central role of a bacterial twocomponent gene regulatory system of previously unknown function in pathogen persistence in human saliva the molecular genetic mechanisms used by bacteria to persist in humans are poorly understood group a streptococcus gas causes the majority of bacterial pharyngitis cases in humans and is prone to persistently inhabit the upper respiratory tract to gain information about how gas survives in and infects the oropharynx we analyzed the transcriptome of a serotype m1 strain grown in saliva the dynamic pattern of changes in transcripts of genes spy08740875 herein named sptr and spts sptrs for saliva persistence encoding a twocomponent gene regulatory system of unknown function suggested that sptrs contributed to persistence of gas in saliva consistent with this idea an isogenic nonpolar mutant strain deltasptr was dramatically less able to survive in saliva compared with the parental strain iterative expression microarray analysis of bacteria grown in saliva revealed that transcripts of several known and putative gas virulence factor genes were decreased significantly in the deltasptr mutant strain compared with the parental strain the isogenic mutant strain also had altered transcripts of multiple genes encoding proteins involved in complex carbohydrate acquisition and utilization pathways western immunoblot analysis and realtime pcr analysis of gas in throat swabs taken from humans with pharyngitis confirmed the findings we conclude that sptrs optimizes persistence of gas in human saliva apparently by strategically influencing metabolic pathways and virulence factor production the discovery of a genetic program that significantly increased persistence of a major human pathogen in saliva enhances understanding of how bacteria survive in the host and suggests new therapeutic strategies