Intestinal damage precedes mucosal immune dysfunction in SIV infection

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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)1-12
Number of pages12
JournalMucosal Immunology
DOIs
StateAccepted/In press - Jun 15 2018

Fingerprint

Th17 Cells
Neutrophil Infiltration
Neutrophils
Infection
T-Lymphocytes
Proteins
HLA-DR Antigens
Proteome
Macaca mulatta
Colon
Up-Regulation
Down-Regulation
HIV
Inflammation
zonulin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Hensley-McBain, T., Berard, A. R., Manuzak, J. A., Miller, C. J., Zevin, A. S., Polacino, P., ... Klatt, N. R. (Accepted/In press). Intestinal damage precedes mucosal immune dysfunction in SIV infection. Mucosal Immunology, 1-12. https://doi.org/10.1038/s41385-018-0032-5

Intestinal damage precedes mucosal immune dysfunction in SIV infection. / Hensley-McBain, Tiffany; Berard, A. R.; Manuzak, Jennifer A.; Miller, Charlene J.; Zevin, Alexander S.; Polacino, Patricia; Gile, Jillian; Agricola, Brian; Cameron, Mark; Hu, Shiu Lok; Estes, Jacob; Reeves, R. Keith; Smedley, Jeremy; Keele, Brandon F.; Burgener, Adam D.; Klatt, Nichole R.

In: Mucosal Immunology, 15.06.2018, p. 1-12.

Research output: Contribution to journalArticle

Hensley-McBain, T, Berard, AR, Manuzak, JA, Miller, CJ, Zevin, AS, Polacino, P, Gile, J, Agricola, B, Cameron, M, Hu, SL, Estes, J, Reeves, RK, Smedley, J, Keele, BF, Burgener, AD & Klatt, NR 2018, 'Intestinal damage precedes mucosal immune dysfunction in SIV infection', Mucosal Immunology, pp. 1-12. https://doi.org/10.1038/s41385-018-0032-5
Hensley-McBain T, Berard AR, Manuzak JA, Miller CJ, Zevin AS, Polacino P et al. Intestinal damage precedes mucosal immune dysfunction in SIV infection. Mucosal Immunology. 2018 Jun 15;1-12. https://doi.org/10.1038/s41385-018-0032-5
Hensley-McBain, Tiffany ; Berard, A. R. ; Manuzak, Jennifer A. ; Miller, Charlene J. ; Zevin, Alexander S. ; Polacino, Patricia ; Gile, Jillian ; Agricola, Brian ; Cameron, Mark ; Hu, Shiu Lok ; Estes, Jacob ; Reeves, R. Keith ; Smedley, Jeremy ; Keele, Brandon F. ; Burgener, Adam D. ; Klatt, Nichole R. / Intestinal damage precedes mucosal immune dysfunction in SIV infection. In: Mucosal Immunology. 2018 ; pp. 1-12.
@article{5926db75dc624e62b017b37cfe26a469,
title = "Intestinal damage precedes mucosal immune dysfunction in SIV infection",
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.",
author = "Tiffany Hensley-McBain and Berard, {A. R.} and Manuzak, {Jennifer A.} and Miller, {Charlene J.} and Zevin, {Alexander S.} and Patricia Polacino and Jillian Gile and Brian Agricola and Mark Cameron and Hu, {Shiu Lok} and Jacob Estes and Reeves, {R. Keith} and Jeremy Smedley and Keele, {Brandon F.} and Burgener, {Adam D.} and Klatt, {Nichole R.}",
year = "2018",
month = "6",
day = "15",
doi = "10.1038/s41385-018-0032-5",
language = "English (US)",
pages = "1--12",
journal = "Mucosal Immunology",
issn = "1933-0219",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Intestinal damage precedes mucosal immune dysfunction in SIV infection

AU - Hensley-McBain, Tiffany

AU - Berard, A. R.

AU - Manuzak, Jennifer A.

AU - Miller, Charlene J.

AU - Zevin, Alexander S.

AU - Polacino, Patricia

AU - Gile, Jillian

AU - Agricola, Brian

AU - Cameron, Mark

AU - Hu, Shiu Lok

AU - Estes, Jacob

AU - Reeves, R. Keith

AU - Smedley, Jeremy

AU - Keele, Brandon F.

AU - Burgener, Adam D.

AU - Klatt, Nichole R.

PY - 2018/6/15

Y1 - 2018/6/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048588130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048588130&partnerID=8YFLogxK

U2 - 10.1038/s41385-018-0032-5

DO - 10.1038/s41385-018-0032-5

M3 - Article

C2 - 29907866

AN - SCOPUS:85048588130

SP - 1

EP - 12

JO - Mucosal Immunology

JF - Mucosal Immunology

SN - 1933-0219

ER -