A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis
Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE virulence remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, indicating that IE pathogenesis depends on coordinated physiological networks. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory adaptations, revealing substantial plasticity within IE fitness networks. Together, these findings redefine streptococcal infective endocarditis as a disease shaped by bacterial fitness.