The transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.

Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

Ubiquitination is a commonly used post-translational modification (PTM) in eukaryotic cells, which regulates a wide variety of cellular processes, such as differentiation, apoptosis, cell cycle, and immunity. Because of its essential role in immunity, the ubiquitin network is a common target of infectious agents, which have evolved various effective strategies to hijack and co-opt ubiquitin signaling for their benefit. The intracellular pathogen Legionella pneumophila represents one such example; it utilizes a large cohort of virulence factors called effectors to modulate diverse cellular processes, resulting in the formation a compartment called the Legionella-containing vacuole (LCV) that supports its replication. Many of these effectors function to re-orchestrate ubiquitin signaling with distinct biochemical activities. In this review, we highlight recent progress in the mechanism of action of L. pneumophila effectors involved in ubiquitination and discuss their roles in bacterial virulence and host cell biology.

Listeria monocytogenes at the interface between ruminants and humans: A comparative pathology and pathogenesis review

The bacterium Listeria monocytogenes ( Lm) is widely distributed in the environment as a saprophyte, but may turn into a lethal intracellular pathogen upon ingestion. Invasive infections occur in numerous species worldwide, but most commonly in humans and farmed ruminants, and manifest as distinct forms. Of those, neuroinfection is remarkably threatening due to its high mortality. Lm is widely studied not only as a pathogen but also as an essential model for intracellular infections and host-pathogen interactions. Many aspects of its ecology and pathogenesis, however, remain unclear and are rarely addressed in its natural hosts. This review highlights the heterogeneity and adaptability of Lm by summarizing its association with the environment, farm animals, and disease. It also provides current knowledge on key features of the pathology and (molecular) pathogenesis of various listeriosis forms in naturally susceptible species with a special focus on ruminants and on the neuroinvasive form of the disease. Moreover, knowledge gaps on pathomechanisms of listerial infections and relevant unexplored topics in Lm pathogenesis research are highlighted.

Quantitative assessment of dry mouth in scrub typhus using salivary scintigraphy

Scrub typhus is an acute febrile illness caused by the intracellular pathogen Orientia tsutsugamushi. The clinical features include fever, myalgia, lymphadenopathy, and dry mouth. However, no studies have assessed the symptom of dry mouth in patients with scrub typhus. We investigated the pattern of salivary scintigraphy during the acute febrile state and compared it with any changes after treatment. Fourteen patients underwent both pre- and post-treatment salivary scintigraphy. Imaging analysis was conducted using radioactivity in the oral cavity, parotid glands, and submandibular glands. During the acute phase, the radioactivity in the oral cavity markedly decreased, while that in the parotid and submandibular glands was preserved. After treatment, radioactivity in the oral cavity showed a significant increase at 20-min, 40-min, and after wash-out. The ejection fraction (%) of the parotid glands also increased after treatment. In contrast, the radioactivity levels of the parotid and submandibular glands were not statistically different after treatment. Salivary scintigraphy indicated that insufficient saliva excretion from the salivary glands into the oral cavity was one reason for the dry mouth reported by patients with scrub typhus. In the future, salivary scintigraphy imaging could contribute to the evaluation of dry mouth in patients with scrub typhus.

Neuroprotective effects of some epigenetic modifying drugs’ on Chlamydia pneumoniae-induced neuroinflammation: A novel model

Chlamydia pneumoniae (Cpn) is a gram-negative intracellular pathogen that causes a variety of pulmonary diseases, and there is growing evidence that it may play a role in Alzheimer’s disease (AD) pathogenesis. Cpn can interact functionally with host histones, altering the host’s epigenetic regulatory system by introducing bacterial products into the host tissue and inducing a persistent inflammatory response. Because Cpn is difficult to propagate, isolate, and detect, a modified LPS-like neuroinflammation model was established using lyophilized cell free supernatant (CFS) obtained from infected cell cultures, and the effects of CFS were compared to LPS. The neuroprotective effects of Trichostatin A (TSA), givinostat, and RG108, which are effective on epigenetic mechanisms, and the antibiotic rifampin, were studied in this newly introduced model and in the presence of amyloid beta (Aβ) 1–42. The neuroprotective effects of the drugs, as well as the effects of CFS and LPS, were evaluated in Aβ-induced neurotoxicity using a real-time cell analysis system, total ROS, and apoptotic impact. TSA, RG108, givinostat, and rifampin all demonstrated neuroprotective effects in both this novel model and Aβ-induced neurotoxicity. The findings are expected to provide early evidence on neuroprotective actions against Cpn-induced neuroinflammation and Aβ-induced neurotoxicity, which could represent a new treatment option for AD, for which there are currently few treatment options.

Chlamydia pneumoniae-Induced Neuroinflammation Cell Model Using Lyophilized Cell-Free Supernatant v1

Chlamydia pneumoniae (Cpn) is a gram-negative intracellular pathogen that causes a variety of pulmonary diseases, and there is growing evidence that it may play a role in Alzheimer's disease (AD) pathogenesis. Cpn can interact functionally with host histones, altering the host's epigenetic regulatory system by introducing bacterial products into the host tissue and inducing a persistent inflammatory response. Because Cpn is difficult to propagate, isolate, and detect, a modified LPS-like neuroinflammation model was established using lyophilized cell free supernatant (CFS) obtained from infected cell cultures, and the effects of CFS were compared to LPS.

Proximity-Labeling Reveals Novel Host and Parasite Proteins at the Toxoplasma Parasitophorous Vacuole Membrane

Toxoplasma is an intracellular pathogen which resides and replicates inside a membrane-bound vacuole in infected cells. This vacuole is modified by both parasite and host proteins which participate in a variety of host-parasite interactions at this interface, including nutrient exchange, effector transport, and immune modulation.

Autophagy in Staphylococcus aureus Infection

Staphylococcus aureus is an invasive, facultative intracellular pathogen that can colonize niches in various host organisms, making it difficult for the host immune system to completely eliminate. Host autophagy is an intracellular clearance pathway involved in degrading S. aureus. Whereas the accessory gene regulatory system of S. aureus that controls virulence factors could resist the host immune defenses by evading and even utilizing autophagy. This article reviews the interaction between autophagy and S. aureus, providing insights on how to use these mechanisms to improve S. aureus infection control.

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

Role of acuK in Control of Iron Acquisition and Gluconeogenesis in Talaromyces marneffei

Talaromyces marneffei is a dimorphic pathogenic fungus causing opportunistic infection in immunocompromised patients. It is a facultative intracellular pathogen and is usually found inside the host macrophages during infection. Alternative carbons and iron are the important nutrients associated with intracellular survival and pathogenesis of T. marneffei. This study reported the importance of the transcription factor AcuK in control of gluconeogenesis and iron acquisition in T. marneffei. Deletion of acuK gene in T. marneffei resulted in retardation of growth and germination in both mold and yeast phases. Microscopically, ΔacuK showed double nuclei hyphae. However, the yeast cells showed normal morphology. The ΔacuK failed to grow in iron-limiting conditions. Additionally, it could not grow in a medium containing gluconeogenic carbon sources. Moreover, ΔacuK showed higher susceptibility to macrophage killing than the wild type. These results demonstrated that AcuK controlled both iron acquisition and gluconeogenesis, and it could contribute to the pathogenicity of this fungus.