Activation Of Host Defense Mechanisms Research Articles

Kaolin Particle Film Protects Grapevine cv. Cabernet Sauvignon Against Downy Mildew by Forming Particle Film at the Leaf Surface, Directly Acting on Sporangia and Inducing the Defense of the Plant.

Downy mildew is a major threat to viticulture, leading to severe yield loss. The use of traditional copper-based fungicides is effective, but has adverse effects on the environment and human health, making it urgent to develop an environmentally friendly disease management program. Multi-functional kaolin particle film (KPF) is promising as an effective and safer treatment strategy, since this material lacks chemically active ingredients. In this study, ability of Kaolin particle film (KPF) pretreatment to protect grapevine leaves from Plasmopara viticola was tested and the mode of action of KPF was analyzed. KPF application reduced the disease severity and the development of intercellular hyphae. Additionally, there was reduced accumulation of H2O2 and malondialdehyde (MDA) with pretreatment. The observation of ultrastructure on the leaf surface showed KPF deposition and stomatal obstruction, indicating that KPF protected plants against disease by preventing the adhesion of pathogens to the leaf surface and blocking invasion through the stomata. KPF pretreatment also activated host defense responses, as evidenced by increased activities of anti-oxidative enzymes [superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT)] and defense-related enzymes [phenylalanine ammonia-lyase (PAL), chitinases, and β-1,3-glucanases], increased phytohormone signals [abscisic acid (ABA), salicylic acid (SA), and jasmonic acid (JA)] and the up-regulation of defense genes related to plant defense. Overall, these results demonstrate that KPF treatment counters grapevine downy mildew by protecting leaves and enhancing plant defense responses.

Zinc Oxide Nanoparticles Prime a Protective Immune Response in Galleria mellonella to Defend Against Candida albicans.

Purpose: Zinc oxide nanoparticles (ZnO-NPs) have exerted antimicrobial properties. However, there is insufficient evaluation regarding the in vivo antifungal activity of ZnO-NPs. This study aimed to investigate the efficacy and mechanism of ZnO-NPs in controlling Candida albicans in the invertebrate Galleria mellonella.Methods: Galleria mellonella larvae were injected with different doses of ZnO-NPs to determine their in vivo toxicity. Non-toxic doses of ZnO-NPs were chosen for prophylactic injection in G. mellonella followed by C. albicans infection. Then the direct in vitro antifungal effect of ZnO-NPs against C. albicans was evaluated. In addition, the mode of action of ZnO-NPs was assessed in larvae through different assays: quantification of hemocyte density, morphology observation of hemocytes, characterization of hemocyte aggregation and phagocytosis, and measurement of hemolymph phenoloxidase (PO) activity.Results: Zinc oxide nanoparticles were non-toxic to the larvae at relatively low concentrations (≤20 mg/kg). ZnO-NP pretreatment significantly prolonged the survival of C. albicans-infected larvae and decreased the fungal dissemination and burden in the C. albicans-infected larvae. This observation was more related to the activation of host defense rather than their fungicidal capacities. Specifically, ZnO-NP treatment increased hemocyte density, promoted hemocyte aggregation, enhanced hemocyte phagocytosis, and activated PO activity in larvae.Conclusion: Prophylactic treatment with lower concentrations of ZnO-NPs protects G. mellonella from C. albicans infection. The innate immune response primed by ZnO-NPs may be part of the reason for the protective effects. This study provides new evidence of the capacity of ZnO-NPs in enhancing host immunity and predicts that ZnO-NPs will be attractive for further anti-infection applications.

Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence.

Bacterial infection activates the innate immune system as part of the host’s defense against invading pathogens. Host response to bacterial pathogens includes leukocyte activation, inflammatory mediator release, phagocytosis, and killing of bacteria. An appropriate host response requires resolution. The resolution phase involves attenuation of neutrophil migration, neutrophil apoptosis, macrophage recruitment, increased phagocytosis, efferocytosis of apoptotic neutrophils, and tissue repair. Specialized Pro-resolving Mediators (SPMs) are bioactive fatty acids that were shown to be highly effective in promoting resolution of infectious inflammation and survival in several models of infection. In this review, we provide insight into the role of SPMs in active host defense mechanisms for bacterial clearance including a new mechanism of action in which an SPM acts directly to reduce bacterial virulence.

