Chlamydia psittaci inclusion membrane protein CPSIT_0842 induces macrophage apoptosis through MAPK/ERK-mediated autophagy

Chlamydia psittaci, a multi-host zoonotic pathogen(Chen et al., 2020), primarily infects and causes respiratory and digestive tract disease in poultry(Gedye et al., 2018). This bacterium can also cause abortion in mammals such as cattle and sheep and reduce the survival rate of their young(Pantchev et al., 2010). Thus, C. psittaci causes appreciable economic damage to the livestock farming industry. Humans who inhale aerosols emanating from the feces and urine of C. psittaci-infected poultry, or come in close contact with other contaminated excretions, can develop respiratory infections and bacteremia, known clinically as psittacosis or ornithosis(Hogerwerf et al., 2017). Without proper treatment, these infections can become persistent(Wu et al., 2016). As a Gram-negative obligate intracellular bacterium, Chlamydia sp. alternates between two developmental stages, the elementary body (EB) and the reticulate body (RB). After adhering to the surface of a eukaryotic cell, the infectious EB is internalized and subsequently differentiates into an intracellular replicative RB in a parasitophorous vacuole called an inclusion. The RB then reproduces by binary fission and asynchronously differentiates back into the EB form(Omsland et al., 2014). After undergoing several rounds of reproduction, environmentally-resistant EBs, which have differentiated from RBs, accumulate within the inclusion until they are released from host cells by cell lysis or extrusion(Hybiske and Stephens, 2007; Jungas et al., 2004).

During early infection, inclusions actively avoid fusing with lysosomes and traffic along microtubules to the peri-Golgi region, thus, preventing Chlamydia from being destroyed and ensuring its stable growth in host cells(Pokrovskaya et al., 2012). In the late stage of Chlamydia infection, the innate immune response is suppressed and the process of host cell damage and death is interrupted by inclusions, allowing Chlamydia to be released from fragmented cells and infect new neighboring cells(Bastidas et al., 2013). Thus, as a protective intracellular niche, inclusion bodies provide a favorable microenvironment for Chlamydia proliferation while evading the host innate immune response(Shaw et al., 2000). Inclusion membrane proteins (Incs) contain a bilobed hydrophobic domain of > 60 residues and are required to maintain the stability of inclusion membranes(Mueller et al., 2014). In the absence of a specific Inc, premature inclusion lysis is targeted by autophagolysosomes, triggering autophagic signaling and activating intrinsic apoptosis, which terminates the Chlamydia developmental cycle(Weber et al., 2017).

Autophagy and apoptosis are innate immune mechanisms, which are used by cells to eliminate infectious pathogens. Autophagy is a pro-survival strategy that delivers misfolded proteins, damaged organelles, and intracellular pathogens to lysosomes for degradation and recycling(Miller and Celli, 2016), whereas apoptosis is a form of programmed cell death. Intracellular pathogens, which are released from apoptotic bodies within infected cells, are captured and internalized by adjacent cells, promoting pathogen spread(Kumar and Derbigny, 2019). Autophagy and apoptosis are regulated by many common signal transduction pathways, which are induced by cellular stress and appear to cross-regulate each other(Marino et al., 2014). In most cases, autophagy precedes apoptosis. By inhibiting autophagosome fusion with the lysosome, caspase-dependent cell death is increased, indicating that autophagic flux plays a protective role(Doherty and Baehrecke, 2018). Chlamydia sp. have evolved a series of strategies to manipulate autophagy and apoptosis in infected cells to promote their survival(Byrne and Ojcius, 2004). These bacteria can actively inhibit host cell apoptosis in the early stage of infection and induce death or apoptosis in the late stage to complete the developmental cycle and promote EB spread(Verbeke et al., 2006; Wen et al., 2021). Research has shown that Chlamydia trachomatis accumulates in a vacuole of eukaryotic host cells during infection; however, the molecular mechanism by which it interferes with lysosomal fusion has not yet been elucidated(Huang and Brumell, 2014; Yasir et al., 2011).

Previous studies have shown that C. psittaci can infect and be transported by human macrophages to cause both local and systemic infection(Chen et al., 2019; Ferreri et al., 2009). Chlamydia sp. establish persistent infection by interfering with host macrophage apoptosis and autophagy pathways and there is evidence that the expression of chlamydial Incs correlates closely with these processes(Sixt et al., 2017; Weber et al., 2017). The Incs are poorly conserved among all Chlamydia sp.(Moore and Ouellette, 2014), and the role of Incs in autophagy or apoptosis during infection remains unknown(Mirrashidi et al., 2015). The C. psittaci inclusion membrane protein CPSIT_0842 possesses the same bilobed hydrophobic region structural characteristics as CPSIT_0844, CPSIT_0846, and CPSIT_0556, all of which are located in the inclusion body membrane (Supplementary Figure 2). Earlier studies showed that CPSIT_0844, CPSIT_0846, and CPSIT_0556 induce the expression of inflammatory cytokines(Wu et al., 2016) and regulate cell apoptosis(He et al., 2021; Tang et al., 2021), which may contribute to persistent infection(Chen et al., 2017; Ran et al., 2017). It has been established that C.-psittaci-infected macrophages die by apoptosis, which can be measured within 1 day of infection(Ojcius et al., 1998). In the present study, we assessed the role of the C. psittaci inclusion membrane protein CPSIT_0842 in macrophage autophagy and apoptosis. In addition, we investigated the potential signaling pathways involved in these processes.

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