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Francisella tularensis  is the causative agent of the lethal disease tularemia. Despite decades of research, little is understood about why  F .  tularensis  is so virulent. Bacterial outer membrane proteins (OMPs) are involved in various virulence processes, including protein secretion, host cell attachment, and intracellular survival. Many pathogenic bacteria require metals for intracellular survival and OMPs often play important roles in metal uptake. Previous studies identified three  F .  tularensis  OMPs that play roles in iron acquisition. In this study, we examined two previously uncharacterized proteins, FTT0267 (named  fmvA , for   F   rancisella   m etal and  v irulence) and FTT0602c ( fmvB ), which are homologs of the previously studied  F .  tularensis  iron acquisition genes and are predicted OMPs. To study the potential roles of FmvA and FmvB in metal acquisition and virulence, we first examined  fmvA  and f mvB  expression following pulmonary infection of mice, finding that  fmvB  was upregulated up to 5-fold during  F .  tularensis  infection of mice. Despite sequence homology to previously-characterized iron-acquisition genes, FmvA and FmvB do not appear to be involved iron uptake, as neither  fmvA  nor  fmvB  were upregulated in iron-limiting media and neither Δ fmvA  nor Δ fmvB  exhibited growth defects in iron limitation. However, when other metals were examined in this study, magnesium-limitation significantly induced  fmvB  expression, Δ fmvB  was found to express significantly higher levels of lipopolysaccharide (LPS) in magnesium-limiting medium, and increased numbers of surface protrusions were observed on Δ fmvB  in magnesium-limiting medium, compared to wild-type  F .  tularensis  grown in magnesium-limiting medium. RNA sequencing analysis of Δ fmvB  revealed the potential mechanism for increased LPS expression, as LPS synthesis genes  kdtA  and  wbtA  were significantly upregulated in Δ fmvB , compared with wild-type  F .  tularensis . To provide further evidence for the potential role of FmvB in magnesium uptake, we demonstrated that FmvB was outer membrane-localized. Finally, Δ fmvB  was found to be attenuated in mice and cytokine analyses revealed that Δ fmvB- infected mice produced lower levels of pro-inflammatory cytokines, including GM-CSF, IL-3, and IL-10, compared with mice infected with wild-type  F .  tularensis . Taken together, although the function of FmvA remains unknown, FmvB appears to play a role in magnesium uptake and  F .  tularensis  virulence. These results may provide new insights into the importance of magnesium for intracellular pathogens.

FmvB: A Francisella tularensis Magnesium-Responsive Outer Membrane Protein that Plays a Role in Virulence