show Abstracthide AbstractThe propensity for some microbial pathogens to alter their host-tropism leading to epidemics in distinct host-species populations is a global public and veterinary health concern. However, our understanding of the evolutionary genetic events underlying successful host-switches is very limited. For some pathogenic viruses, a small number of multi-gene mutations are sufficient, but successful bacterial host jumps may require more complex genetic adaptations affecting multiple pathways{Imai:2012hn}{Russell:2012cr}{Herfst:2012jr}. Here, we trace the evolutionary trajectory of the common rabbit clone of Staphylococcus aureus responsible for major epidemics in commercial rabbitries, and dissect the molecular basis for its host-tropism. The rabbit S. aureus clone evolved through a likely human-to-rabbit host jump associated with specific genetic adaptions which promote infection of rabbits. In contrast to all characterized human and animal clones of S. aureus, adaptation to the rabbit host did not involve acquisition of mobile genetic elements from a host-specific accessory gene pool. Remarkably, we discovered that a single natural mutation of the dltB gene encoding the D-alanine teichoic acid esterification protein was required and sufficient to allow the human clone to infect rabbits at very low inocula. An additional 2 non-synonymous natural mutations of dltB, and loss of function of the global gene regulator rot, further increased infectivity and bacterial recovery from lesions. Related mutations of dltB were found in other rabbit strains of distinct clonal origin suggesting convergent host-adaptive evolution. In conclusion, our data reveal that a single gene mutation may be sufficient to radically alter the host-tropism of the major human and animal pathogen S. aureus, highlighting the remarkable capacity of some bacterial pathogens to expand into novel host species populations.