Abstract
Leptospirosis is a global zoonotic infectious disease caused by pathogenic Leptospira species. Leptospire-induced macrophage apoptosis through the Fas/FasL-caspase-8/3 pathway plays an important role in the survival and proliferation of the pathogen in hosts. Although, the release of mitochondrial apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in leptospire-infected macrophages has been described, the mechanisms linking caspase and mitochondrion-related host-cell apoptosis has not been determined. Here, we demonstrated that leptospire-infection induced apoptosis through mitochondrial damages in macrophages. Apoptosis was caused by the mitochondrial release and nuclear translocation of AIF and/or EndoG, leading to nuclear DNA fragmentation. However, the mitochondrion-related CytC-caspase-9/3 pathway was not activated. Next, we found that the release and translocation of AIF and/or EndoG was preceded by the activation of the BH3-interacting domain death agonist (Bid). Furthermore, our data demonstrated that caspase-8 was activated during the infection and caused the activation of Bid. Meanwhile, high reactive oxygen species (ROS) trigged by the infection caused the dephosphorylation of Akt, which also activated Bid. In conclusion, Bid-mediated mitochondrial release of AIF and/or EndoG followed by nuclear translocation is a major mechanism of leptospire- induced apoptosis in macrophages, and this process is modulated by both caspase-8 and ROS-Akt signal pathways.
Highlights
Pathogenic Leptospira species are the causative agents of leptospirosis, a world-wide zoonotic infectious disease (Bharti et al, 2003)
The results presented in this study indentify the activation of BH3-interacting domain death agonist (Bid)-apoptosis-inducing factor (AIF)/ endonuclease G (EndoG) as a novel mechanism by which pathogenic Leptospira species induce apoptosis in macrophages during an infection
An multiplicity of infection (MOI) of 100 caused maximal early apoptosis in both J774A.1 and THP-1 cells (Figure 1A), and when the macrophages were infected with an MOI of 100, apoptosis was maximal at 4 h (Figure 1B)
Summary
Pathogenic Leptospira species are the causative agents of leptospirosis, a world-wide zoonotic infectious disease (Bharti et al, 2003). Macrophages and neutrophils play important roles in the innate immunity against microbial infections through their ability to phagocytose pathogens. In contrast to many other bacterial pathogens, while both of these phagocytic cells are able to phagocytose leptospires, only macrophages are able to kill intracellular leptospires (Davis et al, 2009). Phagocytosis by macrophages plays a critical role in the defense against leptospiral infection of individuals that lack acquired immunity. The ability to defend against phagocytosis by macrophages contributes to the virulence of Leptospira species (Merien et al, 1997; Xue et al, 2010, 2013)
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