Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection - PubMed (original) (raw)

doi: 10.1038/mi.2010.14. Epub 2010 Mar 31.

L D Harris, C L Vinton, H Sung, J A Briant, B Tabb, D Morcock, J W McGinty, J D Lifson, B A Lafont, M A Martin, A D Levine, J D Estes, J M Brenchley

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Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection

N R Klatt et al. Mucosal Immunol. 2010 Jul.

Abstract

Pigtail macaques (PTMs) rapidly progress to AIDS after simian immunodeficiency virus (SIV) infection. Given the strong association between human immunodeficiency virus (HIV) and SIV disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in PTMs. We found that before SIV infection, PTMs had high levels of microbial translocation that correlated with significant damage to the structural barrier of the gastrointestinal tract. Moreover, this increased microbial translocation correlated with high levels of immune activation and was associated with high frequencies of interleukin-17-producing T cells. These data highlight the relationship among mucosal damage, microbial translocation and systemic immune activation in the absence of SIV replication, and underscore the importance of microbial translocation in the rapid course of disease progression in SIV-infected PTMs. Furthermore, these data suggest that PTM may be an ideal model to study therapeutic interventions aimed at decreasing microbial translocation-induced immune activation.

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Conflict of interest statement

Disclosure: The authors declare no conflicts of interest.

Figures

Figure 1

Figure 1. Uninfected pigtail macaques have high levels of immune activation and memory-effector T cells compared to rhesus macaques and humans

(a) Frequencies of CD4+Ki67+ T cells in blood, (b) Frequencies of CD8+Ki67+ T cells in blood, (c) Frequencies of CD4+ memory-effector T cells in blood and necropsy tissues, (d) Frequencies of CD8+ memory-effector T cells in blood and necropsy tissues. PTM (circles), RM (triangles). Memory-effector T cells were determined by gating on both CD28+C95+ and CD28- subsets as measured by flow cytometry. Horizontal bars indicate median. P values calculated from Mann-Whitney U test.

Figure 2

Figure 2. Uninfected pigtail macaques have high frequencies of CD4+CCR5+T cells compared to rhesus macaques

Frequencies of CD4+CCR5+ T cells in blood and necropsy tissues. PTM (circles), RM (triangles). Horizontal bars indicate median. P values from Mann-Whitney U test.

Figure 3

Figure 3. High frequencies of T cells from uninfected pigtail macaques produce IL-17 compared to rhesus macaques

(a) Frequencies of CD4+ IFNγ producing T cells in blood, (b) Frequencies of CD8+ IFNγ producing T cells in blood, (c) Frequencies of CD4+ IL-17 producing T cells in blood and necropsy tissues, (d) Frequencies of CD8+ IL-17 producing T cells in blood and necropsy tissues, (e) Frequencies of CD4+ vs. CD8+ IL-17 producing T cells in blood of PTM. Correlation (r) determined by Spearman's rank correlation. All samples were stimulated with PMA and Ionomycin. PTM (circles) and RM (triangles). Horizontal bars indicate median. P values from Mann-Whitney U test.

Figure 4

Figure 4. Plasma LPS and Lactulose to Mannitol ratio indicate microbial translocation and gut permeability in uninfected pigtail macaques

(a) Plasma LPS levels. (b) Lactulose to manitol ratio. PTM (circles), RM (triangles), humans (squares). Horizontal bars indicate median. P values from Mann-Whitney U test.

Figure 5

Figure 5. Uninfected pigtail macaques have increased damage to the tight epithelial barrier and high levels of LPS in the lamina propria of the colon

(a) Representative claudin-3 staining (brown) in colon of PTM, (b) Representative claudin-3 staining (brown) in colon of RM, (c) Ratio of measurements of breached epithelial (no claudin) to intact epithelial (claudin) in either PTM and RM, (d) Representative LPS staining (brown) in colon of PTM, (e) Representative LPS staining (brown) in colon of RM, (f) Area of colon lamina propria LPS measured in PTM and RM. PTM (circles), RM (triangles). Horizontal bars indicate median. P values from Mann-Whitney U test.

Figure 6

Figure 6. Breaches in the colon correlates with microbial translocation, and microbial translocation correlates with immune activation in the colon of uninfected pigtail macaques

(a) The breach/intact ratio of the colon as measured by claudin significantly correlates with the amount of microbial tranlsocation into the lamina propria of the colon of PTM (b) The amount of MxA (a specific type I IFN responsive gene) in the colon as measured by IHC staining significantly correlates with the amount of microbial translocation into the colon of PTM. Correlations determined by Spearman's rank correlation. Lines indicate linear regression.

Figure 7

Figure 7. Local microbial translocation and immune activation in the colon results in systemic microbial translocation and immune activation in uninfected pigtail macaques

(a) The amount of LPS measured in the colon significantly correlates with LPS in the mesenteric LN. (b) The amount of MxA in the colon significantly correlates with the amount of MxA in the mesenteric LN. (c) LPS in the mesenteric LN significantly correlates with LPS in the axillary LN. (d) MxA in the mesenteric LN significantly correlates with MxA in the axillary LN. (e) LPS in the colon is associated with sCD14 in plasma, (f) MxA in the colon significantly correlates with sCD14 in plasma. Correlations determined by Spearman's rank correlation. Lines indicate linear regression.

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