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Frontiers in Cellular and Infection... 2023Ebola virus (EBOV) is an RNA virus of the Filoviridae family that is responsible for outbreaks of hemorrhagic fevers in primates with a lethality rate as high as 90%....
INTRODUCTION
Ebola virus (EBOV) is an RNA virus of the Filoviridae family that is responsible for outbreaks of hemorrhagic fevers in primates with a lethality rate as high as 90%. EBOV primarily targets host macrophages leading to cell activation and systemic cytokine storm, and fatal infection is associated with an inhibited interferon response, and lymphopenia. The EBOV surface glycoprotein (GP) has been shown to directly induce T cell depletion and can be secreted outside the virion via extracellular vesicles (EVs), though most studies are limited to epithelial cells and underlying mechanisms remain poorly elucidated.
METHODS
To assess the role of GP on EBOV-induced dysregulation of host immunity, we first utilized EBOV virus-like particles (VLPs) expressing VP40 and NP either alone (Bald-VLP) or in conjunction with GP (VLP-GP) to investigate early inflammatory responses in THP-1 macrophages and in a murine model. We then sought to decipher the role of non-classical inflammatory mediators such as EVs over the course of EBOV infection in two EBOV-infected rhesus macaques by isolating and characterizing circulatory EVs throughout disease progression using size exclusion chromatography, nanoparticle tracking-analysis, and LC-MS/MS.
RESULTS
While all VLPs could induce inflammatory mediators and recruit small peritoneal macrophages, pro-inflammatory cytokine and chemokine gene expression was exacerbated by the presence of GP. Further, quantification of EVs isolated from infected rhesus macaques revealed that the concentration of vesicles peaked in circulation at the terminal stage, at which time EBOV GP could be detected in host-derived exosomes. Moreover, comparative proteomics conducted across EV populations isolated from serum at various time points before and after infection revealed differences in host-derived protein content that were most significantly pronounced at the endpoint of infection, including significant expression of mediators of TLR4 signaling.
DISCUSSION
These results suggest a dynamic role for EVs in the modification of disease states in the context of EBOV. Overall, our work highlights the importance of viral factors, such as the GP, and host derived EVs in the inflammatory cascade and pathogenesis of EBOV, which can be collectively further exploited for novel antiviral development.
Topics: Animals; Mice; Hemorrhagic Fever, Ebola; Macaca mulatta; Chromatography, Liquid; Tandem Mass Spectrometry; Ebolavirus; Chemokines; Extracellular Vesicles
PubMed: 38035334
DOI: 10.3389/fcimb.2023.1275277 -
Molecular Medicine (Cambridge, Mass.) Jul 2023Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis...
BACKGROUND
Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study.
METHODS
IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry.
RESULTS
Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH.
CONCLUSIONS
Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases.
Topics: Animals; Mice; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Lipopolysaccharides; Shock, Septic; Diabetes Mellitus, Type 2; Anti-Inflammatory Agents; Disease Models, Animal; Interleukin-1beta; Mice, Inbred C57BL
PubMed: 37400760
DOI: 10.1186/s10020-023-00671-0 -
Journal of Cellular and Molecular... Aug 2023Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of...
Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of liver granulomas and fibrosis by undergoing polarization from M1 to M2 type during schistosomiasis. Therefore, regulating macrophage polarization is important for controlling pathological changes that occur during this disease. Triggering receptor expressed on myeloid cells 2 (TREM2) expressed on the surface of macrophages, dendritic cells and other immune cells has been shown to play a role in inhibiting inflammatory responses and regulating M2 macrophage polarization, however its role in macrophage polarization in schistosomiasis has not been investigated. In this study, we confirmed that TREM2 expression was upregulated in the livers and peritoneal macrophages of mice infected with Schistosoma japonicum. Moreover, the TREM2 expression trend correlated with the expression of M2 macrophage polarization-related molecules in the liver tissues of S. japonicum-infected mice. Using Trem2 mice, we also showed that Trem2 deletion inhibited Arg1 and Ym1 expression in liver tissues. Trem2 deletion also increased the number of F4/80 + CD86+ cells in peritoneal macrophages of infected mice. In summary, our study suggests that TREM2 may be involved in M2 macrophage polarization during schistosomiasis.
