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Chlamydia trachomatis (Ctr) can persist over extended times within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma (IFN-γ) released by immune cells as a mechanism of immune defence. IFN-γ activates the catabolic depletion of L-tryptophan (Trp) via indoleamine-2,3-dioxygenase (IDO), resulting in persistent Ctr . Here, we show that IFN-γ induces the downregulation of c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued Ctr from IFN-γ-induced persistence in cell lines and human fallopian tube organoids. Trp concentrations control c-Myc levels most likely via the PI3K-GSK3β axis. Unbiased metabolic analysis revealed that Ctr infection reprograms the host cell tricarboxylic acid (TCA) cycle to support pyrimidine biosynthesis. Addition of TCA cycle intermediates or pyrimidine/purine nucleosides to infected cells rescued Ctr from IFN-γ-induced persistence. Thus, our results challenge the longstanding hypothesis of Trp depletion through IDO as the major mechanism of IFN-γ-induced metabolic immune defence and significantly extends the understanding of the role of IFN-γ as a broad modulator of host cell metabolism.

Microbe-induced meningoencephalitis/meningitis is a life-threatening infection of the central nervous system (CNS) that occurs when pathogens are able to cross the blood-brain barrier (BBB) and gain access to the CNS. The BBB consists of highly specialized brain endothelial cells that exhibit specific properties to allow tight regulation of CNS homeostasis and prevent pathogen crossing. However, during meningoencephalitis/meningitis, the BBB fails to protect the CNS. Modeling the BBB remains a challenge due to the specialized characteristics of these cells. In this review, we cover the induced pluripotent stem cell-derived, brain-like endothelial cell model during host-pathogen interaction, highlighting the strengths and recent work on various pathogens known to interact with the BBB. As stem cell technologies are becoming more prominent, the stem cell-derived, brain-like endothelial cell model has been able to reveal new insights which remain challenging with other cell-based models consisting of primary human brain endothelial cells and immortalized human brain endothelial cell lines.

Interferon-γ (IFN-γ) is an immunoregulatory cytokine essential for cellular immunity against intracellular pathogens, including Chlamydia . Interferon-stimulated gene (ISG) 15, a member of the ubiquitin family, contributes to host resistance to viral and bacterial infections. ISG15 can exist either in an unconjugated form or covalently attached to host proteins through a process known as ISGylation. Here, we show that infection with Chlamydia trachomatis (Ct) induces the expression and secretion of ISG15 in human primary cells and mouse female genital tract (FGT) organoids. ISG15 secretion by genital tract epithelial cells resulted in increased IFN-γ release from natural killer (NK) cells. The production of IFN-γ by NK cells in response to ISG15 was completely abolished in NK cells lacking the interleukin-18 receptor alpha (IL-18Ra), demonstrating a co-stimulatory effect of ISG15 with IL-18 in enhancing IFN-γ release. ISG15 was secreted into the FGT and was involved in controlling bacterial load in a murine infection model. Furthermore, ISG15 reduced macrophage responsiveness to IFN-γ as an M1-polarizing signal for pro-inflammatory responses, potentially “shielding” macrophages from excessive IFN-γ. Evidence of uterine horn pathology and reduced IL-10 levels in the FGT of infected ISG15 −/− mice further supports a critical dual function of ISG15 in controlling chlamydial infection and modulating the resulting inflammatory responses.

Coxsackievirus B3 (CVB3) is a significant human pathogen that is commonly found worldwide. CVB3 among other enteroviruses, are the leading causes of aseptic meningo-encephalitis which can be fatal especially in young children. How the virus gains access to the brain is poorly-understood, and the host-virus interactions that occur at the blood-brain barrier (BBB) is even less-characterized. The BBB is a highly specialized biological barrier consisting primarily of brain endothelial cells which possess unique barrier properties and facilitate the passage of nutrients into the brain while restricting access to toxins and pathogens including viruses. To determine the effects of CVB3 infection on the BBB, we utilized a model of human induced-pluripotent stem cell-derived brain-like endothelial cells (iBECs) to ascertain if CVB3 infection may alter barrier cell function and overall survival. In this study, we determined that these iBECs indeed are susceptible to CVB3 infection and release high titers of extracellular virus. We also determined that infected iBECs maintain high transendothelial electrical resistance (TEER) during early infection despite possessing high viral load. TEER progressively declines at later stages of infection. Interestingly, despite the high viral burden and TEER disruptions at later timepoints, infected iBEC monolayers remain intact, indicating a low degree of late-stage virally-mediated cell death, which may contribute to prolonged viral shedding. We had previously reported that CVB3 infections rely on the activation of transient receptor vanilloid potential 1 (TRPV1) and found that inhibiting TRPV1 activity with SB-366791 significantly limited CVB3 infection of HeLa cervical cancer cells. Similarly in this study, we observed that treating iBECs with SB-366791 significantly reduced CVB3 infection, which suggests that not only can this drug potentially limit viral entry into the brain, but also demonstrates that this infection model could be a valuable platform for testing antiviral treatments of neurotropic viruses. In all, our findings elucidate the unique effects of CVB3 infection on the BBB and shed light on potential mechanisms by which the virus can initiate infections in the brain.