Skin inflammation activates intestinal stromal fibroblasts and promotes colitis.

Inflammatory disorders of the skin are frequently associated with inflammatory bowel diseases (IBDs). To explore mechanisms by which these organs communicate, we performed single-cell RNA-Seq analysis on fibroblasts from humans and mice with IBD. This analysis revealed that intestinal inflammation promoted differentiation of a subset of intestinal stromal fibroblasts into preadipocytes with innate antimicrobial host defense activity. Furthermore, this process of reactive adipogenesis was exacerbated if mouse skin was inflamed as a result of skin wounding or infection. Since hyaluronan (HA) catabolism is activated during skin injury and fibroblast-to-adipocyte differentiation is dependent on HA, we tested the hypothesis that HA fragments could alter colon fibroblast function by targeted expression of human hyaluronidase-1 in basal keratinocytes from mouse skin. Hyaluronidase expression in the skin activated intestinal stromal fibroblasts, altered the fecal microbiome, and promoted excessive reactive adipogenesis and increased inflammation in the colon after challenge with dextran sodium sulfate. The response to digested HA was dependent on expression of TLR4 by preadipocytes. Collectively, these results suggest that the association between skin inflammation and IBD may be due to recognition by mesenchymal fibroblasts in the colon of HA released during inflammation of the skin.

An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities.

Viral infectious diseases pose a great challenge to human health around the world. Type I interferons (IFN-Is) function as the first line of host defense and thus play critical roles during virus infection by mediating the transcriptional induction of hundreds of genes. Nevertheless, overactive cytokine immune responses also cause autoimmune diseases, and thus, tight regulation of the innate immune response is needed to achieve viral clearance without causing excessive immune responses. Emerging studies have recently uncovered that the ubiquitin system, particularly deubiquitinating enzymes (DUBs), plays a critical role in regulating innate immune responses. In this review, we highlight recent advances on the diverse mechanisms of human DUBs implicated in IFN-I signaling. These DUBs function dynamically to calibrate host defenses against various virus infections by targeting hub proteins in the IFN-I signaling transduction pathway. We also present a future perspective on the roles of DUB-substrate interaction networks in innate antiviral activities, discuss the promises and challenges of DUB-based drug development, and identify the open questions that remain to be clarified. Our review provides a comprehensive description of DUBs, particularly their differential mechanisms that have evolved in the host to regulate IFN-I-signaling-mediated antiviral responses.

Interplay between membrane active host defense peptides and heme modulates their assemblies and in vitro activity

In the emerging era of antimicrobial resistance, the susceptibility to co-infections of patients suffering from either acquired or inherited hemolytic disorders can lead to dramatic increase in mortality rates. Closely related, heme liberated during hemolysis is one of the major sources of iron, which is vital for both host and invading microorganisms. While recent intensive research in the field has demonstrated that heme exerts diverse local effects including impairment of immune cells functions, it is almost completely unknown how it may compromise key molecules of our innate immune system, such as antimicrobial host defense peptides (HDPs). Since HDPs hold great promise as natural therapeutic agents against antibiotic-resistant microbes, understanding the effects that may modulate their action in microbial infection is crucial. Here we explore how hemin can interact directly with selected HDPs and influence their structure and membrane activity. It is revealed that induced helical folding, large assembly formation, and altered membrane activity is promoted by hemin. However, these effects showed variations depending mainly on peptide selectivity toward charged lipids, and the affinity of the peptide and hemin to lipid bilayers. Hemin-peptide complexes are sought to form semi-folded co-assemblies, which are present even with model membranes resembling mammalian or bacterial lipid compositions. In vitro cell-based toxicity assays supported that toxic effects of HDPs could be attenuated due to their assembly formation. These results are in line with our previous findings on peptide-lipid-small molecule systems suggesting that small molecules present in the complex in vivo milieu can regulate HDP function. Inversely, diverse effects of endogenous compounds could also be manipulated by HDPs.

Rufomycin Exhibits Dual Effects Against Mycobacterium abscessus Infection by Inducing Host Defense and Antimicrobial Activities.

