Intestinal damage precedes mucosal immune dysfunction in SIV infection

Tiffany Hensley-McBain, Alicia R. Berard, Jennifer A. Manuzak, Charlene J. Miller, Alexander S. Zevin, Patricia Polacino, Jillian Gile, Brian Agricola, Mark Cameron, Shiu Lok Hu, Jacob D. Estes, R. Keith Reeves, Jeremy Smedley, Brandon F. Keele, Adam D. Burgener, Nichole R. Klatt

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

HIV and pathogenic SIV infection are characterized by mucosal dysfunction including epithelial barrier damage, loss of Th17 cells, neutrophil infiltration, and microbial translocation with accompanying inflammation. However, it is unclear how and when these contributing factors occur relative to one another. In order to determine whether any of these features initiates the cycle of damage, we longitudinally evaluated the kinetics of mucosal and systemic T-cell activation, microbial translocation, and Th17 cell and neutrophil frequencies following intrarectal SIV infection of rhesus macaques. We additionally assessed the colon proteome to elucidate molecular pathways altered early after infection. We demonstrate increased T-cell activation (HLA-DR+) beginning 3–14 days post-SIV challenge, reduced peripheral zonulin 3–14 days post-SIV, and evidence of microbial translocation 14 days post-SIV. The onset of mucosal dysfunction preceded peripheral and mucosal Th17 depletion, which occurred 14–28 days post-SIV, and gut neutrophil accumulation was not observed. Proteins involved in epithelial structure were downregulated 3 days post-SIV followed by an upregulation of immune proteins 14 days post-SIV. These data demonstrate that immune perturbations such as Th17 loss and neutrophil infiltration occur after alterations to epithelial structural protein pathways, suggesting that epithelial damage occurs prior to widespread immune dysfunction.

Original languageEnglish (US)
Pages (from-to)1429-1440
Number of pages12
JournalMucosal Immunology
Volume11
Issue number5
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank all veterinary staff of the Washington National Primate Research Center for animal studies. This work was supported by 1K22AI098440-01, IR01AI117828, 1DP13A037979, and start-up funds to N.R.K. from the University of Washington and Washington National Primate Research Center. Research reported in this publication was additionally supported in part by the primate center NIH core grant P51OD010425 and federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, the Canadian Institutes for Health Research (TMI-138658), and Public Health Agency of Canada. We thank Stuart McCorrister and Garrett Westmacott for technical assistance. The content of this publication is solely the responsibility of the authors and does not necessarily reflect the views or policies of the National Institutes of Health or the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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