title: Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells.
abstract: Elevated inflammatory cytokines (EMCs) at mucosal surfaces have been associated with HIV susceptibility, but the underlying mechanisms remain unclear. We characterized the soluble mucosal proteome associated with elevated cytokine expression in the female reproductive tract. A scoring system was devised based on the elevation (upper quartile) of at least three of seven inflammatory cytokines in cervicovaginal lavage. Using this score, HIV-uninfected Kenyan women were classified as either having EMC (n=28) or not (n=68). Of 455 proteins quantified in proteomic analyses, 53 were associated with EMC (5% false discovery rate threshold). EMCs were associated with proteases, cell motility, and actin cytoskeletal pathways, whereas protease inhibitor, epidermal cell differentiation, and cornified envelope pathways were decreased. Multivariate analysis identified an optimal signature of 16 proteins that distinguished the EMC group with 88% accuracy. Three proteins in this signature were neutrophil-associated proteases that correlated with many cytokines, especially GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-1β (interleukin-1β), MIP-3α (macrophage inflammatory protein-3α), IL-17, and IL-8. Gene set enrichment analyses implicated activated immune cells; we verified experimentally that EMC women had an increased frequency of endocervical CD4(+) T cells. These data reveal strong linkages between mucosal cytokines, barrier function, proteases, and immune cell movement, and propose these as potential mechanisms that increase risk of HIV acquisition.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Kelly B
authors.initials: KB
authors.lastname: Arnold
authors.affiliation: National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.|Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada.|Unit of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Burgener
authors.affiliation: National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.|Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada.
authors.forename: Kenzie
authors.initials: K
authors.lastname: Birse
authors.affiliation: National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.|Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Romas
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Dunphy
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Kamnoosh
authors.initials: K
authors.lastname: Shahabi
authors.affiliation: National HIV and Retrovirology Laboratory, JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.
authors.forename: Max
authors.initials: M
authors.lastname: Abou
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Westmacott
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.
authors.forename: Stuart
authors.initials: S
authors.lastname: McCorrister
authors.affiliation: Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.
authors.forename: Jessie
authors.initials: J
authors.lastname: Kwatampora
authors.affiliation: Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.
authors.forename: Billy
authors.initials: B
authors.lastname: Nyanga
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada.|Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.affiliation: Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
authors.forename: Lindi
authors.initials: L
authors.lastname: Masson
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
authors.forename: Lenine J
authors.initials: LJ
authors.lastname: Liebenberg
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.|Mailman School of Public Health, Department of Epidemiology, Columbia University, New York, USA.
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.affiliation: Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.|National Health Laboratory Service, South Africa.
authors.forename: Jo-Ann S
authors.initials: JA
authors.lastname: Passmore
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.|Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.|University Health Network, University of Toronto, Toronto, Canada.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.|Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
authors.forename: Lyle R
authors.initials: LR
authors.lastname: McKinnon
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology*; D004198:Disease Susceptibility; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005836:Genitalia, Female / Q000166:cytology / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D015658:HIV Infections; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D007630:Kenya; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology*; D015999:Multivariate Analysis; D010447:Peptide Hydrolases / Q000235:genetics / Q000276:immunology*; D040901:Proteomics; D060386:Sex Workers
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D016207:Cytokines; D003598:Cytoskeletal Proteins; D020381:Interleukin-17; D053583:Interleukin-1beta; D016209:Interleukin-8; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010447:Peptide Hydrolases