The lipid A acylation pattern of Coxiella burnetii prevents detection and clearance by the non-canonical inflammasome in primary murine macrophages

C. burnetii is a Gram-negative, obligate intracellular bacterium and the causative agent of Q fever. The disease is either asymptomatic or manifests as a mild flu-like illness, but pneumonia or hepatitis might also occur. In most cases, the infection is self-limiting and the pathogen is cleared. In a small percentage of patients, the host immune system fails to eliminate the pathogen, potentially allowing the development of chronic Q fever months or even years after primary infection. The elimination of the bacteria, and thereby prevention of disease onset, would require an inflammatory response. Inflammasomes are multimeric protein complexes that induce a pro-inflammatory response to combat pathogens. Here we show that C. burnetii fails to induce a strong activation of the non-canonical inflammasome, independently of its type IVB secretion system. However, the pathogen is unable to prevent external activation of the non-canonical inflammasome, which subsequently results in a reduction of the bacterial burden. Importantly, the acylation pattern of lipid A was identified to be involved in avoiding the activation of the non-canonical inflammasome. C. burnetii harbors a tetra-acylated lipid A. Modification of the C. burnetii lipid A to penta-/hexa-acylation resulted in increased secretion of IL1{beta} and reduced bacterial load. Together, these results suggest that the acylation pattern of lipid A constitutes an important immune evasion strategy of C. burnetii by failing to activate the non-canonical inflammasome. In addition, evidence was provided that oxygen limitation arrests activation of the NLRP3 inflammasome in murine BMDM, which might prevent efficient elimination of bacteria under hypoxic conditions, such as in granulomas or in inflamed tissue. AUTHOR SUMMARYSeveral pathogens have evolved mechanisms to persist in the human host, which allows reoccurring or late onset of infection. The human innate immune system has therefore established several pathways, including the inflammasome, to prevent bacterial survival. Here we show that the obligate intracellular pathogen Coxiella burnetii, the causative agent of Q fever, prevents detection by the non-canonical NLRP3 inflammasome. This is mediated by the acylation pattern of its lipid A. Altering this acylation pattern allows activation of the inflammasome and, consequently, improved clearance of the pathogen. This information opens new avenues to target the immune response to C. burnetii infection with the goal to eliminate the bacteria and thereby prevent disease.