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Metformin strengthens uroepithelial immunity against E. coli infection.

ABSTRACT: Urinary tract infection frequently caused by E. coli is one of the most common bacterial infections. Increasing antibiotic resistance jeopardizes successful treatment and alternative treatment strategies are therefore mandatory. Metformin, an oral antidiabetic drug, has been shown to activate macrophages in the protection against certain infecting microorganisms. Since epithelial cells often form the first line of defense, we here investigated the effect on uroepithelial cells during E. coli infection. Metformin upregulated the human antimicrobial peptides cathelicidin LL-37 and RNase7 via modulation of the TRPA1 channel and AMPK pathway. Interestingly, metformin stimulation enriched both LL-37 and TRPA1 in lysosomes. In addition, metformin specifically increased nitric oxide and mitochondrial, but not cytosolic ROS. Moreover, metformin also triggered mRNA expression of the proinflammatory cytokines IL1B, CXCL8 and growth factor GDF15 in human uroepithelial cells. The GDF15 peptide stimulated macrophages increased LL-37 expression, with increased bacterial killing. In conclusion, metformin stimulation strengthened the innate immunity of uroepithelial cells inducing enhanced extracellular and intracellular bacterial killing suggesting a favorable role of metformin in the host defense.

SUBMITTER: Majhi RK

PROVIDER: S-EPMC8479095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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<i>Lupinus mutabilis</i> Edible Beans Protect against Bacterial Infection in Uroepithelial Cells.

Project description:Lupinus mutabilis is a South American herb with edible beans, known to reduce serum glucose levels in diabetic patients. Furthermore, L. mutabilis contains phytochemicals known to decrease bacterial load. Based on the increased urinary tract infections experienced among patients with diabetes, we investigated the effect of L. mutabilis on bladder epithelial cells in the protection of E. coli infection during normal and high glucose concentrations. We did not observe any direct antibacterial effect by L. mutabilis extract. Instead we observed an influence on the host cells, with indirect impact on bacteria and their possibility of causing infection. L. mutabilis extract decreased adhesion to bladder epithelial cells of uropathogenic bacteria, including drug-resistant strains. Moreover, uroplakin1a, involved in adhesion, was downregulated while the antimicrobial peptide RNase 7 was upregulated in L. mutabilis treated cells irrespectively of glucose concentration. This supports an early effect fighting bacteria. Additionally, L. mutabilis prevented bacterial biofilm formation, which is used by bacteria to evade the immune system and antibiotics. In summary, L. mutabilis protects against bacterial infection in uroepithelial cells by preventing adhesion through alteration of the cell surface, increasing antimicrobial peptide expression, and reducing biofilm formation. Together, this promotes bacterial clearance, suggesting that L. mutabilis as extract or as a dietary item can contribute to the prevention of urinary tract infections, which is of importance in an era of increasing antibiotic resistance.

| S-EPMC6311276 | biostudies-literature

Perfluorooctane sulfonate affects intestinal immunity against bacterial infection.

Project description:Perfluorooctane sulfonate (PFOS) is an environmental contaminant that has been manufactured to be used as surfactants and repellents in industry. Due to long half-life for clearance and degradation, PFOS is accumulative in human body and has potential threat to human health. Previous studies have shown the development and function of immune cells can be affected by PFOS. Although PFOS has a high chance of being absorbed through the oral route, whether and how PFOS affects immune cells in the gut is unknown. Using mouse model of Citrobacter rodentium infection, we investigated the role of PFOS on intestinal immunity. We found at early phase of the infection, PFOS inhibited the expansion of the pathogen by promoting IL-22 production from the group 3 innate lymphoid cell (ILC3) in an aryl hydrocarbon receptor dependent manner. Nevertheless, persistent PFOS treatment in mice finally led to a failure to clear the pathogen completely. At late phase of infection, enhanced bacterial counts in PFOS treated mice were accompanied by increased inflammatory cytokines, reduced mucin production and dysbiosis, featured by decreased level of Lactobacillus casei, Lactobacillus johnsonii and increased E. coli. Our study reveals a deleterious consequence in intestinal bacterial infection caused by PFOS accumulation.

| S-EPMC5507904 | biostudies-other

Th9 Cells Drive Host Immunity against Gastrointestinal Worm Infection.