Topics: Humans; Animals; Mice; Schistosoma japonicum; Macrophages, Peritoneal; Schistosomiasis japonica; Macrophages; Liver; Schistosomiasis; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37430471
DOI: 10.1111/jcmm.17842 -
Peritoneal Dialysis International :... Mar 2024Effective treatment of infections is a growing challenge owing to antimicrobial resistance. Peritoneal dialysis (PD) patients experience more frequent hospitalisations... (Review)
Review
Effective treatment of infections is a growing challenge owing to antimicrobial resistance. Peritoneal dialysis (PD) patients experience more frequent hospitalisations than the general population and have greater exposure to antibiotics, making them particularly vulnerable to this threat. Over the last decade, we have noted a surge in cases of complicated peritoneal dialysis-associated peritonitis (PD peritonitis) caused by antimicrobial-resistant organisms, including extended-spectrum beta-lactamase (ESBL), AmpC beta-lactamase-producing Enterobacterales, and fungi. Practitioners must be alert to these organisms, seek early recognition of these resistance patterns and make timely adjustments in order to avoid delay in treatment that may increase risk of PD catheter removal and technique failure. We present a case of successful treatment of ESBL peritonitis, highlight its challenges, while providing guidance on management of other unusual and complicated PD peritonitis.
PubMed: 38532707
DOI: 10.1177/08968608241237400 -
Surgical Endoscopy Dec 2023The burden of emergency general surgery (EGS) is higher compared to elective surgery. Acute appendicitis (AA) is one of the most frequent diseases and its management is...
BACKGROUND
The burden of emergency general surgery (EGS) is higher compared to elective surgery. Acute appendicitis (AA) is one of the most frequent diseases and its management is dictated by published international clinical practice guidelines (CPG). Adherence to CPG has been reported as heterogeneous. Barriers to clinical implementation were not studied. This study explored barriers to adherence to CPG and the clinico-economic impact of poor compliance.
METHODS
Data were extracted from the three-year data lock of the REsiDENT-1 registry, a prospective resident-led multicenter trial. We identified 7 items from CPG published from the European Association of Endoscopic Surgery (EAES) and the World Society of Emergency Surgery (WSES). We applied our classification proposal and used a five-point Likert scale (Ls) to assess laparoscopic appendectomy (LA) difficulty. Descriptive analyses were performed to explore compliance and group comparisons to assess the impact on outcomes and related costs. We ran logistic regressions to identify barriers and facilitators to implementation of CPG.
RESULTS
From 2019 to 2022, 653 LA were included from 24 centers. 69 residents performed and coordinated data collection. We identified low compliance with recommendations on peritoneal irrigation (PI) (25.73%), abdominal drains (AD) (34.68%), and antibiotic stewardship (34.17%). Poor compliance on PI and AD was associated to higher infectious complications in uncomplicated AA. Hospitalizations were significantly longer in non-compliance except for PI in uncomplicated AA, and costs significantly higher, exception made for antibiotic stewardship in complicated AA. The strongest barriers to CPG implementation were complicated AA and technically challenging LA for PI and AD. Longer operative times and the use of PI negatively affected antibiotic stewardship in uncomplicated AA. Compliance was higher in teaching hospitals and in emergency surgery units.
CONCLUSIONS
We confirmed low compliance with standardized items influenced by environmental factors and non-evidence-based practices in complex LA. Antibiotic stewardship is sub-optimal. Not following CPG may not influence clinical complications but has an impact in terms of logistics, costs and on the non-measurable magnitude of antibiotic resistance. Structured educational interventions and institutional bundles are required.
Topics: Humans; Acute Disease; Anti-Bacterial Agents; Appendectomy; Appendicitis; Hospitalization; Laparoscopy; Prospective Studies; Multicenter Studies as Topic
PubMed: 37884735
DOI: 10.1007/s00464-023-10449-4 -
The Journal of Experimental Medicine Dec 2023Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms...
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.
Topics: Animals; Mice; Cell Differentiation; Hematopoiesis; Immunity, Innate; Myelopoiesis; Sepsis; Tissue Inhibitor of Metalloproteinase-1
PubMed: 37851372
DOI: 10.1084/jem.20230018 -
Virulence Dec 2023(group A streptococcus; GAS) causes a variety of invasive diseases (iGAS) such as bacteremia, toxic shock syndrome, and pneumonia, which are associated with high...
(group A streptococcus; GAS) causes a variety of invasive diseases (iGAS) such as bacteremia, toxic shock syndrome, and pneumonia, which are associated with high mortality despite the susceptibility of the bacteria to penicillin . Epidemiologic studies indicate that respiratory influenza virus infection is associated with an increase in the frequency of iGAS diseases, including those not directly involving the lung. We modified a murine model of influenza A (IAV)-GAS superinfection to determine if viral pneumonia increased the susceptibility of mice subsequently infected with GAS in the peritoneum. The results showed that respiratory IAV infection increased the morbidity (weight loss) of mice infected intraperitoneally (i.p.) with GAS 3, 5, and 10 d after the initial viral infection. Mortality was also significantly increased when mice were infected with GAS 3 and 5 d after pulmonary IAV infection. Increased mortality among mice infected with virus 5 d prior to bacterial infection correlated with increased dissemination of GAS from the peritoneum to the blood, spleen, and lungs. The interval was also associated with a significant increase in the pro-inflammatory cytokines IFN-γ, IL-12, TNF-α, MCP-1 and IL-27 in sera. We conclude, using a murine model, that respiratory influenza virus infection increases the likelihood and severity of systemic iGAS disease, even when GAS infection does not originate in the respiratory tract.
