Antibiotic treatment causes a reduction in antigen-specific T cell memory and increased susceptibility to secondary infection

Abstract

Abstract Salmonella enterica serovar Typhi causes recurrent and relapsing infection in antibiotic-treated individuals, suggesting that rapid bacterial clearance hinders the development of adaptive immunity. We have developed an antibiotic-treatment model in mice to examine this issue. This model demonstrates poor secondary protection after antibiotic treatment and allows the use of antigen-specific reagents to examine this issue in detail. Infection with Salmonella Typhimurium (BRD509-2W1S) caused expansion of Salmonella-specific CD4 T cells that were detected in peripheral blood, lymphoid tissues, and various non-lymphoid tissues. In contrast, antibiotic-treated mice had lower CD4 clonal expansion that persisted for months after infection. This reduced clonal frequency of Salmonella-specific CD4 T cells correlated with diminished protective immunity to secondary infection. In order to examine the protective contribution of circulating and non-circulating CD4 T cells, parabiosis experiments were performed whereby mice previously infected with BRD509-2W1S were paired with naïve mice for 30 days. Previously infected mice were more capable of controlling secondary infection compared to naïve parabionts or naïve control mice, however naïve parabionts were partially protected, indicating the requirement of both tissue resident and circulating cellular populations. Current experiments are underway to restore full protection during antibiotic intervention. Greater understanding of how antibiotics hinder CD4 memory development may allow for therapeutics to boost protective immunity to secondary or relapsing Salmonella infections. (Funding: NIH 5P01AI056172-09)