Nontuberculous mycobacterial pulmonary infection is often aggravated due to antibiotic resistance issues. There is a need for development of new drugs inducing both host immune responses and antimicrobial activities. This study shows that the rufomycins 4/5/6/7 (Rufomycin 4–7), which targets ClpC1 as a subunit of caseinolytic protein complex ClpC1/ClpP1/ClpP2 of mycobacteria, exhibits a dual effect in host innate defense and in vivo antimicrobial activities against a rough morphotype of Mycobacterium abscessus (Mabs-R), a clinically severe morphotype that causes hyperinflammation. Rufomycin 4–7 treatment showed antimicrobial effects against Mabs pulmonary infection in vivo and in macrophages. In addition, Rufomycin 4–7 significantly decreased inflammation, but enhanced the autophagy/lysosomal genes through upregulation of the nuclear translocation of transcription factor EB (TFEB). Furthermore, Rufomycin 4–7 treatment effectively inhibited mitochondrial damage and oxidative stresses in macrophages during Mabs-R infection. Collectively, Rufomycin 4–7-mediated dual effects inducing both antimicrobial activities and host immune defense might confer an advantage to treatment against Mabs-R infection.

Insights into Innate Immune Response Against SARS-CoV-2 Infection

Abstract The innate immune system is mandatory for the activation of antiviral host defense and eradication of the infection. In this regard, dendritic cells, natural killer cells, macrophages, neutrophils representing the cellular component, and cytokines, interferons, complement or Toll-Like Receptors, representing the mediators of unspecific response act together for both activation of the adaptive immune response and viral clearance. Of great importance is the proper functioning of the innate immune response from the very beginning. For instance, in the early stages of viral infection, the defective interferon response leads to uncontrolled viral replication and pathogen evasion, while hypersecretion during the later stages of infection generates hyperinflammation. This cascade activation of systemic inflammation culminates with cytokine storm syndrome and hypercoagulability state, due to a close interconnection between them. Thus an unbalanced reaction, either under- or over- stimulation of the innate immune system will lead to an uncoordinated response and unfavorable disease outcomes. Since both cellular and humoral factors are involved in the time-course of the innate immune response, in this review we aimed to address their gradual involvement in the antiviral response with emphasis on key steps in SARS-CoV-2 infection.

Capsule-dependent metabolic immunosuppression of host cells by Francisella tularensis

Abstract Francisella tularensis subsp. tularensis (Ftt) is a highly pathogenic, intracellular bacterium capable of replicating while avoiding detection by the host immune system. An O-antigen polysaccharide capsule has been identified as an important virulence factor involved in suppressing the immune response. Previous studies have shown that Ftt capsule limits the metabolic shift from oxidative phosphorylation to glycolysis needed for activation of host defense mechanisms. The specific mechanism by which Ftt capsule alters host metabolism is not fully understood but involves improvement of mitochondrial function. In this study, central metabolism in primary cell culture was mapped using targeted metabolomics following TLR stimulation and capsule treatment. Consistent with previous findings, capsule stimulated TCA cycle activity to increase mitochondrial respiration. Ftt capsule treatment did not inhibit increased glycolytic flux associated with TLR-induced metabolic activation. However, capsule limited accumulation of lactate and depletion of acetyl-CoA pools associated with TLR-driven uncoupling of glycolysis and the TCA cycle. These data point to capsule-dependent manipulation of pyruvate dehydrogenase, the enzyme responsible for converting pyruvate made during glycolysis into acetyl-CoA for utilization within the TCA-cycle. Together, these results demonstrate a novel mechanism by which a bacterial capsule can limit inflammation by maintaining coupling of central metabolic pathways.

Патогенетические аспекты терапии воспалительных заболеваний урогенитального тракта у женщин репродуктивного возраста

