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PubMed2005

New ecological aspects of hantavirus infection: a change of a paradigm and a challenge of prevention--a review.

In the last decades a significant number of so far unknown or underestimated pathogens have emerged as fundamental health hazards of the human population despite intensive research and exceptional efforts of modern medicine to embank and eradicate infectious diseases. Almost all incidents caused by such emerging pathogens could be ascribed to agents that are zoonotic or expanded their host range and crossed species barriers. Many different factors influence the status of a pathogen to remain unnoticed or evolves into a worldwide threat. The ability of an infectious agent to adapt to changing environmental conditions and variations in human behavior, population development, nutrition, education, social, and health status are relevant factors affecting the correlation between pathogen and host. Hantaviruses belong to the emerging pathogens having gained more and more attention in the last decades. These viruses are members of the family Bunyaviridae and are grouped into a separate genus known as Hantavirus. The serotypes Hantaan (HTN), Seoul (SEO), Puumala (PUU), and Dobrava (DOB) virus predominantly cause hemorrhagic fever with renal syndrome (HFRS), a disease characterized by renal failure, hemorrhages, and shock. In the recent past, many hantavirus isolates have been identified and classified in hitherto unaffected geographic regions in the New World (North, Middle, and South America) with characteristic features affecting the lungs of infected individuals and causing an acute pulmonary syndrome. Hantavirus outbreaks in the United States of America at the beginning of the 10th decade of the last century fundamentally changed our knowledge about the appearance of the hantavirus specific clinical picture, mortality, origin, and transmission route in human beings. The hantavirus pulmonary syndrome (HPS) was first recognized in 1993 in the Four Corners Region of the United States and had a lethality of more than 50%. Although the causative virus was first termed in connection with the geographic name of its outbreak region the analysis of the individual viruses indicate that the causing virus of HPS was a genetically distinct hantavirus and consequently termed as Sin Nombre virus. Hantaviruses are distributed worldwide and are assumed to share a long time period of co-evolution with specific rodent species as their natural reservoir. The degree of relatedness between virus serotypes normally coincides with the relatedness between their respective hosts. There are no known diseases that are associated with hantavirus infections in rodents underlining the amicable relationship between virus and host developed by mutual interaction in hundreds of thousands of years. Although rodents are the major reservoir, antibodies against hantaviruses are also present in domestic and wild animals like cats, dogs, pigs, cattle, and deer. Domestic animals and rodents live jointly in a similar habitat. Therefore the transmission of hantaviruses from rodents to domestic animals seems to be possible, if the target organs, tissues, and cell parenchyma of the co-habitat domestic animals possess adequate virus receptors and are suitable for hantavirus entry and replication. The most likely incidental infection of species other than rodents as for example humans turns hantaviruses from harmless to life-threatening pathogenic agents focusing the attention on this virus group, their ecology and evolution in order to prevent the human population from a serious health risk. Much more studies on the influence of non-natural hosts on the ecology of hantaviruses are needed to understand the directions that the hantavirus evolution could pursue. At least, domestic animals that share their environmental habitat with rodents and humans particularly in areas known as high endemic hantavirus regions have to be copiously screened. Each transfer of hantaviruses from their original natural hosts to other often incidental hosts is accompanied by a change of ecology, a change of environment, a modulation of numerous factors probably influencing the pathogenicity and virulence of the virus. The new environment exerts a modified evolutionary pressure on the virus forcing it to adapt and probably to adopt a form that is much more dangerous for other host species compared to the original one.

Animals↗
PubMed2006

Molecular and physiological effects of mycobacterial oxyR inactivation.

