Microbial function and genital inflammation in young South African women at high risk of HIV infection

Liam Bell,Smritee Dabee,Linda‐Gail Bekker ,Elizabeth Ross,Nicola Mulder,Zac McDonald,Monalisa T. Manhanzva,Adam Godzik,Christina Balle,Mornè Du Plessis ,David L. Tabb,Nina Radzey,Jo‐Ann S. Passmore ,Arash Iranzadeh,Shaun Barnabas,Matthys Potgieter,Imane Allali,Hoyam Gamieldien,Heather B. Jaspan,Bridget Calder,Arghavan Alisoltani,Lindi Masson,Jonathan M. Blackburn

doi:10.1186/s40168-020-00932-8

Abstract

BackgroundFemale genital tract (FGT) inflammation is an important risk factor for HIV acquisition. The FGT microbiome is closely associated with inflammatory profile; however, the relative importance of microbial activities has not been established. Since proteins are key elements representing actual microbial functions, this study utilized metaproteomics to evaluate the relationship between FGT microbial function and inflammation in 113 young and adolescent South African women at high risk of HIV infection. Women were grouped as having low, medium, or high FGT inflammation by K-means clustering according to pro-inflammatory cytokine concentrations.ResultsA total of 3186 microbial and human proteins were identified in lateral vaginal wall swabs using liquid chromatography-tandem mass spectrometry, while 94 microbial taxa were included in the taxonomic analysis. Both metaproteomics and 16S rRNA gene sequencing analyses showed increased non-optimal bacteria and decreased lactobacilli in women with FGT inflammatory profiles. However, differences in the predicted relative abundance of most bacteria were observed between 16S rRNA gene sequencing and metaproteomics analyses. Bacterial protein functional annotations (gene ontology) predicted inflammatory cytokine profiles more accurately than bacterial relative abundance determined by 16S rRNA gene sequence analysis, as well as functional predictions based on 16S rRNA gene sequence data (p < 0.0001). The majority of microbial biological processes were underrepresented in women with high inflammation compared to those with low inflammation, including a Lactobacillus-associated signature of reduced cell wall organization and peptidoglycan biosynthesis. This signature remained associated with high FGT inflammation in a subset of 74 women 9 weeks later, was upheld after adjusting for Lactobacillus relative abundance, and was associated with in vitro inflammatory cytokine responses to Lactobacillus isolates from the same women. Reduced cell wall organization and peptidoglycan biosynthesis were also associated with high FGT inflammation in an independent sample of ten women.ConclusionsBoth the presence of specific microbial taxa in the FGT and their properties and activities are critical determinants of FGT inflammation. Our findings support those of previous studies suggesting that peptidoglycan is directly immunosuppressive, and identify a possible avenue for biotherapeutic development to reduce inflammation in the FGT. To facilitate further investigations of microbial activities, we have developed the FGT-DB application that is available at http://fgtdb.org/.DwvYvmP_Lqo1TfCUgVQTWuVideo

Highlights

Female genital tract (FGT) inflammation is an important risk factor for HIV acquisition
To facilitate further investigations of microbial activities, we have developed the FGT-DB application that is available at http://fgtdb.org/
Using principal component analysis (PCA), it was found that women with Bacterial vaginosis (BV) clustered separately from women who were BV negative according to the relative abundance of all host and microbial proteins identified (Additional file 1: Fig. S1a)

Summary

Introduction

Female genital tract (FGT) inflammation is an important risk factor for HIV acquisition. The mechanisms by which female genital tract (FGT) inflammation increases HIV risk are likely multifactorial, and increased genital inflammatory cytokine concentrations may facilitate the establishment of a productive HIV infection by recruiting and activating HIV target cells, directly promoting HIV transcription and reducing epithelial barrier integrity [5,6,7]. Arnold et al showed that proteins associated with tissue remodeling processes were upregulated in the FGT, while protein biomarkers of mucosal barrier integrity were downregulated in individuals with an inflammatory profile [7] This suggests that inflammation increases tissue remodeling at the expense of mucosal barrier integrity, which may in turn increase HIV acquisition risk [7]. This theory was further validated by the finding that antiproteases were associated with HIV resistance in a cohort of sex workers from Kenya [8]

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