Inflammasome activation is essential for host immune responses during pathogenic infection and sterile signals insult, whereas excessive activation is injurious. Thus, inflammasome activation is ...tightly regulated at multiple layers. Ubiquitination is an important post-translational modification for orchestrating inflammatory immune responses during pathogenic infection, and a major target hijacked by pathogenic bacteria for promoting their survival and proliferation. This review summarizes recent insights into distinct mechanisms of the inflammasome activation and ubiquitination process triggered by bacterial infection. We discuss the complex regulatory of inflammasome activation mediated by ubiquitination machinery during bacterial infection, and provide therapeutic approaches for specifically targeting aberrant inflammasome activation.
Fungal infections have emerged as a major concern among immunocompromised patients, causing approximately 2 million deaths each year worldwide. However, the regulatory mechanisms underlying ...antifungal immunity remain elusive and require further investigation. The E3 ligase Trim26 belongs to the tripartite motif (Trim) protein family, which is involved in various biological processes, including cell proliferation, antiviral innate immunity, and inflammatory responses. Herein, we report that Trim26 exerts protective antifungal immune functions after fungal infection. Trim26-deficient mice are more susceptible to fungemia than their wild-type counterparts. Mechanistically, Trim26 restricts inflammatory neutrophils infiltration and limits proinflammatory cytokine production, which can attenuate kidney fungal load and renal damage during Candida infection. Trim26-deficient neutrophils showed higher proinflammatory cytokine expression and impaired fungicidal activity. We further demonstrated that excessive neutrophils infiltration in the kidney was because of the increased production of chemokines CXCL1 and CXCL2, which are mainly synthesized in the macrophages or dendritic cells of Trim26-deficient mice after Candida albicans infections. Together, our study findings unraveled the vital role of Trim26 in regulating antifungal immunity through the regulation of inflammatory neutrophils infiltration and proinflammatory cytokine and chemokine expression during candidiasis.
Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic, and degenerative diseases in humans. In this study, we ...identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida Genetic deletion or pharmacological inhibition of cathepsin B down-regulated mechanistic target of rapamycin activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via transcription factor EB, which increased lysosomal biogenesis and activation of autophagy initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome populations and basic recycling functions in the cell.
STAT1 is a master regulator that orchestrates type 1 and 2 interferon (IFN)-induced IFN-stimulated gene (ISG) expression. The mechanisms by which STAT1 is phosphorylated and activated upon IFN ...signaling remain elusive. Our work demonstrated that ubiquitination of STAT1 mediated by the E3 ligase RNF220 contributed significantly to STAT1 activation and innate immune responses. Rnf220 gene deficiency resulted in the downregulation of IFN signaling and decreased expression of ISGs in response to type 1 and 2 IFNs stimulation and Acinetobacter baumannii and HSV-1 infection. Mechanistically, RNF220 interacted with STAT1 and mediated the K63-linked polyubiquitination of STAT1 at residue K110, which promoted the interaction between STAT1 and the kinase JAK1. The expression of RNF220 was induced by pathogenic infection and IFN signaling. RNF220 promoted STAT1 ubiquitination and phosphorylation through a positive feedback loop. RNF220 haploinsufficiency impaired IFN signaling, and RNF220-defective mice were more susceptible to A. baumannii and HSV-1 infection than WT mice. Our work offers novel insights into the mechanisms of STAT1 modulation and provides potential therapeutic targets against bacterial and viral infection and inflammatory diseases.
Abstract The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an ...immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8 + T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.
An outbreak of dengue fever (DF) occurred in Guangdong Province, China in 2013 with the highest number of cases observed within the preceding ten years. DF cases were clustered in the Pearl River ...Delta economic zone (PRD) in Guangdong Province, which accounted for 99.6% of all cases in Guangdong province in 2013. The main vector in PRD was Aedes albopictus. We investigated the socioeconomic and environmental factors at the township level and explored how the independent variables jointly affect the DF epidemic in the PRD.
Six factors associated with the incidence of DF were identified in this project, representing the urbanization, poverty, accessibility and vegetation, and were considered to be core contributors to the occurrence of DF from the perspective of the social economy and the environment. Analyses were performed with Generalized Additive Models (GAM) to fit parametric and non-parametric functions to the relationships between the response and predictors. We used a spline-smooth technique and plotted the predicted against the observed co-variable value. The distribution of DF cases was over-dispersed and fit the negative binomial function better. The effects of all six socioeconomic and environmental variables were found to be significant at the 0.001 level and the model explained 45.1% of the deviance by DF incidence. There was a higher risk of DF infection among people living at the prefectural boundary or in the urban areas than among those living in other areas in the PRD. The relative risk of living at the prefectural boundary was higher than that of living in the urban areas. The associations between the DF cases and population density, GDP per capita, road density, and NDVI were nonlinear. In general, higher "road density" or lower "GDP per capita" were considered to be consistent risk factors. Moreover, higher or lower values of "population density" and "NDVI" could result in an increase in DF cases.
In this study, we presented an effect analysis of socioeconomic and environmental factors on DF occurrence at the smallest administrative unit (township level) for the first time in China. GAM was used to effectively detect the nonlinear impact of the predictors on the outcome. The results showed that the relative importance of different risk factors may vary across the PRD. This work improves our understanding of the differences and effects of socioeconomic and environmental factors on DF and supports effectively targeted prevention and control measures.