Topics: Animals; Mice; Humans; Influenza, Human; Streptococcus pyogenes; Disease Models, Animal; Influenza A virus; Orthomyxoviridae Infections; Lung; Streptococcal Infections; Orthomyxoviridae; Coinfection
PubMed: 37772916
DOI: 10.1080/21505594.2023.2265063 -
Pediatric Rheumatology Online Journal Nov 2023Rheumatic patients have a higher frequency of tuberculosis(TB) than the general population. This study aimed to describe children and adolescents with TB and rheumatic...
BACKGROUND
Rheumatic patients have a higher frequency of tuberculosis(TB) than the general population. This study aimed to describe children and adolescents with TB and rheumatic diseases(RD) who were being treated in a reference center.
METHODS
A series of TB cases were investigated in a reference center for childhood TB in Rio de Janeiro, Brazil, from 1995 to 2022.
RESULTS
Fifteen patients with underlying RD and TB were included with 8(53%) being female. The mean age at RD diagnosis was 7.10years (SD ± 0,57 years), and the mean age at TB diagnosis was 9.81 years(SD ± 0.88 years). A total of 9 cases of pulmonary TB(PTB) and 6 cases of extrapulmonary TB-pleural(2), joint/osteoarticular(1), cutaneous(1), ocular(1), and peritoneal(1)- were described. The RD observed in the 15 patients included juvenile idiopathic arthritis(9), juvenile systemic lupus erythematosus(3), juvenile dermatomyositis(1), polyarteritis nodosa(1), and pyoderma gangrenosum(1). Among the immunosuppressants/immunobiologics, methotrexate(8) was the most commonly used, followed by corticosteroids(6), etanercept(2), mycophenolate mofetil(1), cyclosporine A(1), adalimumab(1), and tocilizumab(1). The most common symptoms were fever and weight loss, and a predominance of PTB cases was noted. GeneXpert MTB/RIF® was performed in six patients and was detectable in two without rifampicin resistance; Xpert Ultra® was performed in five patients, and traces with indeterminate rifampicin resistance were detected in three. One female patient discontinued treatment, and another passed away.
CONCLUSIONS
The case series demonstrated the importance of suspecting and investigating TB in RD affected patients who are using immunosuppressants/ immunobiologics, particularly in countries with high rates of TB such as Brazil.
Topics: Humans; Child; Female; Adolescent; Male; Rifampin; Mycobacterium tuberculosis; Sensitivity and Specificity; Brazil; Tuberculosis; Rheumatic Diseases; Immunosuppressive Agents
PubMed: 37950309
DOI: 10.1186/s12969-023-00918-4 -
Frontiers in Immunology 2024Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the... (Review)
Review
Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.
Topics: Humans; Peritoneal Dialysis; Peritoneum; Animals; Stromal Cells; Cell Communication; Inflammation; Peritonitis
PubMed: 38779674
DOI: 10.3389/fimmu.2024.1387292 -
Microbiology Spectrum Dec 2023Understanding the role of the endoribonuclease non-structural protein 15 (nsp15) (EndoU) in coronavirus (CoV) infection and pathogenesis is essential for vaccine target...
Understanding the role of the endoribonuclease non-structural protein 15 (nsp15) (EndoU) in coronavirus (CoV) infection and pathogenesis is essential for vaccine target discovery. Whether the EndoU activity of CoV nsp15, as a virulence-related protein, has a diverse effect on viral virulence needs to be further explored. Here, we found that the transmissible gastroenteritis virus (TGEV) and feline infectious peritonitis virus (FIPV) nsp15 proteins antagonize SeV-induced interferon-β (IFN-β) production in human embryonic kidney 293 cells. Interestingly, compared with wild-type infection, infection with EnUmt-TGEV or EnUmt-FIPV did not change the IFN-β response or reduce viral propagation in immunocompetent cells. The results of animal experiments showed that EnUmt viruses did not reduce the clinical presentation and mortality caused by TGEV and FIPV. Our findings enrich the understanding of nsp15-mediated regulation of alpha-CoV propagation and virulence and reveal that the conserved functions of nonstructural proteins have diverse effects on the pathogenicity of CoVs.
Topics: Animals; Humans; Coronavirus; Virulence; Endoribonucleases; Uridylate-Specific Endoribonucleases; Coronavirus Infections
PubMed: 37938022
DOI: 10.1128/spectrum.02209-23