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Manganese (Mn) is an essential micronutrient that is not readily available to pathogens during infection due to an active host defense mechanism known as nutritional immunity. To overcome this nutrient restriction, bacteria utilize high-affinity transporters that allow them to compete with host metal-binding proteins. Despite the established role of Mn in bacterial pathogenesis, little is known about the relevance of Mn in the pathophysiology of  E .  faecalis . Here, we identified and characterized the major Mn acquisition systems of  E .  faecalis . We discovered that the ABC-type permease EfaCBA and two Nramp-type transporters, named MntH1 and MntH2, work collectively to promote cell growth under Mn-restricted conditions. The simultaneous inactivation of EfaCBA, MntH1 and MntH2 (Δ efa Δ mntH1 Δ mntH2  strain) led to drastic reductions (>95%) in cellular Mn content, severe growth defects in body fluids (serum and urine)  ex vivo , significant loss of virulence in  Galleria mellonella , and virtually complete loss of virulence in rabbit endocarditis and murine catheter-associated urinary tract infection (CAUTI) models. Despite the functional redundancy of EfaCBA, MntH1 and MntH2 under  in vitro  or  ex vivo  conditions and in the invertebrate model, dual inactivation of  efaCBA  and  mntH2  (Δ efa Δ mntH2  strain) was sufficient to prompt maximal sensitivity to calprotectin, a Mn- and Zn-chelating host antimicrobial protein, and for the loss of virulence in mammalian models. Interestingly, EfaCBA appears to play a prominent role during systemic infection, whereas MntH2 was more important during CAUTI. The different roles of EfaCBA and MntH2 in these sites could be attributed, at least in part, to the differential expression of  efaA  and  mntH2  in cells isolated from hearts or from bladders. Collectively, this study demonstrates that Mn acquisition is essential for the pathogenesis of  E .  faecalis  and validates Mn uptake systems as promising targets for the development of new antimicrobials.

Manganese acquisition is essential for virulence of Enterococcus faecalis