title: Discovery of novel cross-protective Rickettsia prowazekii T-cell antigens using a combined reverse vaccinology and in vivo screening approach.
abstract: Rickettsial agents are some of the most lethal pathogens known to man. Among them, Rickettsia prowazekii is a select agent with potential use for bioterrorism; yet, there is no anti-Rickettsia vaccine commercially available. Owing to the obligate intracellular lifestyle of rickettsiae, CD8(+) T cells are indispensable for protective cellular immunity. Furthermore, T cells can mediate cross-protective immunity between different pathogenic Rickettsia, a finding consistent with the remarkable similarity among rickettsial genomes. However, Rickettsia T cell antigens remain unidentified. In the present study, we report an algorithm that allowed us to identify and validate four novel R. prowazekii vaccine antigen candidates recognized by CD8(+) T cells from a set of twelve in silico-defined protein targets. Our results highlight the importance of combining proteasome-processing as well as MHC class-I-binding predictions. The novel rickettsial vaccine candidate antigens, RP778, RP739, RP598, and RP403, protected mice against a lethal challenge with Rickettsia typhi, which is indicative of cross-protective immunity within the typhus group rickettsiae. Together, our findings validate a reverse vaccinology approach as a viable strategy to identify protective rickettsial antigens and highlight the feasibility of a subunit vaccine that triggers T-cell-mediated cross-protection among diverse rickettsiae.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0609, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Caro-Gomez
authors.affiliation: Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0609, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Gazi
authors.affiliation: Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0609, USA.
authors.forename: Yenny
authors.initials: Y
authors.lastname: Goez
authors.affiliation: Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0609, USA; Sealy Center for Vaccine Development, Center for Tropical Diseases, Center for Biodefense and Emerging Infectious Diseases, Institute for Translational Sciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA. Electronic address: gvalbuen@utmb.edu.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Valbuena
mesh_terms: D000465:Algorithms; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D056738:Cross Protection; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D051379:Mice; D012283:Rickettsia prowazekii / Q000276:immunology*; D012290:Rickettsial Vaccines / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D015395:Histocompatibility Antigens Class I; D012290:Rickettsial Vaccines
keywords: CD8(+) T cells; Reverse vaccinology; Rickettsia; Vaccine