title: The mammalian complement system as an epitome of host-pathogen genetic conflicts.
abstract: The complement system is an innate immunity effector mechanism; its action is antagonized by a wide array of pathogens and complement evasion determines the virulence of several infections. We investigated the evolutionary history of the complement system and of bacterial-encoded complement-interacting proteins. Complement components targeted by several pathogens evolved under strong selective pressure in primates, with selection acting on residues at the contact interface with microbial/viral proteins. Positively selected sites in CFH and C4BPA account for the human specificity of gonococcal infection. Bacterial interactors, evolved adaptively as well, with selected sites located at interaction surfaces with primate complement proteins. These results epitomize the expectation under a genetic conflict scenario whereby the host's and the pathogen's genes evolve within binding avoidance-binding seeking dynamics. In silico mutagenesis and protein-protein docking analyses supported this by showing that positively selected sites, both in the host's and in the pathogen's interacting partner, modulate binding.
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Filippi
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mozzi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pontremoli
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.|Dino Ferrari Centre, Department of Physiopathology and Transplantation, University of Milan, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122, Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Department of Physiopathology and Transplantation, University of Milan, 20090, Milan, Italy.|Don C. Gnocchi Foundation ONLUS, IRCCS, 20148, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, 23842, Bosisio Parini, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000818:Animals; D001419:Bacteria / Q000472:pathogenicity; D005075:Biological Evolution; D003167:Complement Activation; D050716:Complement C4b-Binding Protein / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics*; D005828:Genetics, Population; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate; D062105:Molecular Docking Simulation; D010802:Phylogeny; D011323:Primates / Q000235:genetics*; D025941:Protein Interaction Mapping; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D017242:Complement Factor H; D003165:Complement System Proteins
keywords: complement system; host-pathogen genetic conflict; human-specific infections; positive selection