While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity. Using a YFP–IFN-γ reporter system, we identified Th1 cells in the liver of immunized mice that displayed markers of tissue residence, including P2X7, ARTC2, LFA-1, and CD101. Adoptive transfer of liver memory cells after ARTC2 blockade increased protection against highly virulent bacteria. Taken together, these data demonstrate that noncirculating memory Th1 cells are a vital component of immunity to Salmonella infection and should be the focus of vaccine strategies.
Antibiotic intervention is an effective treatment strategy for many bacterial infections and liberates bacterial antigens and stimulatory products that can induce an inflammatory response. Despite the opportunity for bacterial killing to enhance the development of adaptive immunity, patients treated successfully with antibiotics can suffer from reinfection. Studies in mouse models of Salmonella and Chlamydia infection also demonstrate that early antibiotic intervention reduces host protective immunity to subsequent infection. This heightened susceptibility to reinfection correlates with poor development of Th1 and antibody responses in antibiotic-treated mice but can be overcome by delayed antibiotic intervention, thus suggesting a requirement for sustained T cell stimulation for protection. Although the contribution of memory T cell subsets is imperfectly understood in both of these infection models, a protective role for noncirculating memory cells is suggested by recent studies. Together, these data propose a model where antibiotic treatment specifically interrupts tissue-resident memory T cell formation. Greater understanding of the mechanistic basis of this phenomenon might suggest therapeutic interventions to restore a protective memory response in antibiotic-treated patients, thus reducing the incidence of reinfection.
The development of a sub-unit Salmonella vaccine has been hindered by the absence of detailed information about antigenic targets of protective Salmonella-specific T and B cells. Recent studies have identified SseB as a modestly protective antigen in susceptible C57BL/6 mice, but the mechanism of protective immunity remains undefined. Here, we report that simply combining Salmonella SseB with flagellin substantially enhances protective immunity, allowing immunized C57BL/6 mice to survive for up to 30 days following challenge with virulent bacteria. Surprisingly, the enhancing effect of flagellin did not require flagellin antigen targeting during secondary responses or recognition of flagellin by TLR5. While co-immunization with flagellin did not affect SseB-specific antibody responses, it modestly boosted CD4 responses. In addition, protective immunity was effectively transferred in circulation to parabionts of immunized mice, demonstrating that tissue resident memory is not required for vaccine-induced protection. Finally, protective immunity required host expression of IFN-γR but was independent of iNOS expression. Taken together, these data indicate that Salmonella flagellin has unique adjuvant properties that improve SseB-mediated protective immunity provided by circulating memory.
Aims-In most infectious disease models, it is assumed that gavage needle infection is the most reliable means of pathogen delivery to the gastrointestinal tract. However, this methodology can cause esophageal tearing and induces stress in experimental animals, both of which have the potential to impact early infection and the subsequent immune response. Materials and Methods-C57BL/6 mice were orally infected with virulent SalmonellaTyphimurium SL1344 either by intragastric gavage preceded by sodium bicarbonate, or by contamination of drinking water. Results-We demonstrate that water contamination delivery of Salmonella is equivalent togavage inoculation in providing a consistent model of infection. Furthermore, exposure of mice to contaminated drinking water for as little as 4 hours allowed maximal mucosal and systemic infection, suggesting an abbreviated window exists for natural intestinal entry.Conclusions-Together, these data question the need for gavage delivery for infection with oral pathogens.
Salmonella infection can cause gastroenteritis in healthy individuals or a serious, systemic infection in immunocompromised patients and has a global impact. CD4 Th1 cells represent the main lymphocyte population that participates in bacterial clearance during both primary and secondary infections in mice of the H-2b haplotype. Previous studies have used congenic mice to examine the function of major histocompatibility complex (MHC) molecules in elimination of this pathogen from the host. In this study, we further characterized the ability of H-2b, H-2k, and H-2u molecules to influence adaptive immunity to Salmonella in MHC congenic mice. By depleting different cell populations during infection, we unexpectedly found that CD8 T cells, in addition to CD4 T cells, play a major role in accelerated clearance of bacteria from H-2k congenic hosts. Our data suggest that CD8 T cells accelerate clearance in some MHC congenic mouse strains and could therefore represent an unexpected contributor to the protective efficacy of Salmonella vaccines outside the typical studies in C57BL/6 mice.
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