Abstract
The ability of Coxiella burnetii to modulate host cell death may be a critical factor in disease development. In this study, human monocytic THP-1 cells were used to examine the ability of C. burnetii Nine Mile phase II (NMII) to modulate apoptotic signaling. Typical apoptotic cell morphological changes and DNA fragmentation were detected in NMII infected cells at an early stage of infection. FACS analysis using Annexin-V-PI double staining showed the induction of a significant number of apoptotic cells at an early stage of NMII infection. Double staining of apoptotic cell DNA and intracellular C. burnetii indicates that NMII infected cells undergoing apoptosis. Interestingly, caspase-3 was not cleaved in NMII infected cells and the caspase-inhibitor Z-VAD-fmk did not prevent NMII induced apoptosis. Surprisingly, the caspase-3 downstream substrate PARP was cleaved in NMII infected cells. These results suggest that NMII induces apoptosis during an early stage of infection through a caspase-independent pathway in THP-1 cells. In addition, NMII-infected monocytes were unable to prevent exogenous staurosporine-induced apoptotic death. Western blot analysis indicated that NMII infection induced the translocation of AIF from mitochondria into the nucleus. Cytochrome c release and cytosol-to-mitochondrial translocation of the pore-forming protein Bax in NMII infected cells occurred at 24 h post infection. These data suggest that NMII infection induced caspase-independent apoptosis through a mechanism involving cytochrome c release, cytosol-to-mitochondrial translocation of Bax and nuclear translocation of AIF in THP-1 monocytes. Furthermore, NMII infection increased TNF-α production and neutralization of TNF-α in NMII infected cells partially blocked PARP cleavage, suggesting TNF-α may play a role in the upstream signaling involved in NMII induced apoptosis. Antibiotic inhibition of C. burnetii RNA synthesis blocked NMII infection-induced PARP activation. These results suggest that both intracellular C. burnetii replication and secreted TNF-α contribute to NMII infection-triggered apoptosis during an early stage of infection.
Highlights
Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes acute Q fever and chronic infections in humans [1]
The results indicated that Nine Mile phase II (NMII) were able to infect THP-1 cells
In order to understand whether C. burnetii can modulate host cell death, human monocytic THP-1 cells were used to examine the ability of C. burnetii NMII to modulate host cell apoptotic signaling
Summary
Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes acute Q fever and chronic infections in humans [1]. Acute Q fever manifests as febrile illness, atypical pneumonia or hepatitis that usually is self-limiting or effectively treated by antibiotics. C. burnetii infections in immunocompromised persons, such as HIV or TB patients and pregnant women often develop into chronic disease [2]. Chronic Q fever is a severe, sometimes fatal disease and patients have very limited clinical benefit from various antibiotics regimens [1,3]. The heart is the most frequently involved organ in patients with chronic Q fever and endocarditis is the most common manifestation. The highly infectious nature of C. burnetii and its hardiness in adverse environmental conditions make the organism potentially useful in bioterrorism and biological warfare [4]
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