Project description:Type 2 inflammatory cytokines, including interleukin-4 (IL-4), IL-5, IL-9, and IL-13, drive the characteristic features of immunity against parasitic worms and allergens. Whether IL-9 serves an essential role in the initiation of host-protective responses is controversial, and the importance of IL-9- versus IL-4-producing CD4? effector T cells in type 2 immunity is incompletely defined. Herein, we generated IL-9-deficient and IL-9-fluorescent reporter mice that demonstrated an essential role for this cytokine in the early type 2 immunity against Nippostrongylus brasiliensis. Whereas T helper 9 (Th9) cells and type 2 innate lymphoid cells (ILC2s) were major sources of infection-induced IL-9 production, the adoptive transfer of Th9 cells, but not Th2 cells, caused rapid worm expulsion, marked basophilia, and increased mast cell numbers in Rag2-deficient hosts. Taken together, our data show a critical and nonredundant role for Th9 cells and IL-9 in host-protective type 2 immunity against parasitic worm infection.

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Complicated urinary tract infection is associated with uroepithelial expression of proinflammatory protein S100A8.

Project description:F344 rats chronically infected with Ureaplasma parvum develop two distinct profiles: asymptomatic urinary tract infection (UTI) and UTI complicated by struvite urolithiasis. To identify factors that affect disease outcome, we characterized the temporal host immune response during infection by histopathologic analysis and in situ localization of U. parvum. We also used differential quantitative proteomics to identify distinguishing host cellular responses associated with complicated UTI. In animals in which microbial colonization was limited to the mucosal surface, inflammation was indistinguishable from that which occurred in sham-inoculated controls, and the inflammation resolved by 72 h postinoculation (p.i.) in both groups. However, inflammation persisted in animals with microbial colonization that extended into the deeper layers of the submucosa. Proteome profiling showed that bladder tissues from animals with complicated UTIs had significant increases (P < 0.01) in proteins involved in apoptosis, oxidative stress, and inflammation. Animals with complicated UTIs (2 weeks p.i.) had the highest concentrations of the proinflammatory protein S100A8 (P <or= 0.005) in bladder tissues, and the levels of S100A8 positively correlated with those of proinflammatory cytokines GRO/KC (P <or= 0.003) and interleukin-1 alpha (P <or= 0.03) in urine. The bladder uroepithelium was a prominent cell source of S100A8-S100A9 in animals with complicated UTIs (2 weeks p.i.), which was not detected in animals with asymptomatic UTIs (2 weeks p.i.) or in any bladder tissues harvested at earlier p.i. time points. Based on these results, we surmise that invasive colonization of the bladder triggers chronic inflammation and immune dysregulation, which may be critical to struvite formation.

| S-EPMC2747944 | biostudies-literature

Mucosal Immunity of Puffer Fish against bacterial Infection

Project description:This study established immunological and particularly antibacterial proteins in the skin mucus of Obscure puffer against A. hydrophila infection. These proteins could be potential biomarkers to be studied for prevention of bacterial disease in fish. Overall, the study provides primary insights into the mucosal immune factors in the skin mucus of fish and recommends each protein for functional-based molecular studies.

2024-08-16 | PXD054382 | Pride

Employing Escherichia coli-derived outer membrane vesicles as an antigen delivery platform elicits protective immunity against Acinetobacter baumannii infection.

Project description:Outer membrane vesicles (OMVs) have proven to be highly immunogenic and induced an immune response against bacterial infection in human clinics and animal models. We sought to investigate whether engineered OMVs can be a feasible antigen-delivery platform for efficiently inducing specific antibody responses. In this study, Omp22 (an outer membrane protein of A. baumannii) was displayed on E. coli DH5?-derived OMVs (Omp22-OMVs) using recombinant gene technology. The morphological features of Omp22-OMVs were similar to those of wild-type OMVs (wtOMVs). Immunization with Omp22-OMVs induced high titers of Omp22-specific antibodies. In a murine sepsis model, Omp22-OMV immunization significantly protected mice from lethal challenge with a clinically isolated A. baumannii strain, which was evidenced by the increased survival rate of the mice, the reduced bacterial burdens in the lung, spleen, liver, kidney, and blood, and the suppressed serum levels of inflammatory cytokines. In vitro opsonophagocytosis assays showed that antiserum collected from Omp22-OMV-immunized mice had bactericidal activity against clinical isolates, which was partly specific antibody-dependent. These results strongly indicated that engineered OMVs could display a whole heterologous protein (~22?kDa) on the surface and effectively induce specific antibody responses, and thus OMVs have the potential to be a feasible vaccine platform.

