Evasion of MAIT cell recognition by the African Salmonella Typhimurium ST313 pathovar that causes invasive disease

Lorena Preciado-Llanes,Alison Simmons,Patrick J Moynihan,Benjamin Kumwenda,Melita A Gordon,Jay C D Hinton,Gurdyal S Besra,Siân V Owen,Rocío Canals,Ndaru Jambo,Tonney S Nyirenda,Xiaojun Zhu,Giorgio Napolitani,Ana Sousa Gerós,Kondwani C Jambo,Innocent Kadwala,Natacha Veerapen,Mariolina Salio,Anna Aulicino

doi:10.1073/pnas.2007472117

Abstract

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.

Highlights

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites
To identify potential differences in the response of innate and adaptive T cells to distinct Salmonella pathovars, we focused on two pathovariants of S
T lymphocytes were stained with a panel of fluorescently labeled antibodies to simultaneously identify different T cell populations (MAIT, γδ, CD4, and CD8) and determine their activation status (CD69) and cytokine production (IFN-γ and TNF-α)

Summary

IMMUNOLOGY AND INFLAMMATION

Lorena Preciado-Llanesa, , Anna Aulicinoa , Rocío Canalsb, , Patrick J. 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. Typhimurium ST313 clade has become the major cause of invasive nontyphoidal Salmonella (iNTS) disease in Africa [5, 6] and comprises two subclade lineages [6], termed lineages 1 and 2. A highly invasive multidrug resistant Salmonella Typhimurium sequence type 313 has emerged as a major cause of morbidity and mortality in sub-Saharan Africa, in children and immunosuppressed individuals. Our results suggest that MAIT cell immune protection represents an important “evolutionary bottleneck” for the pathogen

Results

Discussion

Methods