Pseudomonas aeruginosa(P.aeruginosa)is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis,burn wounds,immunodeficiency,chronic obstructive pulmonary disorder(COPD),cancer,and severe infe...Pseudomonas aeruginosa(P.aeruginosa)is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis,burn wounds,immunodeficiency,chronic obstructive pulmonary disorder(COPD),cancer,and severe infection requiring ventilation,such as COVID-19.P.aeruginosa is also a widely-used model bacterium for all biological areas.In addition to continued,intense efforts in understanding bacterial pathogenesis of P.aeruginosa including virulence factors(LPS,quorum sensing,two-component systems,6 type secretion systems,outer membrane vesicles(OMVs),CRISPR-Cas and their regulation),rapid progress has been made in further studying host-pathogen interaction,particularly host immune networks involving autophagy,inflammasome,noncoding RNAs,cGAS,etc.Furthermore,numerous technologic advances,such as bioinformatics,metabolomics,scRNA-seq,nanoparticles,drug screening,and phage therapy,have been used to improve our understanding of P.aeruginosa pathogenesis and host defense.Nevertheless,much remains to be uncovered about interactions between P.aeruginosa and host immune responses,including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways.The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections,especially those caused by multi-drug resistance strains.Benefited from has advancing in research tools and technology,dissecting this pathogen’s feature has entered into molecular and mechanistic details as well as dynamic and holistic views.Herein,we comprehensively review the progress and discuss the current status of P.aeruginosa biophysical traits,behaviors,virulence factors,invasive regulators,and host defense patterns against its infection,which point out new directions for future investigation and add to the design of novel and/or alternative therape展开更多
Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA vaccines.However,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation ef...Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA vaccines.However,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation efficiency of the 5'UTR.We discovered that the optimal 5'UTR for m1y-modified mRNA(m1y-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing mly-5'UTRs rather than directly utilizing high-expression endogenous gene 5'UTRs.In response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1y-5'UTRs in silico.The tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing models.As a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine development.Notably,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.展开更多
The extraordinary advantages associated with mRNA vaccines,including their high efficiency,relatively low severity of side effects,and ease of manufacture,have enabled them to be a promising immunotherapy approach aga...The extraordinary advantages associated with mRNA vaccines,including their high efficiency,relatively low severity of side effects,and ease of manufacture,have enabled them to be a promising immunotherapy approach against various infectious diseases and cancers.Nevertheless,most mRNA delivery carriers have many disadvantages,such as high toxicity,poor biocompatibility,and low efficiency in vivo,which have hindered the widespread use of mRNA vaccines.To further characterize and solve these problems and develop a new type of safe and efficient mRNA delivery carrier,a negatively charged SA@DOTAP-mRNA nanovaccine was prepared in this study by coating DOTAP-mRNA with the natural anionic polymer sodium alginate(SA).Intriguingly,the transfection efficiency of SA@DOTAP-mRNA was significantly higher than that of DOTAP-mRNA,which was not due to the increase in cellular uptake but was associated with changes in the endocytosis pathway and the strong lysosome escape ability of SA@DOTAP-mRNA.In addition,we found that SA significantly increased the expression of LUC-mRNA in mice and achieved certain spleen targeting.Finally,we confirmed that SA@DOTAP-mRNA had a stronger antigen-presenting ability in E.G7-OVA tumor-bearing mice,dramatically inducing the proliferation of OVA-specific CLTs and ameliorating the antitumor effect.Therefore,we firmly believe that the coating strategy applied to cationic liposome/mRNA complexes is of potential research value in the field of mRNA delivery and has promising clinical application prospects.展开更多
Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines.The targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delive...Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines.The targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery systems.Whether the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains unclear.Here,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by DCs.Furthermore,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse model.Collectively,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA vaccines.Our findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.展开更多
Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,m...Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.展开更多
