A SNP in the Cache 1 Signaling Domain of Diguanylate Cyclase STM1987 Leads to Increased In Vivo Fitness of Invasive Salmonella Strains.

Nontyphoidal Salmonella (NTS) strains are associated with gastroenteritis worldwide but are also the leading cause of bacterial bloodstream infections in sub-Saharan Africa. The invasive NTS (iNTS) strains that cause bloodstream infections differ from standard gastroenteritis-causing strains by >700 single-nucleotide polymorphisms (SNPs). These SNPs are known to alter metabolic pathways and biofilm formation and to contribute to serum resistance and are thought to signify iNTS strains becoming human adapted, similar to typhoid fever-causing Salmonella strains. Identifying SNPs that contribute to invasion or increased virulence has been more elusive. In this study, we identified a SNP in the cache 1 signaling domain of diguanylate cyclase STM1987 in the invasive Salmonella enterica serovar Typhimurium type strain D23580. This SNP was conserved in 118 other iNTS strains analyzed and was comparatively absent in global S Typhimurium isolates associated with gastroenteritis. STM1987 catalyzes the formation of bis-(3',5')-cyclic dimeric GMP (c-di-GMP) and is proposed to stimulate production of cellulose independent of the master biofilm regulator CsgD. We show that the amino acid change in STM1987 leads to a 10-fold drop in cellulose production and increased fitness in a mouse model of acute infection. Reduced cellulose production due to the SNP led to enhanced survival in both murine and human macrophage cell lines. In contrast, loss of CsgD-dependent cellulose production did not lead to any measurable change in in vivo fitness. We hypothesize that the SNP in stm1987 represents a pathoadaptive mutation for iNTS strains.