Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
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Protein families can be used to understand many aspects of genomes, both their "live" and their "dead" parts (i.e. genes and pseudogenes). Surveys of genomes have revealed that, in every organism, there are always a few large families and many small ones, with the overall distribution following a power-law. This commonality is equally true for both genes and pseudogenes, and exists despite the fact that the specific families that are enlarged differ greatly between organisms. Furthermore, because of family structure there is great redundancy in proteomes, a fact linked to the large number of dispensable genes for each organism and the small size of the minimal, indispensable sub-proteome. Pseudogenes in prokaryotes represent families that are in the process of being dispensed with. In particular, the genome sequences of certain pathogenic bacteria (Mycobacterium leprae, Yersinia pestis and Rickettsia prowazekii) show how an organism can undergo reductive evolution on a large scale (i.e. the dying out of families) as a result of niche change. There appears to be less pressure to delete pseudogenes in eukaryotes. These can be divided into two varieties, duplicated and processed, where the latter involves reverse transcription from an mRNA intermediate. We discuss these collectively in yeast, worm, fly, and human. The fly has few pseudogenes apparently because of its high rate of genomic DNA deletion. In the other three organisms, the distribution of pseudogenes on the chromosome and amongst different families is highly non-uniform. Pseudogenes tend not to occur in the middle of chromosome arms, and tend to be associated with lineage-specific (as opposed to highly conserved) families that have environmental-response functions. This may be because, rather than being dead, they may form a reservoir of diverse "extra parts" that can be resurrected to help an organism adapt to its surroundings. In yeast, there may be a novel mechanism involving the [PSI+] prion that potentially enables this resurrection. In worm, the pseudogenes tend to arise out of families (e.g. chemoreceptors) that are greatly expanded in it compared to the fly. The human genome stands out in having many processed pseudogenes. These have a character very different from those of the duplicated variety, to a large extent just representing random insertions. Thus, their occurrence tends to be roughly in proportion to the amount of mRNA for a particular protein and to reflect the extent of the intergenic sequences. Further information about pseudogenes is available at http://genecensus.org/pseudogene
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PMID:Studying genomes through the aeons: protein families, pseudogenes and proteome evolution. 1208 9

The detection of ancient microbial DNA offers a new approach for the study of infectious diseases, their occurrence, frequency and host-pathogen interaction in historic times and populations. Moreover, data obtained from skeletal and mummified tissue may represent an important completion of contemporary phylogenetic analyses of pathogens. In the last few years, a variety of bacterial, protozoal and viral infections have been detected in ancient tissue samples by amplification and characterization of specific DNA fragments. This holds particularly true for the identification of the Mycobacterium tuberculosis complex, which seems to be more robust than other microbes due to its waxy, hydrophobic and lipid-rich cell wall. These observations provided useful information about the occurrence, but also the frequency of tuberculosis in former populations. Moreover, these studies suggest new evolutionary models and indicate the route of transmission between human and animals. Until now, other pathogens, such as Mycobacterium leprae, Yersinia pestis, Plasmodium falciparum and others, have occasionally been identified - mostly in single case studies or small sample sizes - as well, although much less information is available on these pathogens in ancient settings. The main reason therefore seems to be the degradation and modification of ancient DNA by progressive oxidative damage. Furthermore, the constant risk of contamination by recent DNA forces to take time and cost effective measures and renders the analysis of ancient microbes difficult. Nevertheless, the study of microbial ancient DNA significantly contributes to the understanding of transmission and spread of infectious diseases, and potentially to the evolution and phylogenetic pathways of pathogens.
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PMID:Molecular analysis of ancient microbial infections. 1216 30

The polymerase chain reaction (PCR) offers a sensitive and specific way of detecting microbial DNA in clinical samples. The aims of the present study were to develop an assay, based on a single-tube, nested PCR, for identifying Brucella in samples of human blood and then to explore the use of this test in diagnosis. The primers chosen were derived from IS711, the insertion sequence gene found in all species of Brucella. The assay amplified a 52-bp final product which was detected colorimetrically. The PCR was sensitive and specific, giving positive reactions with 14 strains of Brucella from five species. The lower limit of detection in vitro was 30 organisms. There were no false-positive reactions either with a range of bacteria known to evoke serological cross-reactions with Brucella (Vibrio cholerae, Yersinia enterocolitica, Serratia marcescens, Haemophilus influenzae, Pseudomonas aeruginosa and Escherichia coli K12) or with organisms producing similar clinical syndromes (Mycobacterium tuberculosis and Salmonella typhi). The results of a preliminary field trial of the assay in Kuwait indicate that the assay may be a valuable technique in the diagnosis of human brucellosis, meriting further study with larger numbers of cases. All 28 subjects with brucellosis (diagnosed on the basis of typical clinical features and confirmed by positive serology and, in three cases, by positive blood cultures) were PCR-positive whereas 28 healthy controls and 28 patients with febrile illness attributable to infections other than brucellosis were PCR-negative.
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PMID:Single-tube, nested PCR for the diagnosis of human brucellosis in Kuwait. 1217 21