This paper discusses one of the important gynecological issues, inflammatory diseases of the urogenital tract caused by opportunistic microbes. The treatment and long-term control over these conditions are challenging and depend on their occurrence and high risk of complications. Impaired local anti-infectious protection is one of the risk factors of chronic inflammation. Since the disease may recur even after successful treatment, domestic and foreign authors increasingly focus on immunotherapy as a part of complex strategy and isolated entity. Local immunotherapy may prevent recurrences and activate host defense. This paper describes the management of two women with mixed infections. The first woman with chronic recurrent inflammation (cervicitis caused by U. urealyticum, vulvovaginal candidiasis, and aerobic vaginitis) in whom prior etiological therapy was ineffective received immunotherapy which resulted in long-term remission. The second woman with coexistent papillomavirus infection (genital warts) and bacterial vaginosis received immunotherapy and topical etiological treatment. As a result, clinical symptoms, the size and number of genital warts reduced which greatly facilitated their chemical destruction. KEYWORDS: genital tract, urogenital infections, papillomavirus infection, bacterial vaginosis, local immunity, biofilms. FOR CITATION: Letyaeva O.I., Ziganshin O.R. Pathogenic treatment of the inflammatory diseases of the urogenital tract in women of reproductive age. Russian Journal of Woman and Child Health. 2021;4(1):59–64. DOI: 10.32364/2618-8430-2021-4-1-59-64.

NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense.

Viral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid-inducible protein-I-like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms, including type I IFN induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. In this study, we show that NUDT21, an RNA-binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of viral dsRNA. We found that despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection in both human HeLa cells and mouse macrophage cell line RAW264.7 cells. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.

Inflammasome activation and evasion by bacterial pathogens.

Innate immune system plays an essential role in combating infectious diseases by recognizing invading pathogens and activating host defense response. Inflammasomes complexes are a central component of the cytosolic innate immune surveillance and are vital in host defense against bacterial pathogens. Bacterial products or pathogen-induced modifications in the intracellular environment are sensed by the inflammasome receptors that form complexes that serve as a platform for caspase-1-dependent or caspase-11-dependent induction of pyroptosis and secretion of cytokines, IL-1β and IL-18. However, several pathogenic bacteria have developed strategies to evade inflammasome activation. This review highlights the recent advances in the mechanism of inflammasome activation by bacterial pathogens and some of the bacterial evasion strategies of inflammasome activation.

The Microbiota and Gut-Related Disorders: Insights from Animal Models.

Over the past decade, the scientific committee has called for broadening our horizons in understanding host–microbe interactions and infectious disease progression. Owing to the fact that the human gut harbors trillions of microbes that exhibit various roles including the production of vitamins, absorption of nutrients, pathogen displacement, and development of the host immune system, particular attention has been given to the use of germ-free (GF) animal models in unraveling the effect of the gut microbiota on the physiology and pathophysiology of the host. In this review, we discuss common methods used to generate GF fruit fly, zebrafish, and mice model systems and highlight the use of these GF model organisms in addressing the role of gut-microbiota in gut-related disorders (metabolic diseases, inflammatory bowel disease, and cancer), and in activating host defense mechanisms and amending pathogenic virulence.

Interleukin-26 activates macrophages and facilitates killing of Mycobacterium tuberculosis

Tuberculosis-causing Mycobacterium tuberculosis (Mtb) is transmitted via airborne droplets followed by a primary infection of macrophages and dendritic cells. During the activation of host defence mechanisms also neutrophils and T helper 1 (TH1) and TH17 cells are recruited to the site of infection. The TH17 cell-derived interleukin (IL)-17 in turn induces the cathelicidin LL37 which shows direct antimycobacterial effects. Here, we investigated the role of IL-26, a TH1- and TH17-associated cytokine that exhibits antimicrobial activity. We found that both IL-26 mRNA and protein are strongly increased in tuberculous lymph nodes. Furthermore, IL-26 is able to directly kill Mtb and decrease the infection rate in macrophages. Binding of IL-26 to lipoarabinomannan might be one important mechanism in extracellular killing of Mtb. Macrophages and dendritic cells respond to IL-26 with secretion of tumor necrosis factor (TNF)-α and chemokines such as CCL20, CXCL2 and CXCL8. In dendritic cells but not in macrophages cytokine induction by IL-26 is partly mediated via Toll like receptor (TLR) 2. Taken together, IL-26 strengthens the defense against Mtb in two ways: firstly, directly due to its antimycobacterial properties and secondly indirectly by activating innate immune mechanisms.

Probiotic Properties of Escherichia coli Nissle in Human Intestinal Organoids.