There are currently approximately 4000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide.Universal vaccines with high efficacy and safety urgently need to...There are currently approximately 4000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide.Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic.Here,we described a novel self-assembling universal mRNA vaccine containing a heterologous receptorbinding domain(HRBD)-based dodecamer(HRBD^(dodecamer))against SARS-CoV-2 variants,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(B.1.1.28.1),Delta(B.1.617.2)and Omicron(B.1.1.529).HRBD containing four heterologous RBD(Delta,Beta,Gamma,and Wild-type)can form a stable dodecameric conformation under T4 trimerization tag(Flodon,FD).The HRBD^(dodecamer)-encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid(4N4T).The obtained universal mRNA vaccine(4N4T-HRBD^(dodecamer))presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs,initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation.These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic.展开更多
The therapeutic use of messenger RNA(mRNA)has fueled great hope to combat a wide range of incurable diseases.Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any func...The therapeutic use of messenger RNA(mRNA)has fueled great hope to combat a wide range of incurable diseases.Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any functional protein/peptide in the human body by introducing mRNA as a vaccine or therapeutic agent.This represents a rising precision medicine field with great promise for preventing and treating many intractable or genetic diseases.In addition,in vitro transcribed mRNA has achieved programmed production,which is more effective,faster in design and production,as well as more flexible and cost-effective than conventional approaches that may offer.Based on these extraordinary advantages,mRNA vaccines have the characteristics of the swiftest response to large-scale outbreaks of infectious diseases,such as the currently devastating pandemic COVID-19.It has always been the scientists’desire to improve the stability,immunogenicity,translation efficiency,and delivery system to achieve efficient and safe delivery of mRNA.Excitingly,these scientific dreams have gradually been realized with the rapid,amazing achievements of molecular biology,RNA technology,vaccinology,and nanotechnology.In this review,we comprehensively describe mRNA-based therapeutics,including their principles,manufacture,application,effects,and shortcomings.We also highlight the importance of mRNA optimization and delivery systems in successful mRNA therapeutics and discuss the key challenges and opportunities in developing these tools into powerful and versatile tools to combat many genetic,infectious,cancer,and other refractory diseases.展开更多
Bitter receptors function primarily in sensing taste,but may also have other functions,such as detecting pathogenic organisms due to their agile response to foreign objects.The mouse taste receptor type-2 member 138(T...Bitter receptors function primarily in sensing taste,but may also have other functions,such as detecting pathogenic organisms due to their agile response to foreign objects.The mouse taste receptor type-2 member 138(TAS2R138)is a member of the G-protein-coupled bitter receptor family,which is not only found in the tongue and nasal cavity,but also widely distributed in other organs,such as the respiratory tract,gut,and lungs.Despite its diverse functions,the role of TAS2R138 in host defense against bacterial infection is largely unknown.Here,we show that TAS2R138 facilitates the degradation of lipid droplets(LDs)in neutrophils during Pseudomonas aeruginosa infection through competitive binding with PPARG(peroxisome proliferator-activated receptor gamma)antagonist:A/-(3-oxododecanoyl)-L-homoserine lactone(AHL-12),which coincidently is a virulence-bound signal produced by this bacterium(P.aeruginosa).The released PPARG then migrates from nuclei to the cytoplasm to accelerate the degradation of LDs by binding PLIN2(perilipin-2).Subsequently,the TAS2R138-AHL-12 complex targets LDs to augment their degradation,and thereby facilitating the clearance of AHL-12 in neutrophils to maintain homeostasis in the local environment.These findings reveal a crucial role for TAS2R138 in neutrophil-mediated host immunity against P.aeruginosa infection.展开更多
Autophagy and inflammasomes are shown to interact in various situations including infectious disease,cancer,diabetes and neurodegeneration.Since multiple layers of molecular regulators contribute to the interplay betw...Autophagy and inflammasomes are shown to interact in various situations including infectious disease,cancer,diabetes and neurodegeneration.Since multiple layers of molecular regulators contribute to the interplay between autophagy and inflammasome activation,the detail of such interplay remains largely unknown.Non-coding RNAs(ncRNAs),which have been implicated in regulating an expanding list of cellular processes including immune defense against pathogens and inflammatory response in cancer and metabolic diseases,may join in the crosstalk between inflammasomes and autophagy in physiological or disease conditions.In this review,we summarize the latest research on the interlink among ncRNAs,inflammasomes and autophagy and discuss the emerging role of these three in multiple signaling transduction pathways involved in clinical conditions.By analyzing these intriguing interconnections,we hope to unveil the mechanism inter-regulating these multiple processes and ultimately discover potential drug targets for some refractory diseases.展开更多
基金supported by National Institutes of Health Grants R01 AI109317-06 and AI138203-3 to M.W.Some icons or graphic element in the Figures(Figs.1–7)are adapted from BioRender.com(2022).
