Transient Loss of Protection Afforded by a Live Attenuated Non-typhoidal Salmonella Vaccine in Mice Co-infected with Malaria

• Published in: PLoS neglected tropical diseases 2015-09, Vol.9 (9), p.e0004027-e0004027
• Main Authors: Mooney, Jason P, Lee, Seung-Joo, Lokken, Kristen L, Nanton, Minelva R, Nuccio, Sean-Paul, McSorley, Stephen J, Tsolis, Renée M
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bacterial - blood; Bacteremia - complications; Bacteremia - immunology; Bacterial vaccines; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Disease Models, Animal; Female; Immune response; Immune Tolerance; Malaria; Malaria - complications; Malaria - immunology; Medical research; Medicine, Experimental; Medicine, Preventive; Mice, Inbred C57BL; Mice, Inbred CBA; Observations; Parasites; Patient outcomes; Plasmodium falciparum; Plasmodium yoelii; Prevention; Preventive health services; Rodents; Salmonella; Salmonella Infections, Animal - complications; Salmonella Infections, Animal - immunology; Salmonella typhimurium; Salmonella Vaccines - immunology; Vaccines; Vaccines, Attenuated - immunology
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004027

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.