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.
Highlights
In immunocompetent individuals, non-typhoidal Salmonella serovars (NTS) cause gastroenteritis, a localized enteric infection characterized by intestinal neutrophil recruitment and diarrhea [1]
Salmonella Immunity during Malaria strategy to protect African children against disseminated NTS infection, we interrogated the effect of malaria on vaccine-induced memory responses to NTS
Our results from a mouse infection model show that infection with malaria parasites temporarily suspends protective immunity conferred by a live, attenuated vaccine and suppresses adaptive immune responses to NTS that are mediated by T cells
Summary
Non-typhoidal Salmonella serovars (NTS) cause gastroenteritis, a localized enteric infection characterized by intestinal neutrophil recruitment and diarrhea [1]. NTS are an important cause of gastroenteritis in Sub-Saharan Africa [3]. In addition these pathogens are often the most common cause of bloodstream infections, with Salmonella enterica serovars Enteritidis and Typhimurium Typhimurium) accounting for the majority of cases [4,5,6,7,8]. This syndrome, known as NTS bacteremia, is not a diarrheal disease, as symptoms of gastroenteritis are commonly absent [9]. Typhimurium, ST313, that is resistant to multiple antibiotics [10,11]
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