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Contributions of macrophages in lymph nodes and gut mucosa to SIV disease control and progression

Swan, Zachary Duane Jameson (2017) Contributions of macrophages in lymph nodes and gut mucosa to SIV disease control and progression. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The lymph nodes and gastrointestinal tract are principal sites of inflammation and T cell dysfunction in progressive human immunodeficiency virus type 1 (HIV) infection, and a leading hypothesis is that aberrant responses by innate immune cells, such as macrophages, are actively involved in this process. Macrophages promote and resolve tissue inflammation in health and in response to pathogen insult through cytokine release, phagocytosis, and wound repair, but currently their role in HIV/AIDS pathogenesis remains unclear. Using the pathogenic simian immunodeficiency virus (SIV)-rhesus macaque model, I investigated the macrophage response at different stages of SIV infection and AIDS, as well as longitudinally in macaques anticipated to control or progress to disease based on set-point viral load. I hypothesized that macrophages promote a protective response during acute SIV infection that becomes inadequate and/or detrimental to the host in chronic infection and associates with disease progression. I found that macrophage density uniformly increased in lymph nodes and gut mucosa in acute SIV infection and then declined at the onset of chronic infection except for in gut mucosa of SIV progressors, where macrophage numbers remained elevated and were increased above pre-infection in AIDS. Lymph node macrophages were activated, apoptotic, and inflammatory, spontaneously secreting TNF-α, IL-6, and IFN-α in the acute and chronic stages of infection with minor differences between groups. In contrast, macrophages in small intestine were functionally non-inflammatory, except in AIDS, and macrophage phagocytic capacity in SIV progressors was markedly impaired, inversely correlating with gut macrophage abundance, enteropathy, and plasma but not tissue viral burden. Collectively, these data suggest an inflammatory function for macrophages in lymph nodes that participates in SIV-associated inflammation and T cell loss but does not contribute to disease outcome. At the same time, macrophages in gut mucosa appear to resolve rather than promote inflammation through phagocytosis, and their impairment is associated with hallmarks of progressive SIV infection and eventual harmful activity in AIDS. Defining macrophage involvement in HIV/AIDS pathogenesis could elucidate novel pathways for adjunctive therapeutic intervention through direct or indirect augmentation of macrophages and therefore has considerable public health significance.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Swan, Zachary Duane Jamesonzds8@pitt.eduZDS8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBarratt-Boyes, Simon M.smbb@pitt.edu
Committee MemberFlynn, JoAnne L.joanne@pitt.ed
Committee MemberRinaldo, Jr., Charles R.rinaldo@pitt.edu
Committee MemberThomson, Angus W.thomsonaw@upmc.edu
Date: 24 February 2017
Date Type: Publication
Defense Date: 9 December 2016
Approval Date: 24 February 2017
Submission Date: 23 November 2016
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 140
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: macrophages, HIV/AIDS, nonhuman primates, gut mucosa, inflammation, innate immunity
Date Deposited: 24 Feb 2017 20:21
Last Modified: 01 Jan 2019 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/30595

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