Recently, a highly invasive multidrug-resistant strain of Salmonella Typhimurium (ST313) has emerged as a major cause of morbidity and mortality in sub-Saharan Africa, causing an estimated 77,500 deaths annually worldwide. Infection with the strain results in invasive bloodstream infections, particularly in children and immunosuppressed people. In a study published in PNAS, a team led by Dr Mariolina Salio and Professor Alison Simmons at the MRC Human Immunology Unit has identified a mechanism by which these resistant bacterial strains evade detection by the immune system.
Mucosal-associated invariant T (MAIT) cells are a subset of immune system T lymphocytes that are activated by bacteria that produce specific vitamin B2 metabolites (known as 5-OP-RU and 5-OE-RU), providing an early defence mechanism against pathogens at mucosal surfaces.
The researchers hypothesised that MAIT cells might be important in the early immune recognition of intestinal pathogens. They investigated the ability of MAIT cells to recognise and respond to isolates of diverse invasive Salmonella strains and discovered that both typhoidal and nontyphoidal Salmonella 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.
Their results showed that the strains escape MAIT detection through overexpression of ribB, a bacterial enzyme of the riboflavin (vitamin B2) biosynthetic pathway. This led to an increase in biomolecules produced from riboflavin known as flavin mononucleotides, metabolites that are not recognised by MAIT cells. The findings suggest that MAIT cell immune protection represents an important “evolutionary bottleneck” for the pathogen. The team propose that ribB overexpression, involving a single gene, is an evolved trait by the pathogen that facilitates evasion from immune recognition and contributes to invasive pathogenesis. This mechanism adds to previous findings from the Simmons lab, describing evasion from dendritic cell maturation by the same Salmonella strain.
The findings suggest that MAIT cells play a crucial role in defence against invasive Salmonella disease in humans and that evasion from MAIT cell recognition is a critical mechanism for the invasiveness of ST313 isolates. The team hypothesise that differences in MAIT cell activation may also be linked to different disease outcomes caused by other closely related microorganisms.
The increased susceptibility of immunocompromised patients to the ST313 strains suggests that MAIT cells might play a particularly relevant role in the context of waning protective adaptive immunity, where protection relies mostly on the innate immune response. For example, following HIV coinfection or malnutrition. The findings suggest that harnessing MAIT cells through agonistic metabolites might offer novel therapeutic opportunities.
Left: Salmonella typhimurium infects the gut and is recognised by mucosal immune cells, including MAIT and gamma delta T cells, which limit the systemic spread of the disease. Right: African isolates of Salmonella typhimurium evade MAIT cell recognition through RibB overexpression and limited antigen availability, leading to invasive disease. Figure credit: Eliza Wolfson
This study was funded by the MRC Human Immunology Unit, Wellcome Trust, and NIHR Oxford Biomedical Research Council.