Avoidance of the NLRP3 inflammasome by the stealth pathogen, coxiella burnetii

Authors: DELANEY, MARTHA - University Of Washington; DEN HARTIGH, ANDREAS - University Of Washington; CARPENTIER, SAMUEL - University Of Washington; BIRKLAND, TIMOTHY - University Of Washington; KNOWLES, DONALD - Retired ARS Employee; COOKSON, BRAD - University Of Washington; FREVERT, CHARLES - University Of Washington

Submitted to: Veterinary Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/21/2020
Publication Date: 12/28/2020
Citation: Delaney, M.A., Hartigh, A.D., Carpentier, S.J., Birkland, T.P., Knowles, D.P., Cookson, B.T., Frevert, C.W. 2020. Avoidance of the NLRP3 inflammasome by the stealth pathogen, coxiella burnetii. Veterinary Pathology. 58(4):624-642. https://doi.org/10.1177/0300985820981369.
DOI: https://doi.org/10.1177/0300985820981369

Interpretive Summary: Coxiella burnetii is a bacterial pathogen of both ruminant livestock and human beings, and most human Q Fever outbreaks have been blamed on ruminant livestock. Ruminant agriculture sustains coxiellosis losses in the millions of dollars per year due to abortions, abortion storms, weak offspring, and lost milk production during treatment. Human Q Fever can involve varying degrees of fever, aches and pains, pneumonia, hepatitis, adverse pregnancy outcomes, and endocarditis (potentially fatal swelling in the heart). A very large outbreak of both ruminant coxiellosis and human Q Fever in The Netherlands had costs exceeding 300 million Euros. One key component of both ruminant coxiellosis and human Q Fever is inflammation. We used cell culture and a mouse model of respiratory infection to show that C. burnetii primes but avoids detection by NLRP3 inflammasomes. Better understanding of how C. burnetii interferes with inflammatory processes and potetnial immune responses will be beneficial to the development of preventative and interventional therapies for ruminant coxiellosis and human Q fever.

Technical Abstract: Coxiella burnetii, a highly adapted obligate intracellular bacterial pathogen and the cause of the zoonosis Q fever, is a re-emerging public health threat. C. burnetii employs a Type IV secretion system (T4SS) to establish and maintain its intracellular niche and to modulate host immune responses including the inhibition of apoptosis, a form of caspase-mediated cell death. Interactions between C. burnetii and caspase-1-mediated inflammasomes are not fully elucidated. We show that C. burnetii does not activate caspase-1 during infection of mouse macrophages in vitro. C. burnetii-infected cells did not develop NLRP3 and ASC foci indicative of lack of cytosolic detection. C. burnetii is unable to inhibit pyroptosis and IL-1' secretion induced by potent inflammasome stimuli but rather enhanced these caspase-1-mediated effects. We found that C. burnetii upregulates pro-IL-1' and robustly primes NLRP3 inflammasomes via TLR2 and MyD88 signaling. As for wild-type C. burnetii, T4SS-deficient mutants primed and potentiated NLRP3 inflammasomes. We also developed an in vivo model of pulmonary infection in C57BL/6 mice. Mice deficient in NLRP3 or caspase-1/11 were similar to wild-type mice in the development and resolution of splenomegaly, histologic lesions and macrophage kinetics, but a suggestion of slightly higher pulmonary bacterial burdens at peak infection. Together these findings indicate that C. burnetii primes but avoids cytosolic detection by NLRP3 inflammasomes, which are not required for the clinical resistance of C57BL/6 mice. Determining mechanisms employed by C. burnetii to avoid cytosolic detection by NLRP3 inflammasomes will be beneficial to the development of preventative and interventional therapies for Q fever.