While canonical Wnt signaling is well recognized for its crucial regulatory functions in cell fate decisions, the role of non-canonical Wnt signaling in adult stem cells remains elusive and ...contradictory. Here, we identified Mcam, a potential member of the non-canonical Wnt signaling, as an important negative regulator of mammary gland epithelial cells (MECs) by genome-scale CRISPR-Cas9 knockout (GeCKO) library screening. Loss of Mcam increases the clonogenicity and regenerative capacity of MECs, and promotes the proliferation, differentiation, and ductal morphogenesis of mammary epithelial in knockout mice. Mechanically, Mcam knockout recruits and polarizes macrophages through the Il4-Stat6 axis, thereby promoting secretion of the non-canonical Wnt ligand Wnt5a and its binding to the non-canonical Wnt signaling receptor Ryk to induce the above phenotypes. These findings reveal Mcam roles in mammary gland development by orchestrating communications between MECs and macrophages via a Wnt5a/Ryk axis, providing evidences for non-canonical Wnt signaling in mammary development.
The avian influenza A (H7N9) virus is a zoonotic virus that is closely associated with live poultry markets. It has caused infections in humans in China since 2013. Five waves of the H7N9 influenza ...epidemic occurred in China between March 2013 and September 2017. H7N9 with low-pathogenicity dominated in the first four waves, whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave, causing wide concern. Specialists and officials from China and other countries responded quickly, controlled the epidemic well thus far, and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts. Here, we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease. It was summarized and discussed from the perspectives of molecular epidemiology, clinical features, virulence and pathogenesis, receptor binding, T-cell responses, monoclonal antibody development, vaccine development, and disease burden. These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses, such as SARS-CoV-2.
Tick-borne encephalitis (TBE) is endemic to Europe and some Asian countries and is prevalent in northeast China. We analyzed the epidemiology of TBE in China from 2007 to 2018. A total of 3,364 TBE ...cases were reported in mainland China from 2007 to 2018, for an annual incidence of 0.09 to 0.44/100,000. Among the TBE cases, 89.92% were reported in forest areas (41.94% in DaXingAnLing, 8.70% in XiaoXingAnLing, and 39.21% in ChangBaiShan) in northeast China. The TBE cases were primarily male with a proportion of 67.15% (2,259/3,364 cases) and in 40-49-year age group with a proportion of 31.89% (1,073/3,364 cases). The epidemiology of TBE differed slightly among the three forest regions. Domestic workers and forestry workers accounted for the most of the TBE cases in DaXingAnLing, and domestic workers and farmers in XiaoXingAnLing and ChangBaiShan, respectively. The TBE cases mainly occurred from April to August with a peak in June. The TBE laboratory confirmed rate in DaXingAnLing (84.14%, 1,189/1,413 cases) was highest, compared with XiaoXingAnLing and ChangBaiShan (13.99% and 11.37%, respectively). Moreover, the hospital with the highest laboratory confirmed rate (88.01%, 1,336/1,518 cases) was Inner Mongolia Forestry General Hospital of DaXingAnling region. Systematic enhanced TBE surveillance and a vaccination program are needed to improve the laboratory confirmed rate and reduce the incidence of TBE in northeast China.
Animal models of Zika virus (ZIKV) infection have recently been established in mice, guinea pigs, and nonhuman primates. Tree shrews (
) are an emerging experimental animal in biomedical ...applications, but their susceptibility to ZIKV infection has not been explored. In the present study, we show that subcutaneous inoculation of ZIKV led to rapid viremia and viral secretion in saliva, as well as to typical dermatological manifestations characterized by massive diffuse skin rash on the trunk. Global transcriptomic sequencing of peripheral blood mononuclear cells isolated from ZIKV-infected animals revealed systematic gene expression changes related to the inflammatory response and dermatological manifestations. Importantly, ZIKV infection readily triggered the production of high-titer neutralizing antibodies, thus preventing secondary homologous infection in tree shrews. However, neonatal tree shrews succumbed to ZIKV challenge upon intracerebral infection. The tree shrew model described here recapitulates the most common dermatological manifestations observed in ZIKV-infected patients and may greatly facilitate the elucidation of ZIKV pathogenesis and the development of novel vaccines and therapeutics.
The reemergence of Zika virus (ZIKV) has caused a global public health crisis since 2016, and there are currently no vaccines or antiviral drugs to prevent or treat ZIKV infection. However, considerable advances have been made in understanding the biology and pathogenesis of ZIKV infection. In particular, various animal models have been successfully established to mimic ZIKV infection and its associated neurological diseases and to evaluate potential countermeasures. However, the clinical symptoms in these mouse and nonhuman primate models are different from the common clinical manifestations seen in human ZIKV patients; in particular, dermatological manifestations are rarely recapitulated in these animal models. Here, we developed a new animal model of ZIKV infection in tree shrews, a rat-sized, primate-related mammal.
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characterization of ZIKV infection in tree shrews established a direct link between ZIKV infection and the immune responses and dermatological manifestations. The tree shrew model described here, as well as other available animal models, provides a valuable platform to study ZIKV pathogenesis and to evaluate vaccines and therapeutics.
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