Human adenovirus type 55(HAdV-B55) is a re-emergent acute respiratory disease pathogen that causes adult communityacquired pneumonia(CAP). Previous studies have shown that the receptor of HAdV-B14, which genome is hig...Human adenovirus type 55(HAdV-B55) is a re-emergent acute respiratory disease pathogen that causes adult communityacquired pneumonia(CAP). Previous studies have shown that the receptor of HAdV-B14, which genome is highly similar with HAdV-B55, is human Desmoglein 2(DSG2). However, whether the receptor of HAdV-B55 is DSG2 is undetermined because there are three amino acid mutations in the fiber gene between HAdV-B14 and HAdV-B55. Here, firstly we found the 3T3 cells, a mouse embryo fibroblast rodent cell line which does not express human DSG2, were able to be infected by HAdV-B55 after transfected with pcDNA3.1-DSG2, while normal 3T3 cells were still unsusceptible to HAdV-B55 infection. Next, A549 cells with h DSG2 knock-down by siRNA were hard to be infected by HAdV-B3/-B14/-B55, while the control siRNA group was still able to be infected by all these types of HAdVs. Finally, immunofluorescence confocal microscopy indicated visually that Cy3-conjugated HAdV-B55 viruses entered A549 cells by binding to DSG2 protein.Therefore, DSG2 is a major receptor of HAdV-B55 causing adult CAP. Our finding is important for better understanding of interactions between adenoviruses and host cells and may shed light on the development of new drugs that can interfere with these processes as well as for the development of potent prophylactic vaccines.展开更多
Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mut...Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mutations in desmosome proteins,with Desmoglein-2(DSG2)mutations as a common etiology.However,the mechanism underlying the accumulation of fibrofatty in ACM remains unknown,which impedes the development of curative treatment.Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2(CS-Dsg2^(-/-)).Heart failure and cardiac lipid accumulation were observed in CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.展开更多
Sudden unexplained death(SUD)remains a puzzle in forensic medicine.Desmoglein‑2(DSG2)has been linked to arrhythmogenic right ventricular cardiomyopathy which may cause life‑threatening ventricular arrhythmias and sudd...Sudden unexplained death(SUD)remains a puzzle in forensic medicine.Desmoglein‑2(DSG2)has been linked to arrhythmogenic right ventricular cardiomyopathy which may cause life‑threatening ventricular arrhythmias and sudden death.Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy.We hypothesized that DSG2 mutations may be responsible for certain Chinese SUD cases.We sequenced all 15 exons of DSG2 in DNA extracted from postmortem heart tissues of 25 Chinese patients dying from SUD.The primers were designed using the Primer Express 3.0 software.Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130 Xl Genetic Analyzer.Mutation damage prediction was made using Mutation Taster,PolyPhen,and SIFT software.In 2 of 25 cases of Chinese SUD samples,two DSG2 heterozygous mutations(p.P927 L and p.T1070M)were identified,and one is probably damaging.We concluded that DSG2 mutations may be related to the occurrence of part of SUD cases in the Chinese Han population.展开更多
基金This work was supported by grants from the National Key Research and Development Program of China(2018YFE0204503)Natural Science Foundation of Guangdong Province(2021A1515010788 and 2018B030312010)the Guangzhou Healthcare Collaborative Innovation Major Project(201803040004 and 201803040007)。
文摘Human adenovirus type 55(HAdV-B55) is a re-emergent acute respiratory disease pathogen that causes adult communityacquired pneumonia(CAP). Previous studies have shown that the receptor of HAdV-B14, which genome is highly similar with HAdV-B55, is human Desmoglein 2(DSG2). However, whether the receptor of HAdV-B55 is DSG2 is undetermined because there are three amino acid mutations in the fiber gene between HAdV-B14 and HAdV-B55. Here, firstly we found the 3T3 cells, a mouse embryo fibroblast rodent cell line which does not express human DSG2, were able to be infected by HAdV-B55 after transfected with pcDNA3.1-DSG2, while normal 3T3 cells were still unsusceptible to HAdV-B55 infection. Next, A549 cells with h DSG2 knock-down by siRNA were hard to be infected by HAdV-B3/-B14/-B55, while the control siRNA group was still able to be infected by all these types of HAdVs. Finally, immunofluorescence confocal microscopy indicated visually that Cy3-conjugated HAdV-B55 viruses entered A549 cells by binding to DSG2 protein.Therefore, DSG2 is a major receptor of HAdV-B55 causing adult CAP. Our finding is important for better understanding of interactions between adenoviruses and host cells and may shed light on the development of new drugs that can interfere with these processes as well as for the development of potent prophylactic vaccines.
基金supported by grants from the National Natural Science Foundation of China(82170818,81770794,31401001)the Fundamental Research Funds for the Central Universities(21620423,China)the Science and Technology Project of Zhuhai(20191210E030072,China)。
文摘Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mutations in desmosome proteins,with Desmoglein-2(DSG2)mutations as a common etiology.However,the mechanism underlying the accumulation of fibrofatty in ACM remains unknown,which impedes the development of curative treatment.Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2(CS-Dsg2^(-/-)).Heart failure and cardiac lipid accumulation were observed in CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.
基金This study was funded by the National Natural Science Foundation of China(NSFC fund:81501630)the Opening Project of Shanghai Key Laboratory of Crime Scene Evidence(No.2016XCWZK20)+1 种基金This study was funded by the National Natural Science Foundation of China(NSFC fund:81501630)the Opening Project of Shanghai Key Laboratory of Crime Scene Evidence(No.2016XCWZK20).
文摘Sudden unexplained death(SUD)remains a puzzle in forensic medicine.Desmoglein‑2(DSG2)has been linked to arrhythmogenic right ventricular cardiomyopathy which may cause life‑threatening ventricular arrhythmias and sudden death.Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy.We hypothesized that DSG2 mutations may be responsible for certain Chinese SUD cases.We sequenced all 15 exons of DSG2 in DNA extracted from postmortem heart tissues of 25 Chinese patients dying from SUD.The primers were designed using the Primer Express 3.0 software.Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130 Xl Genetic Analyzer.Mutation damage prediction was made using Mutation Taster,PolyPhen,and SIFT software.In 2 of 25 cases of Chinese SUD samples,two DSG2 heterozygous mutations(p.P927 L and p.T1070M)were identified,and one is probably damaging.We concluded that DSG2 mutations may be related to the occurrence of part of SUD cases in the Chinese Han population.