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Project description:The mutation responsible for Duffy negativity, which impedes Plasmodium vivax infection, has reached high frequencies in certain human populations. Conversely, mutations capable of blocking the more lethal P. falciparum have not succeeded in malarious zones. Here we present an evolutionary-epidemiological model of malaria which demonstrates that if adaptive immunity against the most virulent effects of malaria is gained rapidly by the host, mutations which prevent infection per se are unlikely to succeed. Our results (i) explain the rarity of strain-transcending P. falciparum infection blocking adaptations in humans; (ii) make the surprising prediction that mutations which block P. falciparum infection are most likely to be found in populations experiencing low or infrequent malaria transmission, and (iii) predict that immunity against some of the virulent effects of P. vivax malaria may be built up over the course of many infections.

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Sp100 provides intrinsic immunity against human papillomavirus infection.

Project description:UnlabelledMost DNA viruses associate with, and reorganize, nuclear domain 10 (ND10) bodies upon entry into the host nucleus. In this study, we examine the roles of the ND10 components PML, Sp100, and Daxx in the establishment of human papillomavirus type 18 (HPV18) infection of primary human keratinocytes. HPV18 DNA or HPV18 quasivirus was introduced into primary human keratinocytes depleted of each ND10 protein by small interfering RNA technology, and genome establishment was determined by using a quantitative immortalization assay and measurements of viral transcription and DNA replication. Keratinocyte depletion of Sp100 resulted in a substantial increase in the number of HPV18-immortalized colonies and a corresponding increase in viral transcription and DNA replication. However, Sp100 repressed viral transcription and replication only during the initial stages of viral establishment, suggesting that Sp100 acts as a repressor of incoming HPV DNA.ImportanceThe intrinsic immune system provides a first-line defense against invading pathogens. Host cells contain nuclear bodies (ND10) that are important for antiviral defense, yet many DNA viruses localize here upon cell entry. However, viruses also disrupt, reorganize, and modify individual components of the bodies. In this study, we show that one of the ND10 components, Sp100, limits the infection of human skin cells by human papillomavirus (HPV). HPVs are important pathogens that cause many types of infection of the cutaneous and mucosal epithelium and are the causative agents of several human cancers. Understanding how host cells counteract HPV infection could provide insight into antimicrobial therapies that could limit initial infection.

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Project description:The central nervous system (CNS) is an immunologically specialized organ where restrictive barrier structures protect the parenchyma from inflammation and infection. This protection is important in preventing damage to non-renewable resident cell populations, such as neurons, responsible for functions ranging from executive to autonomic. Despite these barriers, the CNS can be infected through several entry portals, giving rise to meningitis and encephalitis. Following infection, resident cells recruit peripherally derived immune cells to sites of viral infection. In this review, we discuss recent advances in immune recruitment and entry at barrier structures as well as current immunotherapeutic strategies for the treatment of persistent viral infections.

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Project description:Hantaan virus (HTNV), the prototype virus of hantavirus, could escape innate immunity by restraining type I interferon (IFN) responses. It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells. Here, we demonstrate that the stimulator of interferon genes (STING) strengthens the host IFN-independent anti-hantaviral immunity. HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress, which further facilitates the subcellular translocation and activation of STING. During this process, STING triggers cellular autophagy by interacting with Rab7A, thus restricting viral replication. To note, the anti-hantaviral effects of STING are independent of canonical IFN signaling. Additionally, neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo. However, the administration of plasmids exogenously expressing the mutant C-terminal tail (ΔCTT) STING, which would not trigger the type I IFN responses, protected the nude mice from lethal HTNV infection. In summary, our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway, which offered novel therapeutic strategies against hantavirus infection.

| S-EPMC10436061 | biostudies-literature

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