title: Distinct effects on diversifying selection by two mechanisms of immunity against Streptococcus pneumoniae.
abstract: Antigenic variation to evade host immunity has long been assumed to be a driving force of diversifying selection in pathogens. Colonization by Streptococcus pneumoniae, which is central to the organism's transmission and therefore evolution, is limited by two arms of the immune system: antibody- and T cell- mediated immunity. In particular, the effector activity of CD4(+) T(H)17 cell mediated immunity has been shown to act in trans, clearing co-colonizing pneumococci that do not bear the relevant antigen. It is thus unclear whether T(H)17 cell immunity allows benefit of antigenic variation and contributes to diversifying selection. Here we show that antigen-specific CD4(+) T(H)17 cell immunity almost equally reduces colonization by both an antigen-positive strain and a co-colonized, antigen-negative strain in a mouse model of pneumococcal carriage, thus potentially minimizing the advantage of escape from this type of immunity. Using a proteomic screening approach, we identified a list of candidate human CD4(+) T(H)17 cell antigens. Using this list and a previously published list of pneumococcal Antibody antigens, we bioinformatically assessed the signals of diversifying selection among the identified antigens compared to non-antigens. We found that Antibody antigen genes were significantly more likely to be under diversifying selection than the T(H)17 cell antigen genes, which were indistinguishable from non-antigens. Within the Antibody antigens, epitopes recognized by human antibodies showed stronger evidence of diversifying selection. Taken together, the data suggest that T(H)17 cell-mediated immunity, one form of T cell immunity that is important to limit carriage of antigen-positive pneumococcus, favors little diversifying selection in the targeted antigen. The results could provide new insight into pneumococcal vaccine design.
authors.affiliation: Department of Epidemiology and Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America. liyuan@hsph.harvard.edu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Todd
authors.initials: T
authors.lastname: Gierahn
authors.forename: Claudette M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Trzciński
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Ford
authors.forename: Nicholas
authors.initials: N
authors.lastname: Croucher
authors.forename: Paulo
authors.initials: P
authors.lastname: Gouveia
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Flechtner
authors.forename: Richard
authors.initials: R
authors.lastname: Malley
authors.forename: Marc
authors.initials: M
authors.lastname: Lipsitch
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D057131:Immune Evasion; D007111:Immunity, Cellular; D051379:Mice; D008807:Mice, Inbred BALB C; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D022242:Pneumococcal Vaccines / Q000276:immunology / Q000627:therapeutic use; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D000939:Epitopes; D022242:Pneumococcal Vaccines