The majority of slow-growing mycobacteria have a functional oxyR, the central regulator of the bacterial oxidative stress response. In contrast, this gene has been inactivated during the evolution of Mycobacterium tuberculosis. Here we inactivated the oxyR gene in Mycobacterium marinum, an organism used to model M. tuberculosis pathogenesis. Inactivation of oxyR abrogated induction of ahpC, a gene encoding alkylhydroperoxide reductase, normally activated upon peroxide challenge. The absence of oxyR also resulted in increased sensitivity to the front-line antituberculosis drug isoniazid. Inactivation of oxyR in M. marinum did not affect either virulence in a fish infection model or survival in human macrophages. Our findings demonstrate, at the genetic and molecular levels, a direct role for OxyR in ahpC regulation in response to oxidative stress. Our study also indicates that oxyR is not critical for virulence in M. marinum. However, oxyR inactivation confers increased sensitivity to isonicotinic acid hydrazide, suggesting that the natural loss of oxyR in the tubercle bacillus contributes to the unusually high sensitivity of M. tuberculosis to isoniazid.

Animals↗
PubMed2003

[Molecular genetic characteristics of rifampicin-resistant Mycobacterium tuberculosis isolates in Novosibirsk].

Forty rifampicin-resistant clinical isolates from patients living in Novosibirsk were studied. Six alleles earlier described in the literature were identified by the sequencing technique. The frequency of mutations in the studied samples slightly differs from that earlier reported for other geographic regions: 21 (52.5%) strains carried the mutated codon TTG in position 531 (Ser-->Leu), 7 (17.5%) had GTC in position 516 (Asp-->Val) and 2 (5%) had the GAC substitution in position 526 (His-->Asp), which is prevalent elsewhere. Sequence analysis revealed no mitations in 5 (12.5%) of the 40 isolates although this isolate was repeatedly resistant to rifampicin. VNTR-typing targeted to tandem repeats (ETR A, B, C, D, and E) was carried out to establish a genetic relationship for rifampicin-resistant isolates. Nine genetic types with VNTR-profiles termed as 12322, 32122, 32123, 32124, 32125, 32522, 23524, 12223, 22222, 33433 were revealed. There was no strict correlation between the type of mutation in the rpoB gene and the VNTR-type, which reflects different rates of evolution and the level of selective pressure on these genetic targets. The isolates of VNTR-types 32123 and 32125 with mutations in codon 531, and type 32122 in codons 531, 526, 516 showed a high clustering. This is likely to reflect the recent transmission and clonal dissemination of the epidemic strains of Mycobacterium tuberculosis. Thus, mutations in the rpoB gene did not reduce the virulence and transmissivity of these clones. Twenty-six of 27 clinical isolates selected by rifampicin-resistance were also resistant to isoniazid, which confirms the known fact that rifampicin-resistance may be used as a marker of isoniazid-resistance.

Antitubercular Agents↗
PubMed1991

Structural and genetic analysis of the bvg locus in Bordetella species.

The bvg locus contains two genes, bvgA and bvgS, which control the expression of the virulence-associated genes in Bordetella species by a system similar to the two-component systems used by a variety of bacterial species to respond to environmental stimuli. We determined the nucleotide sequence of the bvg loci of Bordetella parapertussis and Bordetella bronchiseptica and compared them with the previously determined sequence of Bordetella pertussis. The nucleotide and amino acid sequences of the bvg loci of these species are well conserved in those regions coding for the protein domains which have putative kinase and DNA-binding activities. In marked contrast, the region of BvgS that codes for the protein domain with putative sensor activity shows a high degree of variability. In total, we find 198 base-pair changes in the bvg loci of B. parapertussis and B. bronchiseptica relative to the bvg locus of B. pertussis. One hundred and seventy-three of these base-pair changes are identical in B. parapertussis and B. bronchiseptica. This confirms our previous observation that B. parapertussis and B. bronchiseptica are more related to each other than to B. pertussis. We have mapped the mutations that cause phase changes in B. bronchiseptica and we have found that in three cases these are due to spontaneous deletions in the bvgS gene. The wild-type bvg locus present on a multicopy plasmid cannot complement avirulent derivatives of B. bronchiseptica to wild-type levels, but it can do so when the bvgA gene on the plasmid is inactivated. This suggests that hyperexpression of bvgA down-regulates the bvg system.

