Abstract:

Nontyphoidal Salmonella serotypes are a common cause of self-limiting diarrhoeal illnesses in healthy adults. However, recently, a highly invasive multidrug resistant Salmonella Typhimurium sequence type 313 has emerged as a major cause of morbidity and mortality in sub-Saharan Africa, particularly in children and immunosuppressed individuals. In this paper we describe escape from MAIT cell recognition as an additional mechanism of immune evasion of S. Typhimurium ST313. As MAIT cells represent an early defense mechanism against pathogens at mucosal surfaces, and their frequency and function are altered in immunosuppressed individuals in sub-Saharan Africa, harnessing their function may offer an important therapeutic strategy to improve mucosal immunity.Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites. Mouse models of infection have demonstrated a role for MAIT cells in antimicrobial defense. However, proposed protective roles of MAIT cells in human infections remain unproven and clinical conditions associated with selective absence of MAIT cells have not been identified. We report that typhoidal and nontyphoidal Salmonella enterica strains activate MAIT cells. However, S. Typhimurium sequence type 313 (ST313) lineage 2 strains, which are responsible for the burden of multidrug-resistant nontyphoidal invasive disease in Africa, escape MAIT cell recognition through overexpression of ribB. This bacterial gene encodes the 4-dihydroxy-2-butanone-4-phosphate synthase enzyme of the riboflavin biosynthetic pathway. The MAIT cell-specific phenotype did not extend to other innate lymphocytes. We propose that ribB overexpression is an evolved trait that facilitates evasion from immune recognition by MAIT cells and contributes to the invasive pathogenesis of S. Typhimurium ST313 lineage 2.All data have been made available in the manuscript.