title: Human lymphocyte apoptosis after exposure to influenza A virus.
abstract: Infection of humans with influenza A virus (IAV) results in a severe transient leukopenia. The goal of these studies was to analyze possible mechanisms behind this IAV-induced leukopenia with emphasis on the potential induction of apoptosis of lymphocytes by the virus. Analysis of lymphocyte subpopulations after exposure to IAV showed that a portion of CD3(+), CD4(+), CD8(+), and CD19(+) lymphocytes became apoptotic (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling positive). The percentage of cells that are infected was shown to be less than the percentage of apoptotic cells, suggesting that direct effects of cell infection by the virus cannot account fully for the high level of cell death. Removal of monocytes-macrophages after IAV exposure reduced the percent of lymphocytes that were apoptotic. Treatment of virus-exposed cultures with anti-tumor necrosis factor alpha did not reduce the percentage of lymphocytes that were apoptotic. In virus-exposed cultures treated with anti-FasL antibody, recombinant soluble human Fas, Ac-DEVD-CHO (caspase-3 inhibitor), or Z-VAD-FMK (general caspase inhibitor), apoptosis and production of the active form of caspase-3 was reduced. The apoptotic cells were Fas-high-density cells while the nonapoptotic cells expressed a low density of Fas. The present studies showed that Fas-FasL signaling plays a major role in the induction of apoptosis in lymphocytes after exposure to IAV. Since the host response to influenza virus commonly results in recovery from the infection, with residual disease uncommon, lymphocyte apoptosis likely represents a part of an overall beneficial immune response but could be a possible mechanism of disease pathogenesis.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, 301 University Ave., Galveston, TX 77555-0435, USA. jnichols@utmb.edu
authors.forename: J E
authors.initials: JE
authors.lastname: Nichols
authors.forename: J A
authors.initials: JA
authors.lastname: Niles
authors.forename: N J
authors.initials: NJ
authors.lastname: Roberts
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D053222:Fas Ligand Protein; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D008214:Lymphocytes / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000032:analysis; D009842:Oligopeptides / Q000494:pharmacology; D019014:fas Receptor / Q000032:analysis
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor