Coxiella burnetii establishes a small cell variant (SCV)-like persistent form to survive adverse intracellular conditions.

Coxiella burnetii is an obligate intracellular zoonotic bacterium that causes Q fever. Infections can be either acute or chronic. Of note, chronic Q fever can develop months or years after primary infection without clinical symptoms, suggesting bacterial persistence. Yet, information about the induction, regulation, and/or location of C. burnetii persistence is rare. We have shown that during infection of primary macrophages, hypoxia-induced citrate limitation results in inhibition of C. burnetii replication without affecting viability. Here, primary murine macrophages were infected with C. burnetii under normoxic (21% O2) and hypoxic (0.5% O2) conditions to clarify how C. burnetii survives this environmental stress condition. Our data suggest that under hypoxic conditions, C. burnetii does not undergo the stringent response, but instead enters an SCV-like form, which is smaller in size, possesses condensed chromatin material and a thicker cell wall. These changes have functional consequences, as the SCV-like persistent form of C. burnetii is more infectious, more tolerant to antibiotics and less sensitive to clearance by IFNγ activated macrophages. Hence, the development of the SCV-like persistent form of C. burnetii prevents elimination of the pathogen, which in turn allows the pathogen to thrive once the conditions again change in its favor.