Host glutathione is required for Rickettsia parkeri cell division and intracellular survival

Intracellular bacteria rely on eukaryotic metabolites for their fitness
and pathogenesis. Yet, the mechanisms of how host metabolites promote
bacterial physiology and immune evasion are often unclear. Here, we
employed obligate cytosolic Rickettsia, which parasitizes over fifty host
metabolites, to study bacterial utilization of host glutathione (GSH). We
observed that GSH depletion strongly impaired R. parkeri intracellular
survival. Super-resolution microscopy revealed that GSH depletion caused
dramatic bacterial chaining in the host cytosol, prohibiting proper
actin-based motility and cell-to-cell spread. GSH was especially critical
for R. parkeri survival in primary macrophages, where it enabled R.
parkeri to evade ubiquitylation and antibacterial autophagy. Cell division
and survival defects were restored by supplementing N-acetylcysteine,
suggesting that GSH serves as a cysteine source for R. parkeri. Together,
these data suggest that Rickettsia requires GSH as a nutrient source to
promote cell division, actin-based motility, evasion of antibacterial
autophagy, and intracellular survival. This knowledge contributes to the
expanding paradigm that GSH plays diverse roles in the pathogenesis of
intracellular bacteria and represents a promising target for host-acting
therapeutics.