文摘Pseudomonas aeruginosa(P.aeruginosa)is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis,burn wounds,immunodeficiency,chronic obstructive pulmonary disorder(COPD),cancer,and severe infection requiring ventilation,such as COVID-19.P.aeruginosa is also a widely-used model bacterium for all biological areas.In addition to continued,intense efforts in understanding bacterial pathogenesis of P.aeruginosa including virulence factors(LPS,quorum sensing,two-component systems,6 type secretion systems,outer membrane vesicles(OMVs),CRISPR-Cas and their regulation),rapid progress has been made in further studying host-pathogen interaction,particularly host immune networks involving autophagy,inflammasome,noncoding RNAs,cGAS,etc.Furthermore,numerous technologic advances,such as bioinformatics,metabolomics,scRNA-seq,nanoparticles,drug screening,and phage therapy,have been used to improve our understanding of P.aeruginosa pathogenesis and host defense.Nevertheless,much remains to be uncovered about interactions between P.aeruginosa and host immune responses,including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways.The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections,especially those caused by multi-drug resistance strains.Benefited from has advancing in research tools and technology,dissecting this pathogen’s feature has entered into molecular and mechanistic details as well as dynamic and holistic views.Herein,we comprehensively review the progress and discuss the current status of P.aeruginosa biophysical traits,behaviors,virulence factors,invasive regulators,and host defense patterns against its infection,which point out new directions for future investigation and add to the design of novel and/or alternative therape
基金This work was financially supported by the Postdoctoral Research Foundation of National Key S&T Special Projects(2018ZX09201018-024,China)Sichuan Province Science and Technology Support Program(2022YFH0001 and 2021YFH0003,China).
文摘Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA vaccines.However,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation efficiency of the 5'UTR.We discovered that the optimal 5'UTR for m1y-modified mRNA(m1y-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing mly-5'UTRs rather than directly utilizing high-expression endogenous gene 5'UTRs.In response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1y-5'UTRs in silico.The tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing models.As a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine development.Notably,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.
基金supported by the National Key Research and Development Program of China(2021YFE0206600)the Sichuan Province Science and Technology Support Program(2021YF-SY0008 and 2020YJ023,China)+1 种基金the Translational Medicine Fund of West China Hospital(CGZH19002,China)the 1.3.5 Project for Disciplines of excellence,West China Hospital,Sichuan University(ZYGD18020/ZYJC18006,China).
文摘The extraordinary advantages associated with mRNA vaccines,including their high efficiency,relatively low severity of side effects,and ease of manufacture,have enabled them to be a promising immunotherapy approach against various infectious diseases and cancers.Nevertheless,most mRNA delivery carriers have many disadvantages,such as high toxicity,poor biocompatibility,and low efficiency in vivo,which have hindered the widespread use of mRNA vaccines.To further characterize and solve these problems and develop a new type of safe and efficient mRNA delivery carrier,a negatively charged SA@DOTAP-mRNA nanovaccine was prepared in this study by coating DOTAP-mRNA with the natural anionic polymer sodium alginate(SA).Intriguingly,the transfection efficiency of SA@DOTAP-mRNA was significantly higher than that of DOTAP-mRNA,which was not due to the increase in cellular uptake but was associated with changes in the endocytosis pathway and the strong lysosome escape ability of SA@DOTAP-mRNA.In addition,we found that SA significantly increased the expression of LUC-mRNA in mice and achieved certain spleen targeting.Finally,we confirmed that SA@DOTAP-mRNA had a stronger antigen-presenting ability in E.G7-OVA tumor-bearing mice,dramatically inducing the proliferation of OVA-specific CLTs and ameliorating the antitumor effect.Therefore,we firmly believe that the coating strategy applied to cationic liposome/mRNA complexes is of potential research value in the field of mRNA delivery and has promising clinical application prospects.
基金financially supported by National Key S&T Special Projects(No.2018ZX09201018-024)Henan Medical Science and Technology Joint Building Program(No.SBGJ202102132)+3 种基金China Postdoctoral Science Foundation(No.2020TQ0282)Henan Province Youth Talent Promoting Project(No.2022HYTP047)Key Research and Development Project of Henan Province(No.232102311224)Sichuan Provincial Science and Technology Innovation(Seedling Project)Cultivation Projects(No.MZGC20230034).
文摘Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines.The targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery systems.Whether the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains unclear.Here,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by DCs.Furthermore,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse model.Collectively,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA vaccines.Our findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.
基金This study was supported by the Youth Fund of National Natural Science Foundation of China(No.82104081)Sichuan Province Science and Technology Support Program(No.2020JDRC0052)+1 种基金the 1.3.5 Project for Disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18020/ZYJC18006)Science and Technology Project of Xinjiang Production and Construction Corps(No.2022AB020).
文摘Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.