Escherichia coli strain Nissle has been used as a probiotic and therapeutic agent for over a century. Reports suggest that Nissle protects mice from enterohemorrhagic E. coli (EHEC) O157:H7 strains; however, mice are not very susceptible to O157:H7 and are not accurate models for O157:H7 infection in humans. Also, Nissle is closely related to uropathogenic E. coli (UPEC) strain CFT073, suggesting that Nissle could have pathogenic potential. To assess the safety of and protection conferred by Nissle, we modeled infection in stem cell-derived human intestinal organoids (HIOs). HIOs replicate the structure and function of human intestinal tissue. HIOs have a lumen enclosed by a single cell layer of differentiated epithelium, which is surrounded by a diffuse mesenchymal layer. An epithelial barrier which excludes the luminal contents from the surrounding cell layers and medium develops. Nissle appeared to be nonpathogenic; 103 CFU were microinjected into the lumen, and after 3 days, 107 CFU were recovered and the epithelial barrier remained intact. In contrast, microinjected EHEC and UPEC bacteria destroyed the epithelial barrier. To assess the protection conferred by Nissle, HIOs microinjected with Nissle were challenged after 18 to 24 h with EHEC or UPEC. Preincubation with Nissle prevented the loss of the epithelial barrier function, the loss of E-cadherin expression, the increased production of reactive oxygen species, and apoptosis. Nissle did not replicate in the HIO coculture, while the pathogenic strains did replicate, suggesting that Nissle conferred protection via activation of host defenses and not by eliminating competing strains. Nissle was shown to be susceptible to some Shiga toxin phage, and Nissle lysogens could produce Shiga toxin.IMPORTANCE Probiotic, or beneficial, bacteria, such as E. coli Nissle, hold promise for the treatment of human disease. More study is needed to fully realize the potential of probiotics. Safety and efficacy studies are critically important; however, mice are poor models for many human intestinal diseases. We used stem cell-derived human intestinal organoid tissues to evaluate the safety of Nissle and its ability to protect from pathogenic E. coli bacteria. Nissle was found to be safe. Human intestinal tissues were not harmed by the Nissle bacteria introduced into the digestive tract. In contrast, pathogenic E. coli bacteria destroyed the intestinal tissues, and importantly, Nissle conferred protection from the pathogenic E. coli bacteria. Nissle did not kill the pathogenic E. coli bacteria, and protection likely occurred via the activation of human defenses. Human intestinal tissues provide a powerful way to study complex host-microbe interactions.

Evaluation of the susceptibility of Prunus rootstock genotypes to Armillaria and Desarmillaria species

Variation in susceptibility of 28 Prunus rootstock genotypes to the causal agents of Armillaria root rot, Armillaria mellea, A. solidipes, and Desarmillaria tabescens, were studied by conducting in vitro root screening assays. Root segments with wounded and intact periderm were placed next to and on the top of the fungal cultures. At day 21, the percent success of fungal penetration and the circumferential and longitudinal lengths of fungal growth were measured. A parallel investigation using the inoculated root segments was carried out to characterize the active host defense mechanisms involved, including anatomical responses in bark and wood. Overall, the success of penetration and the longitudinal and circumferential spread of Armillaria spp. and D. tabescens were significantly different among various Prunus rootstock genotypes. None of the tested rootstock genotypes were completely resistant to infection. However, plum and plum derived rootstocks, and some of the cherry genotypes were less susceptible to infection compared to the peach genotypes. The host’s ability to limit infection by Armillaria spp. and D. tabescens was not limited to a single mechanism but appeared to be regulated by several collective nonspecific host responses acting together. Differential levels of a series of non-specific coordinated events were triggered in Prunus genotypes such as the formation of new callus tissue on the root surface, a colored reaction zone, necrophylactic periderm, new cells, and new vascular cambium to compartmentalize the pathogen. The host responses were elevated in the genotypes with low level of infection as compared to highly infected genotypes.

Aspergillus fumigatus.

Humans inhale hundreds of Aspergillus fumigatus conidia daily. Conidia germinate and produce hyphae or mycelia that eventually form a colony. The recognition of A. fumigatus pathogen-associated molecular patterns (PAMPs) by the pattern-recognition receptors (PRRs) of innate immune cells induces the phagocytosis and killing of the fungus and cytokine signaling that regulates the activation of adaptive immune responses and epithelial host defense. Severe asthma with fungal sensitization (SAFS), allergic bronchial pulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), invasive pulmonary aspergillosis (IPA), and invasive bronchial aspergillosis (IBA) are some of the human diseases caused by Aspergillus species. A. fumigatus is able to evade the host’s innate immune system through the production of conidial hydrophobin (that can mask PAMPs on the cell wall) and melanin (which blocks the acidification of the phagosome and inhibits the NADPH oxidase complex responsible for the production of antifungal reactive oxygen species).

