Metaproteomics Approaches to Understand Mucosal Inflammation and Target Cell Activation Associated with HIV Acquisition in African Women Arghavan Alisoltanidehkordi1, Matthys Potgieter1, Liam Bell2, Elizabeth Waldron2, Smritee Dabee1, Arash Iranzadeh1, Zac McDonald2, Imane Allali1, Shaun Barnabas1, Heather Jaspan1,3, Nicola Mulder1, David Tabb4, Jonathan Blackburn1, Linda-Gail Bekker5, Jo-Ann Passmore1,6,7, Lindi Masson1,6 1Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa; 2Centre for Proteomic and Genomic Research (CPGR), Cape Town, South Africa; 3Seattle Children's Research Institute, University of Washington, Seattle, Washington, USA; 4Division of Molecular Biology and Human Genetics, University of Stellenbosch, Cape Town, South Africa;5Desmond Tutu HIV Foundation, Cape Town, South Africa; 6Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; 7National Health Laboratory Service, South Africa
Young South African women are at exceptionally high risk of HIV infection. Genital inflammatory markers, which are associated with increased HIV acquisition risk, are elevated in younger women and may partly explain their vulnerability to infection. We aimed to improve our understanding of causes of genital inflammation in young South African women. Liquid chromatography tandem mass spectrometry was used to evaluate metaproteomic profiles in vaginal swabs collected at two time-points from 109 women (16-22 years) from Cape Town. Proteins were identified using MaxQuant and a custom database generated using de novo sequencing. Bacterial vaginosis (BV) was assessed by Nugent scoring. To define genital inflammation, cytokines were measured using Luminex and women were grouped using bi-clustering. A total of 3,589 proteins and 17,774 peptides were identified. Protein expression differed substantially between BV positive and negative women, and women with high versus low inflammation. Both microbial populations and functions differed significantly between women with high versus low inflammation. Up-regulated microbial proteins in women with inflammation included BV-associated bacteria (Gardnerella vaginalis, Prevotella, Megasphaera) and fungi. Lactobacillus crispatus and L. jensenii were most abundant in women with low inflammation and L. iners in women with medium inflammation. Over-represented pathways associated with inflammation included chronic antigenic inflammatory response and alpha-beta T cell differentiation, while cell-cell junction organisation and epithelial barrier development were under-represented. In summary, both presence and function of bacteria and fungi were associated with genital inflammation, which may increase susceptibility to HIV infection by increasing HIV target cells and impairing epithelial barrier function.
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