title: Transient Loss of Protection Afforded by a Live Attenuated Non-typhoidal Salmonella Vaccine in Mice Co-infected with Malaria.
abstract: In immunocompetent individuals, non-typhoidal Salmonella serovars (NTS) are associated with gastroenteritis, however, there is currently an epidemic of NTS bloodstream infections in sub-Saharan Africa. Plasmodium falciparum malaria is an important risk factor for invasive NTS bloodstream in African children. Here we investigated whether a live, attenuated Salmonella vaccine could be protective in mice, in the setting of concurrent malaria. Surprisingly, mice acutely infected with the nonlethal malaria parasite Plasmodium yoelii 17XNL exhibited a profound loss of protective immunity to NTS, but vaccine-mediated protection was restored after resolution of malaria. Absence of protective immunity during acute malaria correlated with maintenance of antibodies to NTS, but a marked reduction in effector capability of Salmonella-specific CD4 and CD8 T cells. Further, increased expression of the inhibitory molecule PD1 was identified on memory CD4 T cells induced by vaccination. Blockade of IL-10 restored protection against S. Typhimurium, without restoring CD4 T cell effector function. Simultaneous blockade of CTLA-4, LAG3, and PDL1 restored IFN-γ production by vaccine-induced memory CD4 T cells but was not sufficient to restore protection. Together, these data demonstrate that malaria parasite infection induces a temporary loss of an established adaptive immune response via multiple mechanisms, and suggest that in the setting of acute malaria, protection against NTS mediated by live vaccines may be interrupted.
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Mooney
authors.affiliation: Center for Comparative Medicine, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Seung-Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lokken
authors.affiliation: Center for Comparative Medicine, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Minelva R
authors.initials: MR
authors.lastname: Nanton
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Sean-Paul
authors.initials: SP
authors.lastname: Nuccio
authors.affiliation: Center for Comparative Medicine, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McSorley
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tsolis
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D016470:Bacteremia / Q000150:complications / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance; D008288:Malaria / Q000150:complications* / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012481:Salmonella Infections, Animal / Q000150:complications* / Q000276:immunology*; D022562:Salmonella Vaccines / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated