title: An ahemolytic pneumolysin of Streptococcus pneumoniae manipulates human innate and CD4⁺ T-cell responses and reduces resistance to colonization in mice in a serotype-independent manner.
abstract: BACKGROUND
  Some Streptococcus pneumoniae serotypes express an ahemolytic pneumolysin (PLYa). Serotypes that commonly express PLYa, including serotype 8 (ST8) and ST1, are often associated with a low prevalence during colonization but a higher propensity to cause invasive disease. We sought to study the host response to ST8 PLYa in a homologous and heterologous capsular background.
  
  
  METHODS
  We genetically exchanged the PLYa of ST8 strain 6308 with the hemolytic PLY (PLYh) of ST3 A66.1 and vice versa and determined the impact of the exchange on nasopharyngeal colonization in mice. Then, to compare the response of human cells to PLYa-expressing and PLYh-expressing strains, we infected human peripheral blood mononuclear cells (PBMCs) with PLY-switched strains and assessed dendritic cell and CD4(+) T-cell responses by intracellular cytokine staining.
  
  
  RESULTS
  Mice colonized with PLYa-expressing strains had significantly higher colonization densities than those colonized with PLYh-expressing strains, irrespective of capsular background. Compared with infection of PBMCs with PLYh-expressing strains, infection with PLYa-expressing strains induced diminished innate (dendritic cell cytokines, costimulatory receptor, and apoptotic) and adaptive (CD4(+) T-cell proliferative and memory interleukin 17A) responses.
  
  
  CONCLUSIONS
  Our findings demonstrate that PLYa has the potential to manipulate host immunity irrespective of capsule type. PLY exchange between STs expressing PLYa and PLYh could lead to unexpected colonization or invasion phenotypes.
authors.affiliation: Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine and Montefiore Medical Center.
authors.forename: M Nadeem
authors.initials: MN
authors.lastname: Khan
authors.affiliation: Biology Department, SUNY-Farmingdale State College, Farmingdale, New York.
authors.forename: John Robert
authors.initials: JR
authors.lastname: Coleman
authors.affiliation: Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine and Montefiore Medical Center.
authors.forename: Joshua
authors.initials: J
authors.lastname: Vernatter
authors.affiliation: Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine and Montefiore Medical Center.
authors.forename: Avanish Kumar
authors.initials: AK
authors.lastname: Varshney
authors.affiliation: Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine and Montefiore Medical Center.
authors.forename: Chad
authors.initials: C
authors.lastname: Dufaud
authors.affiliation: Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine and Montefiore Medical Center Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx.
authors.forename: Liise-Anne
authors.initials: LA
authors.lastname: Pirofski
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D057131:Immune Evasion; D008297:Male; D008810:Mice, Inbred C57BL; D065288:Serogroup; D013296:Streptococcus pneumoniae / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D013301:Streptolysins / Q000235:genetics / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D013301:Streptolysins; D037521:Virulence Factors; C032290:plY protein, Streptococcus pneumoniae
keywords: Streptococcus pneumoniae; T cell; apoptosis; colonization; dendritic cell; invasion; mice; pneumolysin; serotype