Phytophthora nicotianae Infection of Citrus Leaves and Host Defense Activation Compared to Root Infection.

Currently, little is known about the host pathogen interaction between Phytophthora spp. and citrus roots versus leaves. Therefore, we compared the molecular events occurring in citrus roots and leaves after zoospore inoculation with Phytophthora nicotianae. We analyzed the physical characteristics and genetic responses to P. nicotianae infection of leaves and roots for susceptible and tolerant citrus rootstocks to examine the potential for leaves to model root responses to P. nicotianae infection. Leaves responded faster and stronger to P. nicotianae infection than roots, and leaves showed greater differential response than roots. In addition to differences in hormonal responses, sugar, phospholipase D (PLD), and phospholipase A (PLA) involvement in the interaction between citrus and P. nicotianae was identified. This work, for the first time, creates a solid P. nicotianae zoospore infection protocol, reports P. nicotianae infection on citrus leaves through stomata, and provides evidence that different host organs respond to the pathogen differentially in timing and magnitude. This work identifies the hormones, sugars, pathogenesis-related genes, PLDs, and PLAs that are involved in the molecular events occurring in citrus under infection of P. nicotianae zoospore, and advances our understanding of the mechanisms underlying the interaction.

Fungal lesion length and expansion rate for the root pathogen Armillaria ostoyae in Douglas‐fir affecting root colonization and damage

AbstractPlant lesions affect disease impact, progression and host resistance. Root lesions caused by Armillaria ostoyae (Romagn.) Herink were inspected on 24‐ to 34‐year‐old planted Douglas‐fir (Pseudotsuga menziesii (Mirb.) Franco) pulled from the soil in five locations. Four hundred seventy‐nine lesions were measured for length (mm), expansion rate (mm/year) and lesion type. Lesion types were patch lesions on a root side, girdled lesions covering the root circumference and root collar lesions on the stem below ground. Non‐linear mixed modelling revealed that fungal lesion length at girdled and collar lesions increased but the expansion rate slowed as a power function of time, indicating increasing secondary inoculum and host resistance. Average fungal lesion expansion rate in girdled root and collar lesions was 127 mm the first year which then declined non‐linearly to 26 mm/year after 10 years. Fungal lesion length in patch lesions showed little change after the first year of infection. For girdled and collar lesions, fungal lesion length increased with tree size at the time of infection. Sites with a longer frost‐free period had shorter girdled root and stem lesions, probably because of more active host defence. Results indicate that mortality would be rare from one infection event. Furthermore, patch lesions pose a lower risk of mortality than other lesions because of a lower fungal lesion expansion rate and secondary inoculum. Tree size, lesion position, lesion type and fungal lesion expansion rate need to be considered when assessing the risk of lesions to individual tree survival. Techniques to minimize the disease impact are discussed.

HGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis

Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of GTPases and conveys host defense against intracellular bacteria and parasites. During infection, hGBP1 is recruited to pathogen-containing vacuoles, such as Chlamydia trachomatis inclusions, restricts pathogenic growth, and induces the activation of the inflammasome pathway. hGBP1 has a unique catalytic activity to hydrolyze guanosine triphosphate (GTP) to guanosine monophosphate (GMP) in two consecutive cleavage steps. However, the functional significance of this activity in host defense remains elusive. Here, we generate a structure-guided mutant that specifically abrogates GMP production, while maintaining fast cooperative GTP hydrolysis. Complementation experiments in human monocytes/macrophages show that hGBP1-mediated GMP production is dispensable for restricting Chlamydia trachomatis growth but is necessary for inflammasome activation. Mechanistically, GMP is catabolized to uric acid, which in turn activates the NLRP3 inflammasome. Our study demonstrates that the unique enzymology of hGBP1 coordinates bacterial growth restriction and inflammasome signaling.