Abstract
Tropheryma whipplei, the etiological agent of Whipple's disease, is an intracellular bacterium that infects macrophages. We previously showed that infection of macrophages results in M2 polarization associated with induction of apoptosis and interleukin (IL)-16 secretion. In patients with Whipple's disease, circulating levels of apoptotic markers and IL-16 are increased and correlate with the activity of the disease. To gain insight into the understanding of the pathophysiology of this rare disease, we examined the molecular pathways involved in T. whipplei-induced apoptosis of human macrophages. Our data showed that apoptosis induction depended on bacterial viability and inhibition of bacterial protein synthesis reduced the apoptotic program elicited by T. whipplei. Induction of apoptosis was also associated with a massive degradation of both pro- and anti-apoptotic mediators. Caspase-specific inhibition experiments revealed that initiator caspases 8 and 10 were required for apoptosis, in contrast to caspases 2 and 9, in spite of cytochrome-c release from mitochondria. Finally, the effector caspases 3 and 6 were mandatory for apoptosis induction. Collectively, these data suggest that T. whipplei induces apoptosis through the extrinsic pathway and that, beside M2 polarization of macrophages, apoptosis induction contributes to bacterial replication and represents a virulence trait of this intracellular pathogen.
Highlights
Whipple’s disease is a rare systemic chronic disease caused by the intracellular pathogen Tropheryma whipplei
To evaluate the effects of T. whipplei on monocyte-derived macrophage (MDM) apoptosis, cells were infected for 4 h with T. whipplei, washed to discard unbound bacteria and incubated for 24 and 48 h before Annexin V staining
To examine whether de novo T. whipplei protein synthesis was required for inducing apoptosis, MDM were infected with T. whipplei in the presence of the bacterial protein synthesis inhibitor, chloramphenicol
Summary
Whipple’s disease is a rare systemic chronic disease caused by the intracellular pathogen Tropheryma whipplei. This rod-shaped microorganism is a Gram-positive bacterium, classified in the Actinobacteria phylum. The intrinsic pathway is initiated from cellular stress signals and involves activation of Bcl-2-like pro-apoptotic proteins of the Bax group (Bax and Bak), which oligomerize and permeabilize the mitochondrial membrane, resulting in cytochrome-c release and initiator caspase activation through apoptosome assembly. Apoptosis can promote efficient pathogen clearance because the death of the host cell is generally associated with the death of the infecting agent. Our results showed that T. whipplei-induced macrophage apoptosis involved the repression of numerous anti-apoptotic mediators, cytochrome-c release from mitochondria, and caspase 8/10 and 3/6 activation, leading to IL-16 production and favoring bacterial replication
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