Rickettsia heilongjiangensis suppresses RIPK1 kinase-mediated host cell death during the infection.

Spotted fever group Rickettsia (SFGR) poses a significant challenge in the field of tick-borne diseases, characterized by its obligate intracellular lifestyle and its ability to disrupt various host cellular pathways. A deeper understanding of Rickettsia's interactions with immune signaling is crucial for the development of novel therapeutic strategies. While previous research has shown that SFGR infection manipulates host cell death responses, the specific effects on receptor-interacting protein kinase 1 (RIPK1)-mediated multiple cell death pathways-collectively referred to as PANoptosis-remain poorly understood. In this study, we reveal that infection with Rickettsia heilongjiangensis suppresses RIPK1 kinase-dependent apoptosis and necroptosis in human microvascular endothelial cells (HMEC-1). However, mitochondria-dependent apoptosis during the late stages of infection is essential for bacterial replication. Interestingly, inhibition of caspase-8 does not sensitize Rickettsia-infected host cells to necroptosis. Transcriptomic analysis further reveals that Rickettsia infection upregulates the host tumor necrosis factor (TNF) and NF-κB signaling pathways, which subsequently suppress RIPK1 kinase activity and contribute to the inhibition of host cell death. These findings provide new insights into the molecular mechanisms by which Rickettsia evades host defenses.