MPT63 is a small, major secreted protein of unknown function from Mycobacterium tuberculosis that has been shown to have immunogenic properties and has been implicated in virulence. A BLAST search identified that MPT63 has homologs only in other mycobacteria, and is therefore mycobacteria specific. As MPT63 is a secreted protein, mycobacteria specific, and implicated in virulence, MPT63 is an attractive drug target against the deadliest infectious disease, tuberculosis (TB). As part of the TB Structural Genomics Consortium, the X-ray crystal structure of MPT63 was determined to 1.5-Angstrom resolution with the hope of yielding functional information about MPT63. The structure of MPT63 is an antiparallel beta-sandwich immunoglobulin-like fold, with the unusual feature of the first beta-strand of the protein forming a parallel addition to the small antiparallel beta-sheet. MPT63 has weak structural similarity to many proteins with immunoglobulin folds, in particular, Homo sapiens beta2-adaptin, bovine arrestin, and Yersinia pseudotuberculosis invasin. Although the structure of MPT63 gives no conclusive evidence to its function, structural similarity suggests that MPT63 could be involved in cell-host interactions to facilitate endocytosis/phagocytosis.
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PMID:Crystal structure of a major secreted protein of Mycobacterium tuberculosis-MPT63 at 1.5-A resolution. 1244 86

Several human pathogens (e.g., Bacillus anthracis, Yersinia pestis, Bordetella pertussis, Plasmodium falciparum, and Mycobacterium tuberculosis) have very restricted unselected allelic variation in structural genes, which hinders study of the genetic relationships among strains and strain-trait correlations. To address this problem in a representative pathogen, 432 M. tuberculosis complex strains from global sources were genotyped on the basis of 230 synonymous (silent) single nucleotide polymorphisms (sSNPs) identified by comparison of four genome sequences. Eight major clusters of related genotypes were identified in M. tuberculosis sensu stricto, including a single cluster representing organisms responsible for several large outbreaks in the United States and Asia. All M. tuberculosis sensu stricto isolates of previously unknown phylogenetic position could be rapidly and unambiguously assigned to one of the eight major clusters, thus providing a facile strategy for identifying organisms that are clonally related by descent. Common clones of M. tuberculosis sensu stricto and M. bovis are distinct, deeply branching genotypic complexes whose extant members did not emerge directly from one another in the recent past. sSNP genotyping rapidly delineates relationships among closely related strains of pathogenic microbes and allows construction of genetic frameworks for examining the distribution of biomedically relevant traits such as virulence, transmissibility, and host range.
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PMID:Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains. 1252 30

Emerging water-borne pathogens constitute a major health hazard in both developed and developing nations. A new dimension to the global epidemiology of cholera-an ancient scourge-was provided by the emergence of Vibrio cholerae O139. Also, water-borne enterohaemorrhagic Escherichia coli ( E. coli O157:H7), although regarded as a problem of the industrialized west, has recently caused outbreaks in Africa. Outbreaks of chlorine-resistant Cryptosporidium have motivated water authorities to reassess the adequacy of current water-quality regulations. Of late, a host of other organisms, such as hepatitis viruses (including hepatitis E virus), Campylobacter jejuni, microsporidia, cyclospora, Yersinia enterocolitica, calciviruses and environmental bacteria like Mycobacterium spp, aeromonads, Legionella pneumophila and multidrug-resistant Pseudomonas aeruginosa have been associated with water-borne illnesses. This review critically examines the potential of these as emerging water-borne pathogens. It also examines the possible reasons, such as an increase in the number of immunocompromised individuals, urbanization and horizontal gene transfer, that may underlie their emergence. Further, measures required to face the challenge posed by these pathogens are also discussed.
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PMID:Emerging water-borne pathogens. 1268 49