In recent years, substantial progress has been made in the understanding of the intracellular lifestyle of Chlamydia trachomatis and how the bacteria establish themselves in the human host. As an obligate intracellular pathogenic bacterium with a strongly reduced coding capacity, C. trachomatis depends on the provision of nutrients from the host cell. In this Review, we summarize the current understanding of how C. trachomatis establishes its intracellular replication niche, how its metabolism functions in the host cell, how it can defend itself against the cell autonomous and innate immune response and how it overcomes adverse situations through the transition to a persistent state. In particular, we focus on those processes for which a mechanistic understanding has been achieved.In this Review, Stelzner, Vollmuth and Rudel summarize current knowledge of Chlamydia trachomatis intracellular replication, its metabolism within the host cell and how it defends against host cell autonomous and innate immune responses, as well as its transition to a persistence state.

Quercetin, one of the major natural flavonoids, has demonstrated great pharmacological potential as an antioxidant and in overcoming drug resistance. However, its low aqueous solubility and poor stability limit its potential applications. Previous studies suggest that the formation of quercetin-metal complexes could increase quercetin stability and biological activity. In this paper, we systematically investigated the formation of quercetin-iron complex nanoparticles by varying the ligand-to-metal ratios with the goal of increasing the aqueous solubility and stability of quercetin. It was found that quercetin-iron complex nanoparticles could be reproducibly synthesized with several ligand-to-iron ratios at room temperature. The UV-Vis spectra of the nanoparticles indicated that nanoparticle formation greatly increased the stability and solubility of quercetin. Compared to free quercetin, the quercetin-iron complex nanoparticles exhibited enhanced antioxidant activities and elongated effects. Our preliminary cellular evaluation suggests that these nanoparticles had minimal cytotoxicity and could effectively block the efflux pump of cells, indicating their potential for cancer treatment.

Obligate intracellular bacteria such as Chlamydia trachomatis undergo a complex developmental cycle between infectious, non-replicative elementary-body and non-infectious, replicative reticulate-body forms. Elementary bodies transform to reticulate bodies shortly after entering a host cell, a crucial process in infection, initiating chlamydial replication. As Chlamydia fail to replicate outside the host cell, it is unknown how the replicative part of the developmental cycle is initiated. Here we show, using a cell-free approach in axenic media, that the uptake of glutamine by the bacteria is crucial for peptidoglycan synthesis, which has a role in Chlamydia replication. The increased requirement for glutamine in infected cells is satisfied by reprogramming the glutamine metabolism in a c-Myc-dependent manner. Glutamine is effectively taken up by the glutamine transporter SLC1A5 and metabolized via glutaminase. Interference with this metabolic reprogramming limits the growth of Chlamydia . Intriguingly, Chlamydia failed to produce progeny in SLC1A5-knockout organoids and mice. Thus, we report on the central role of glutamine for the development of an obligate intracellular pathogenic bacterium and the reprogramming of host glutamine metabolism, which may provide a basis for innovative anti-infection strategies. This study describes the mechanism by which Chlamydia trachomatis reprogrammes host glutamine metabolism in a c-Myc-dependent manner. The authors show that glutamine uptake via the SLC15A transporter and glutaminolysis are crucial for peptidoglycan synthesis and Chlamydia replication.

Epidemiological studies provide the first indications of a connection between cervical and ovarian cancer and infections with Chlamydia trachomatis . Chlamydia is the most common bacterial cause of sexually transmitted diseases. These obligate intracellular bacteria manipulate their host cells to support progeny formation. In this article, we present possible mechanisms that allow the bacteria to survive in the host cell, but at the same time may contribute to the development of cancer.

A Correction to this paper has been published: https://doi.org/10.1038/s41564-021-00874-3.

Interferon-[gamma] (IFN-[gamma]) is an immunoregulatory cytokine essential for cellular immunity against intracellular pathogens, including Chlamydia. Interferon-stimulated gene (ISG) 15, a member of the ubiquitin family, contributes to host resistance to viral and bacterial infections. ISG15 can exist either in and unconjugated form or covalently attached to host proteins through a process known as ISGylation. Here, we show that infection with Chlamydia trachomatis (Ct) induces the expression and secretion of ISG15 in human primary cells and mouse female genital tract (FGT) organoids. ISG15 secretion by genital tract epithelial cells resulted in increased IFN-[gamma] release from natural killer (NK) cells. The production of IFN-[gamma] by NK cells in response to ISG15 was completely abolished in NK cells lacking the interleukin-18 receptor alpha (IL-18Ra), demonstrating a co-stimulatory effect of ISG15 with IL-18 in enhancing IFN-[gamma] release. ISG15 was secreted into the FGT and was involved in controlling bacterial load in a murine infection model. Furthermore, ISG15 reduced macrophage responsiveness to IFN-[gamma] as an M1-polarizing signal for pro-inflammatory responses, potentially \"shielding\" macrophages from excessive IFN-[gamma]. Evidence of uterine horn pathology and reduced IL-10 levels in the FGT of infected ISG15.sup.-/- mice further supports a critical dual function of ISG15 in controlling chlamydial infection and modulating the resulting inflammatory responses.