Abstract
Salmonella enterica serovars are intracellular bacteria capable of causing typhoid fever and gastroenteritis of significant morbidity and mortality worldwide. Current prophylactic and therapeutic treatment is hampered by the emergence of multidrug-resistant (MDR) strains of Salmonella, and vaccines provide only temporal and partial protection in vaccinees. To develop more effective Salmonella vaccines, it is important to understand the development of protective adaptive immunity to virulent Salmonella. Here we report the identification of novel CD4+ T cell peptide epitopes, which are conserved among Salmonella serovars. Immunization of Salmonella-infected mice with these peptide epitopes reduces the burden of Salmonella disease. Furthermore, we show that distinct polyfunctional (interferon-γ+, tumor necrosis factor+, and interleukin-2+) Salmonella-specific CD4+ T cell responses develop with respect to magnitude and kinetics. Moreover, we found that CD4+ T cell responses against immunodominant epitopes are predictive for active Salmonella disease. Collectively, these data could contribute to improved diagnosis of Salmonella-related diseases and rational design of Salmonella vaccines.
Highlights
Salmonella enterica serovars are intracellular bacteria capable of causing localized and systemic disease of significant morbidity and mortality [1,2,3]
CD4+ T cell responses control virulent Salmonella infection We initially set up a natural course of virulent Salmonella infection in the susceptible mouse strain C57BL/6 with the Salmonella enterica serovar Typhimurium
Our results indicate that polyfunctional CD4+ T cell responses, which develop during Salmonella infection, can predict important elements of disease activity
Summary
Salmonella enterica serovars are intracellular bacteria capable of causing localized and systemic disease of significant morbidity and mortality [1,2,3]. Salmonella enterica serovar Typhi causes typhoid fever in humans with an estimated 21 million cases annually, resulting in more than 200,000 deaths per year in endemic areas [6,7]. The closely related Salmonella enterica serovar Typhimurium and Enteriditis cause gastroenteritis, a foodborne disease which constitutes a major public health burden and represents a significant cost to society in many countries [2,8]. Infections with Salmonella (salmonellosis) are a health concern in developing nations but are an important cause of gastrointestinal infections in developed nations where contaminated food products are rapidly and widely distributed. The immune mechanisms mediating protection by such vaccination are not well understood, and which antigens are important for the induction of immunity to Salmonella is largely unknown
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