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

Abstract Coxiella burnetii is an obligate intracellular zoonotic bacterium that causes Q fever. Infections can be either acute or chronic. Of note, chronic Q fever develops 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% O 2 ) and hypoxic (0.5% O 2 ) conditions to clarify how C. burnetii survives this environmental stress condition. Our data suggests that under hypoxic conditions C. burnetii does not undergo stringent response, but instead enters a SCV-like form, which is smaller in size and 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.