基金financially supported by the Postdoctoral Research Foundation of China(2022TQ0225)Sichuan Province Science and Technology Support Program(2021YFH0003,2021YFSY008,2020YFH0065,2020YJ0238,China)the Chengdu Key S&T Innovation Projects(2019-YF08-00139-GX,China)。
文摘There are currently approximately 4000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide.Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic.Here,we described a novel self-assembling universal mRNA vaccine containing a heterologous receptorbinding domain(HRBD)-based dodecamer(HRBD^(dodecamer))against SARS-CoV-2 variants,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(B.1.1.28.1),Delta(B.1.617.2)and Omicron(B.1.1.529).HRBD containing four heterologous RBD(Delta,Beta,Gamma,and Wild-type)can form a stable dodecameric conformation under T4 trimerization tag(Flodon,FD).The HRBD^(dodecamer)-encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid(4N4T).The obtained universal mRNA vaccine(4N4T-HRBD^(dodecamer))presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs,initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation.These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic.
基金supported by the Sichuan Province Science and Technology Support Program(2021YFH0003,2021YFSY008,2020YFH0065,and 2020YJ0238)the Chengdu Key S&T Innovation Projects(2019-YF08-00139-GX).
文摘The therapeutic use of messenger RNA(mRNA)has fueled great hope to combat a wide range of incurable diseases.Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any functional protein/peptide in the human body by introducing mRNA as a vaccine or therapeutic agent.This represents a rising precision medicine field with great promise for preventing and treating many intractable or genetic diseases.In addition,in vitro transcribed mRNA has achieved programmed production,which is more effective,faster in design and production,as well as more flexible and cost-effective than conventional approaches that may offer.Based on these extraordinary advantages,mRNA vaccines have the characteristics of the swiftest response to large-scale outbreaks of infectious diseases,such as the currently devastating pandemic COVID-19.It has always been the scientists’desire to improve the stability,immunogenicity,translation efficiency,and delivery system to achieve efficient and safe delivery of mRNA.Excitingly,these scientific dreams have gradually been realized with the rapid,amazing achievements of molecular biology,RNA technology,vaccinology,and nanotechnology.In this review,we comprehensively describe mRNA-based therapeutics,including their principles,manufacture,application,effects,and shortcomings.We also highlight the importance of mRNA optimization and delivery systems in successful mRNA therapeutics and discuss the key challenges and opportunities in developing these tools into powerful and versatile tools to combat many genetic,infectious,cancer,and other refractory diseases.
基金The authors thank the National Institutes of Health for Grants R01 AM 138203,R01 All09317-01 Al,and AI097532-01A1 for M.W.,as well as P20 GM113123 and P20 GM103442 for Imaging,Histology,and Flow Cytometry Core Facility.
文摘Bitter receptors function primarily in sensing taste,but may also have other functions,such as detecting pathogenic organisms due to their agile response to foreign objects.The mouse taste receptor type-2 member 138(TAS2R138)is a member of the G-protein-coupled bitter receptor family,which is not only found in the tongue and nasal cavity,but also widely distributed in other organs,such as the respiratory tract,gut,and lungs.Despite its diverse functions,the role of TAS2R138 in host defense against bacterial infection is largely unknown.Here,we show that TAS2R138 facilitates the degradation of lipid droplets(LDs)in neutrophils during Pseudomonas aeruginosa infection through competitive binding with PPARG(peroxisome proliferator-activated receptor gamma)antagonist:A/-(3-oxododecanoyl)-L-homoserine lactone(AHL-12),which coincidently is a virulence-bound signal produced by this bacterium(P.aeruginosa).The released PPARG then migrates from nuclei to the cytoplasm to accelerate the degradation of LDs by binding PLIN2(perilipin-2).Subsequently,the TAS2R138-AHL-12 complex targets LDs to augment their degradation,and thereby facilitating the clearance of AHL-12 in neutrophils to maintain homeostasis in the local environment.These findings reveal a crucial role for TAS2R138 in neutrophil-mediated host immunity against P.aeruginosa infection.
基金Thisworkwas supported by National Institutes of Health(Grants No.AI101973-01,AI109317-01A1,and AI097532-01A1 aswell as P20 GM103442 and GM113123 for the UND COREs).
文摘Autophagy and inflammasomes are shown to interact in various situations including infectious disease,cancer,diabetes and neurodegeneration.Since multiple layers of molecular regulators contribute to the interplay between autophagy and inflammasome activation,the detail of such interplay remains largely unknown.Non-coding RNAs(ncRNAs),which have been implicated in regulating an expanding list of cellular processes including immune defense against pathogens and inflammatory response in cancer and metabolic diseases,may join in the crosstalk between inflammasomes and autophagy in physiological or disease conditions.In this review,we summarize the latest research on the interlink among ncRNAs,inflammasomes and autophagy and discuss the emerging role of these three in multiple signaling transduction pathways involved in clinical conditions.By analyzing these intriguing interconnections,we hope to unveil the mechanism inter-regulating these multiple processes and ultimately discover potential drug targets for some refractory diseases.
