title: Enhanced innate antiviral gene expression, IFN-α, and cytolytic responses are predictive of mucosal immune recovery during simian immunodeficiency virus infection.
abstract: The mucosa that lines the respiratory and gastrointestinal (GI) tracts is an important portal of entry for pathogens and provides the first line of innate immune defense against infections. Although an abundance of memory CD4(+) T cells at mucosal sites render them highly susceptible to HIV infection, the gut and not the lung experiences severe and sustained CD4(+) T cell depletion and tissue disruption. We hypothesized that distinct immune responses in the lung and gut during the primary and chronic stages of viral infection contribute to these differences. Using the SIV model of AIDS, we performed a comparative analysis of the molecular and cellular characteristics of host responses in the gut and lung. Our findings showed that both mucosal compartments harbor similar percentages of memory CD4(+) T cells and displayed comparable cytokine (IL-2, IFN-γ, and TNF-α) responses to mitogenic stimulations prior to infection. However, despite similar viral replication and CD4(+) T cell depletion during primary SIV infection, CD4(+) T cell restoration kinetics in the lung and gut diverged during acute viral infection. The CD4(+) T cells rebounded or were preserved in the lung mucosa during chronic viral infection, which correlated with heightened induction of type I IFN signaling molecules and innate viral restriction factors. In contrast, the lack of CD4(+) T cell restoration in the gut was associated with dampened immune responses and diminished expression of viral restriction factors. Thus, unique immune mechanisms contribute to the differential response and protection of pulmonary versus GI mucosa and can be leveraged to enhance mucosal recovery.
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA 95616.
authors.forename: David
authors.initials: D
authors.lastname: Verhoeven
authors.forename: Michael D
authors.initials: MD
authors.lastname: George
authors.forename: William
authors.initials: W
authors.lastname: Hu
authors.forename: Angeline T
authors.initials: AT
authors.lastname: Dang
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Smit-McBride
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Reay
authors.forename: Monica
authors.initials: M
authors.lastname: Macal
authors.forename: Anne
authors.initials: A
authors.lastname: Fenton
authors.forename: Sumathi
authors.initials: S
authors.lastname: Sankaran-Walters
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D020127:Recovery of Function / Q000235:genetics / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000502:physiology; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D014409:Tumor Necrosis Factor-alpha