Fibrinogen-like protein 2 (Fgl2, fibroleukin) is a leukocyte product that exhibits significant homology to secreted proteins of diverse function, including growth factors, lectins, and components of extracellular matrix. Prior studies found that Fgl2 is IFN gamma-inducible, possesses direct coagulant activity, and inhibits T cell proliferation and dendritic cell maturation in vitro. Here, we demonstrate that Fgl2 expression is up-regulated during type 1 immunity in vivo and establish that such up-regulation is IFN gamma-, signal transducer and activation of transcription protein 1-, and IFN response factor 1-dependent. To investigate functional roles for Fgl2 during type 1 immunity, we generated Fgl2-deficient mice. Those animals are born at predicted Mendelian frequencies, appear overtly healthy, and contain normal numbers and frequencies of lymphoid cells. Although Fgl2 is IFN gamma-inducible and putatively regulates T cell activation/proliferation, we demonstrate that Fgl2-deficient and control mice exhibit similar degrees of T cell expansion, immunopathology, and/or pathogen burdens during protozoan (Toxoplasma gondii), bacterial (Yersinia enterocolitica, Listeria monocytogenes, and Mycobacterium tuberculosis), and viral (murine gamma-herpesvirus-68 and Sendai) infections. Fgl2-deficient mice also reject allografts with similar kinetics as control mice. Moreover, despite prior reports that Fgl2 functions as a procoagulant enzyme, we demonstrate that Fgl2-deficient and control mice produce similar levels of fibrin, a product of the coagulation cascade, during T. gondii infection and allograft rejection. Together, our findings suggest that Fgl2, although highly conserved and IFN gamma-inducible, is not a critical mediator of either type 1 immunity or immune-associated coagulant activity.
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PMID:Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFN gamma-inducible fibrinogen-like protein 2. 1497 52

The mystery surrounding the apparent lack of iron within the macrophages of individuals with hereditary hemochromatosis, a condition of excessive uptake of dietary iron, has yet to be fully explained. We have suggested that iron deficiency of macrophages in people with hereditary hemochromatosis mutations is associated with increased resistance to infection by Yersinia and other intracellular pathogens, a selection pressure resulting in unusually high current population frequencies of hereditary hemochromatosis mutations. Such selection pressure has been called Epidemic Pathogenic Selection (EPS). In support of the theory of EPS, a considerable number of virulent species of bacteria multiply mainly in iron-rich macrophages of their mammalian hosts. Among these fastidious pathogens are strains of Chlamydia, Coxiella, Francisella, Legionella, Mycobacterium, Salmonella and Yersinia. Iron deficiency of macrophages of persons with hereditary hemochromatosis gene mutations may result in increased resistance to members of these bacterial pathogens. People with genes that result in hereditary hemochromatosis may be protected against coronary artery disease associated with Chlamydia and Coxiella infection in the absence of iron overload. In the clinical setting, when a patient appears to be iron deficient, the reason for this should be carefully evaluated. Iron supplementation may adversely affect the health of individuals who have mounted an acute phase response to infection, injury or stress, or who carry genes predisposing them to iron overload disorders.
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PMID:Hemochromatosis and the enigma of misplaced iron: implications for infectious disease and survival. 1508 40

In experiments on guinea pigs immunized with Francisella tularensis 15, or live tularemia vaccine (LTV), the level of heterologous protective effect to dangerous infectious diseases caused by Yersinia pestis, Burkholderia pseudomallei, B. mallei, Mycobacterium tuberculosis was studied. The study revealed that during the first 4 weeks after the subcutaneous immunization with LTV the level of resistance of the immunized animals to heterologous infective agent reliably increased as indicated by the survival rate of the animals, as well as by the survival time of those killed by infection, in comparison with the controls. Later (on day 150 after immunization) differences in death rate between the groups perceptibly decreased. Nevertheless, the 1 1/2-fold increase of the survival time of the challenged immunized animals in comparison with the controls proved the possibility of using immunization with LTV for the urgent prophylaxis and treatment not only of tularemia, but also of plague, glanders, melioidosis and tuberculosis.
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PMID:[Experimental study on the possibility of using live tularemia vaccine to increase resistance to heterologous infection disease]. 1518 57

Cross-reacting antigens in B. mallei, B. pseudomallei, B. thailandensis, Francisella tularensis, Yersinia pestis and Mycobacterium tuberculosis were studied with the use of immuno- and electrophoretic techniques. The set of antigens was shown to be almost identical in the causative agents of glanders, melioidosis, as well as in B. thailandensis, though in the latter organism 200-kD glycoprotein was absent. The analysis of immuno- and proteinograms demonstrated the presence of cross-reactions in the representatives of the genus Burkholderia with the causative agents of plague, tularemia and tuberculosis, which served as the basis for making the scheme of their antigenic relationships. The use of immunosorption techniques with subsequent analysis of the preparations by means of the SDS polyacryl gel electrophoresis and immunoblotting made it possible to characterize cross-reacting antigens of the pathogenic microorganisms under study, to establish their molecular weights (81-15 kD) and to show that some detected antigens are analogous to B. pseudomallei outer membrane proteins (34 and 30 kD).
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PMID:[Cross-reacting antigens of pathogenic Burkholderia and some dangerous causative agents of infectious diseases]. 1588 32


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