Autoimmune hepatitis(AIH),primary sclerosing cholangitis(PSC) and primary biliary cirrhosis(PBC) are considered as putative autoimmune diseases of the liver.Whereas strong evidence that bacterial infection may trigger...Autoimmune hepatitis(AIH),primary sclerosing cholangitis(PSC) and primary biliary cirrhosis(PBC) are considered as putative autoimmune diseases of the liver.Whereas strong evidence that bacterial infection may trigger PBC exists,the etiologies for PSC and AIH remain unknown.Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases,their associations with environmental triggers and the subsequent implications have been difficult to elucidate.While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4(CTLA-4) have been suggested as genetic susceptibility factors for all three disorders,we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC,where Novosphingobium aromaticivorans,an ubiquitous alphaproteobacterium,has recently been specifically associated with the pathogenesis of this devastating liver disease.Ultimately,the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers,establish infection and damage respective target organs.展开更多
Antibiotic resistance has emerged as a major global threat to human health. Among the strategies employed by pathogens to acquire resistance the use of metallo-β-lactamases (MBLs), a family of dinuclear metalloenzyme...Antibiotic resistance has emerged as a major global threat to human health. Among the strategies employed by pathogens to acquire resistance the use of metallo-β-lactamases (MBLs), a family of dinuclear metalloenzymes, is among the most potent. MBLs are subdivided into three groups (i.e. B1, B2 and B3) with most of the virulence factors belonging to the B1 group. The recent discovery of AIM-1, a B3-type MBL, however, has illustrated the potential health threat of this group of MBLs. Here, we employed a bioinformatics approach to identify and characterize novel B3-type MBLs from Novosphingobium pentaromativorans and Simiduia agarivorans. These enzymes may not yet pose a direct risk to human health, but their structures and function may provide important insight into the design and synthesis of a still elusive universal MBL inhibitor.展开更多
基金Supported by a Grant from the Deutsche Forschungsgemein-schaft(MA 2621/2-1)the Lupus Research Institute and by Award Number R01DK084054 from the National Institute of Diabetes and Digestive and Kidney Diseases
文摘Autoimmune hepatitis(AIH),primary sclerosing cholangitis(PSC) and primary biliary cirrhosis(PBC) are considered as putative autoimmune diseases of the liver.Whereas strong evidence that bacterial infection may trigger PBC exists,the etiologies for PSC and AIH remain unknown.Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases,their associations with environmental triggers and the subsequent implications have been difficult to elucidate.While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4(CTLA-4) have been suggested as genetic susceptibility factors for all three disorders,we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC,where Novosphingobium aromaticivorans,an ubiquitous alphaproteobacterium,has recently been specifically associated with the pathogenesis of this devastating liver disease.Ultimately,the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers,establish infection and damage respective target organs.
基金N.M.thanks the Science Foundation Ireland(SFI)for financial support in form of a President of Ireland Young Researcher Award(PIYRA)G.S.acknowledges the award of a Future Fellowship from the Australian Research Council(FT120100694)is grateful to the National Health and Medical Research Council of Australia for funding.
文摘Antibiotic resistance has emerged as a major global threat to human health. Among the strategies employed by pathogens to acquire resistance the use of metallo-β-lactamases (MBLs), a family of dinuclear metalloenzymes, is among the most potent. MBLs are subdivided into three groups (i.e. B1, B2 and B3) with most of the virulence factors belonging to the B1 group. The recent discovery of AIM-1, a B3-type MBL, however, has illustrated the potential health threat of this group of MBLs. Here, we employed a bioinformatics approach to identify and characterize novel B3-type MBLs from Novosphingobium pentaromativorans and Simiduia agarivorans. These enzymes may not yet pose a direct risk to human health, but their structures and function may provide important insight into the design and synthesis of a still elusive universal MBL inhibitor.
