Editorial: New insights in Chlamydia: host interactions and pathogenesis

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Editorial on the Research Topic
New insights in Chlamydia: host interactions and pathogenesis Chlamydia are ancient and successful pathogens, evolutionary distinct from most bacteria and highly adapted to an intracellular lifestyle.To propagate, Chlamydia deploy a plethora of resources oriented to fulfill different steps of their pathogenic strategy, including infection and invasion of their host cells, the transition from infectious elementary bodies to replicative reticulate bodies, establishing an intracellular replicative niche inside a membrane-enclosed compartment (the "inclusion"), transition back to elementary bodies and finally, exit of the host cell.Each of these steps involves complex and poorly understood interactions with their hosts.
As obligate intracellular pathogens, Chlamydia have evolved many strategies to acquire nutrients and manipulate cell pathways to evade the anti-bacterial responses elicited by the host.Technical advances in imaging, high-throughput "omics", sequencing, and genetic tools have contributed to unraveling some of the chlamydial adaptive mechanisms and virulence factors.The ability to manipulate the chlamydial genome, which has been an unreachable challenge until only a few years ago, opened the door to elucidate, at the molecular level, the chlamydial factors relevant for the intracellular lifestyle, the pathogenic mechanisms, and immune evasion that these bacteria use to establish acute or persistent infections.Discovering how Chlamydia exploit host cell signaling, vesicular transport, and metabolism will help to unravel obligate intracellular bacterial survival mechanisms.Gathering recent breakthroughs in Chlamydia biology, pathogenesis, interactions with host cells, strategies for intracellular survival, persistence, and bacterial mechanism for immune response evasion constitutes a key platform for developing novel preventive and therapeutic anti-chlamydial approaches, including vaccines.A detailed assessment of bacterial proteins, effectors and enzymes involved in any step of Chlamydia development (cell invasion, inclusion development, replication and exit from host cells) is crucial for understanding the rampant success of Chlamydia intracellular lifestyle.Moreover, the characterization of Chlamydia persistence is critical for expanding current information about chronic infections and relapse after treatment.In this context, uncovering the molecular basis of Chlamydia-host interactions opens the door to identifying novel targets control chlamydial infections.Furthermore, studies to increase available data about chlamydial strategies to subvert adaptive and innate immune responses certainly will contribute to designing preventive vaccines.
In this Research Topic, seven papers address different aspects and new developments in the Chlamydia-Host interactions and pathogenesis field.
Triboulet et al. demonstrated that the Chlamydia trachomatiss protein CT295 is a phosphoglucomutase that mediates the conversion of glucose-1-phosphate into glucose-6-phosphate in the lumen of the chlamydial inclusion.This reaction plays a crucial role in the catabolism of glycogen molecules that accumulate in the inclusion lumen of C. trachomatis, C. muridarum, and C. suis.Interestingly, the authors identified a type three secretion (T3S) signal sequence in CT295 recognized by the T3S machinery of Shigella.Thus, to catabolize accumulated glycogen, CT295 chlamydial phosphoglucomutase may access the inclusion lumen via the chlamydial T3S machinery.
Pereira et al. studied the role of CteG, a previously described T3S effector of C. trachomatis shown to localize in the plasma membrane at late stages post-infection.Taking advantage of a CteG-null mutant, these authors observed that lack of CteG resulted in a defective chlamydial lytic exit from the host cell.A plasmid expressing CteG can rescue the normal phenotype.Thus, this study identified the first chlamydial T3S effector involved in lytic exit from the host cell.
Wang et al. contributed a review article addressing the role of tryptophan in C. trachomatis persistence.In this review, the authors compiled relevant findings related to critical aspects of persistent Chlamydia, including the biosynthesis and regulation of tryptophan in the host cell, the influence of tryptophan on C. trachomatis infection, and the relationship of C. trachomatis persistence with the tryptophan/IFNɣ axis.
Gravitte et al. investigated the impact of the hormonal environment in the Chlamydia muridarum infection in vivo.These investigators used ovariectomized mice to study how the administration of estrogen influences the progression of C. muridarum in vaginal infections and the immune response against this pathogen.Also, these authors used mice knock-outs for estrogen receptors ERa and ERb to investigate the impact of these receptors on C. muridarum infection and immune response.The main findings of this study indicated that the hormonal environment altered T cell recruitment and IFNƐ production in the genital tract of both infected ovariectomized and sham mice.Additionally, the lack of ERa impaired the shedding of C. muridarum and resulted in faster clearance of the infection, which correlated with an increased number of regulatory T-cells and higher expression of IFNƐ at early times post-infection in these mice.
Wang and Wang contributed a review article focused on the role of leukemia inhibitory factor (LIF) in chlamydial pathogenesis.LIF is a member of the IL-6 cytokine family that is induced by C. trachomatis infection.This review addresses the biology and physiological role of LIF and its receptor (LIFR) and analyzes the potential effects of LIF/LIFR-mediated signaling in C. trachomatis pathogenesis.The authors found that the available evidence indicates that the production of LIF aims to maintain epithelial homeostasis and tissue repair in the context of C. trachomatis infection.However, the prolonged LIF/LIFR-mediated signaling results in a harmful transformation of the microenvironment of the fallopian tube and the cellular composition of the epithelium, which may lead to an increased risk of infertility, ectopic pregnancy, and cancer.
Caven et al. performed a transcriptomic analysis of Chlamydiainfected epithelial cells and found that target genes of the host protein YAP, a transcriptional coactivator involved in cell proliferation, wound healing, and fibrosis, are induced during chlamydial infection.These findings correlated with increased nuclear translocation of YAP and de novo protein synthesis during mid-cycle infection.The evidence presented in this manuscript supports a Chlamydia-directed process resulting in alterations of the transcriptome of infected cells potentially linked to chlamydial fibrosis and sequelae.
Jiang et al. researched if pyroptosis, previously found to be induced during Chlamydia infection, impacts chlamydial growth.These authors found that C. trachomatis L2-infected RAW 264.7 mouse macrophages underwent pyroptosis accompanied by caspase-1, caspase-11, and gasdermin D activation.Additionally, the results of this manuscript show that pyroptosis induced by C. trachomatis resulted in significant inhibition of intracellular chlamydial growth and that the inactivation of caspase-1, caspase-11, or gasdermin D rescued bacterial yields.These findings support the idea that pyroptosis may act as an intrinsic mechanism of the host to restrict C. trachomatis intracellular growth.
The understanding of Chlamydia-host interactions and pathogenesis is crucial not only for elucidating the microbiology of these intriguing bacteria but also a path for discovering host cell responses and for the design of evidence-based strategies, to mitigate the impact of chlamydial infections on human health.This Research Topic gathers relevant and original discoveries about new bacterial effectors and mechanisms of invasion and host cell exit.In addition, it contains new data about the hijacking of host signaling and metabolism as well as bacterial mechanisms of evasion of host innate and adaptive immune response.Altogether, the findings collected in this Research Topic make valuable contributions aimed toward a better understanding of Chlamydial-host interactions.