
Date Type: Publication
Defense Date: 17 March 2020
Approval Date: 15 June 2020
Submission Date: 27 May 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 158
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: macrophage, Klebsiella pneumoniae, heme metabolism, porphyrin, STAT1, interferon, immunosuppression
Date Deposited: 16 Jun 2020 01:42
Last Modified: 16 Jun 2020 01:42
URI: http://d-scholarship.pitt.edu/id/eprint/39124

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item