Exploring Factor H recruitment by Treponema pallidum to avoid complement-mediated killing - ABSTRACT In several high-income nations, including the United States, infectious syphilis has been resurgent for over two decades now, while syphilis is still endemic in low- and middle-income countries. Syphilis is therefore still a public global health concern, particularly in consideration that it can lead to neurological sequelae such as dementia and stroke-like syndrome, as well as cardiovascular manifestations potentially leading to death. Furthermore, every year, about half a million pregnancies are adversely affected by congenital transmission of the pathogen. The partial success of recent syphilis control campaigns promoted by the CDC and WHO clearly highlights the necessity of devising novel ways to control this serious infection. Improving our understanding of syphilis pathogenesis and the virulence factors that allow the syphilis agent, Treponema pallidum subsp. pallidum (Tp) to establish infection and persist in the host despite a robust immune response might be the key to new control strategies. A key aspect of the pathogenesis of early syphilis is the hematogenous dissemination of Tp to virtually every bodily organ. However, to reach distant tissues via the bloodstream, Tp must avoid killing by the rapid activation of the complement alternative pathway (AP). Complement evasion is a virtually unexplored topic in syphilis research, and yet it is critical to understanding pathogen persistence. To escape killing, many pathogens employ binding factors to recruit the host complement inhibitor Factor H (FH) from body fluids, thus hijacking its host-protecting function. We demonstrated that also Tp recruits human FH via a 43.1 kDa FH binding protein, and that recruitment occurs by recognizing the FH short consensus repeats (SCR) modules 19-20. Removal of sialic acid from the Tp surface with neuraminidase did not affect FH recruitment by the 43.1 kDa protein. However, studies from the 80’s by T.J. Fitzgerald implied that sialylation of still unidentified macromolecules on Tp surface contributes to evading the AP, which is consistent with the fact that FH SRC19-20 can be recruited by both sialic acid and binding protein(s). In this proposal, we aim to identify the 43.1 kDa ligand. Additionally, we will test the hypothesis that Tp mutants lacking the 43.1 kDa protein or the gene encoding the pathogen’s NeuB sialic acid synthase will be more susceptible to killing by the AP and impaired in their ability to disseminate and cause infection in the rabbit model. If successful, these studies will provide our research community with information about a novel virulence factor of Tp and mutants of this pathogen to be used in comparative studies, in addition to a better understanding of syphilis pathogenesis.
