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. 2023 Jan 31;42(1):112020.
doi: 10.1016/j.celrep.2023.112020. Epub 2023 Jan 23.

Experimental bacterial dysbiosis with consequent immune alterations increase intrarectal SIV acquisition susceptibility

Alexandra M Ortiz  1 , Phillip J Baker  1 , Charlotte A Langner  1 , Jennifer Simpson  1 , Apollo Stacy  2 , Jacob K Flynn  1 , Carly E Starke  1 , Carol L Vinton  1 , Christine M Fennessey  3 , Yasmine Belkaid  4 , Brandon F Keele  3 , Jason M Brenchley  5
Affiliations

Experimental bacterial dysbiosis with consequent immune alterations increase intrarectal SIV acquisition susceptibility

Alexandra M Ortiz et al. Cell Rep. .

Abstract

Variations in the composition of the intestinal bacterial microbiome correlate with acquisition of some sexually transmitted pathogens. To experimentally assess the contribution of intestinal dysbiosis to rectal lentiviral acquisition, we induce dysbiosis in rhesus macaques (RMs) with the antibiotic vancomycin prior to repeated low-dose intrarectal challenge with simian immunodeficiency virus (SIV) SIVmac239X. Vancomycin administration reduces T helper 17 (TH17) and TH22 frequencies, increases expression of host bacterial sensors and antibacterial peptides, and increases numbers of transmitted-founder (T/F) variants detected upon SIV acquisition. We observe that SIV acquisition does not correlate with measures of dysbiosis but rather associates with perturbations in the host antimicrobial program. These findings establish a functional association between the intestinal microbiome and susceptibility to lentiviral acquisition across the rectal epithelial barrier.

Keywords: CP: Immunology; CP: Microbiology; HIV; SIV; T(H)17; T(H)22; macaque; men who have sex with men; microbiome.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Vancomycin induces intestinal dysbiosis in healthy macaques
(A) Study design. Our study was composed of a pre-challenge phase, where baseline responses to vancomycin treatment were established for each animal, and a challenge phase. Samples were collected as depicted. (B) Relative fecal bacterial abundance of control and vancomycin (Vanc) animals 7 days after Vanc treatment (3 days after the last dose). Taxa are color grouped by phylum and individually shaded by family. Significant differences in phylum abundance between groups are indicated in the figure legend. (C) Fold change frequencies of fecal ASVs identified by MetaLonDA as longitudinally, differentially abundant over the pre-challenge period. Data show Vanc: control frequency fold change color grouped by phylum and individually shaded by family. (D) Longitudinal observed, Chao1, and Shannon indices of fecal bacterial α-diversity. Lines represent mean per group. (E) Principal-coordinate analysis (PCoA) of unweighted and weighted UniFrac, Bray-Curtis, and Jaccard measures of fecal bacteria β-diversity. Data points are derived from 1 biological replicate, n = 7–8 per group. Significance methods as follows: LEfSe (B), MetaLonDA (C), unpaired two-way t tests (D), and Adonis (E).
Figure 2.
Figure 2.. Vanc treatment disrupts intestinal antimicrobial immunity in healthy macaques
(A) Longitudinal, rectal CD4+ T cell frequencies. (B) Radar plot depicting fold change from baseline (post- versus pre-Vanc) expression of rectal CD4+ TM activation markers and stimulation-induced cytokines. (C) Longitudinal rectal TH17 (left) and TH22 (right) cell frequencies. (D) NanoString-quantified counts of the top three rectal genes identified as longitudinally, differentially expressed in response to Vanc. (E) p values and Z scores of the top 5 longitudinally increased and decreased pathways (Z score >|±2|) as identified by IPA from NanoString-quantified transcript counts in rectal homogenates. (F) Relative expression of DUOX1, DUOX2, and SUCNR1 in rectal homogenates post-Vanc. Diamond denotes undetected transcript normalized to the limit of detection. Lines in (A)–(D) and (F) represent mean per group. Data points are derived from 1 biological replicate, n = 5–8 per group. Significance methods as follows: unpaired or paired two-way t tests (A–D and F) and Fisher’s exact test (E). Horizontal p values color coded by group with longitudinal significance. Vertical p value denotes significance post-treatment.
Figure 3.
Figure 3.. Vanc-mediated intestinal dysbiosis contributes to rectal SIV acquisition through disruption of host antimicrobial immunity
(A) Survival curve depicting the remaining percentage of uninfected animals after each challenge. (B) Number of T/F variants detected in acute SIV infection. Lines represent mean per group. (C) Longitudinal SIV plasma viral load in acute SIV infection. (D) Correlation heatmap of post-treatment measures of intestinal dysbiosis versus measures of SIV susceptibility for all animals. (E) Correlation matrix of identified Vanc-responsive measures of antimicrobial immunity versus measures of SIV susceptibility for all animals. (F) PCA of identified Vanc-responsive measures of antimicrobial immunity, grouped by acquired T/F variant acquisition (left) or time to acquisition (right), for all animals.. Data points are derived from 1 biological replicate, n = 5–8 per group. Significance methods as follows: Mantel-Cox log-rank (A), unpaired one-way (B) or two-way (C) t test, Pearson correlation (D and E), and Adonis (F).
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