Differential stress responsiveness determines intraspecies virulence heterogeneity and host adaptation in Listeria monocytogenes

Microbial pathogenesis is mediated by the expression of virulence genes. However, as microbes with identical virulence gene content can differ in their pathogenic potential, other virulence determinants must be involved. Here, by combining comparative genomics and transcriptomics of a large collection of isolates of the model pathogen Listeria monocytogenes, time-lapse microscopy, in vitro evolution and in vivo experiments, we show that the individual stress responsiveness of L. monocytogenes isolates determines their respective levels of virulence in vivo and reflects their degree of host adaptation. The transcriptional signature that accounts for the heterogeneity in the virulence of L. monocytogenes species is mediated by the stress response regulator SigB and driven by differential stress responsiveness. The tuning of SigB pathway responsiveness is polygenic and influenced by multiple, individually rare gene variations. This study reveals an overarching determinant of microbial virulence, challenging the paradigm of accessory virulence gene content as the major determinant of intraspecies virulence heterogeneity.