Amino Acid Sequence↗
PubMed2001

Reversion of a live porcine reproductive and respiratory syndrome virus vaccine investigated by parallel mutations.

A live attenuated porcine reproductive and respiratory syndrome (PRRS) vaccine virus has been shown to revert to virulence under field conditions. In order to identify genetic virulence determinants, ORF1 from the attenuated vaccine virus and three Danish vaccine-derived field isolates was sequenced and compared with the parental strain of the vaccine virus (VR2332). This revealed five mutations that had occurred independently in all three vaccine-derived field isolates, indicating strong parallel selective pressure on these positions in the vaccine virus when used in swine herds. Two of these parallel mutations were direct reversions to the parental VR2332 sequence and were situated in a papain-like cysteine protease domain and in the helicase domain. The remaining parallel mutations might be seen as second-site compensatory mutations for one or more of the mutations that accumulated in the vaccine virus sequence during cell-culture adaptation. Evaluation of the remaining mutations in the ORF1 sequence revealed stronger selective pressure for amino acid conservation during spread in pigs than during vaccine production. Furthermore, it was found that the selective pressure did not change during the time period studied. The implications of these findings for PRRS vaccine attenuation and reversion are discussed.

Amino Acid Sequence↗
PubMed2000

Infectious history.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1976

The evolution of modern treatment of corpus cancer.

The treatment of endometrial cancer has been surgical, traditionally, with preoperative radiation gaining favor in the past three decades. This surgical treatment has been confined to simple hysterectomy and bilateral salpingo-oophorectomy in most clinics because of the pattern of spread of corpus cancer and the alleged benignity of this disease. Even now, the role of radical surgery, the timing of radiation therapy and its mode, and the place of hormonal treatment for primary disease are still the subject of discussion and clinical investigation. The definition of virulence factors and an appropriate staging dependent upon these factors has helped to clarify some of these problems and will help the analysis of cure rates when we can understand the selection of the material. With such a prospect for quality control and establishment of a protocol of individualization of treatment, we have a right to expect that appropriate surgical and radiotherapeutic measures will gain their proper priority and adjuvant hormonal therapy and chemotherapy may be incorporated.

Female↗
PubMed2000

Full-length sequence of a Canadian porcine reproductive and respiratory syndrome virus (PRRSV) isolate.

Presently, one of the most economically important pathogens affecting swine is the porcine reproductive and respiratory syndrome virus (PRRSV). This virus is prevalent in herds throughout the world and continues to pose a significant threat as newer and more virulent disease phenotypes emerge. In this report we describe the full-length nucleotide sequence of a Canadian PRRSV isolate, designated PA8. A consecutive sequence of 15,411 nucleotides was obtained from a set of overlapping cDNA clones. In order to determine the extent of genetic variation among isolates recovered from swine in Canada and the US, as well as to understand the molecular mechanisms governing the evolution of PRRSV, the full-length sequence of PA8 was compared with that of two US isolates, VR2332 and 16244B. The genomic sequence of PA8 shared 98.2% and 99.2% identity with 16244B and VR2332, respectively. The untranslated regions (UTR) at the 5' and 3' ends of the genome were very well conserved. Notable exceptions include an eight nucleotide difference at the 5' end of the 5' UTR of VR2332 relative to PA8 and 16244B and a two nucleotide difference in the 3' UTR of PA8 relative to VR2332 and 16244B. In contrast to PA8 and VR2332, 16244B possessed two nucleotide differences within the RNA pseudoknot structure of the ribosomal frameshift region between open reading frame (ORF)1a and ORF1b. Amino acid differences were distributed throughout the genome, however they appeared to be most extensive in Nsp1beta and ORF5 of the nonstructural and structural coding regions, respectively, suggesting that the evolutionary pressure to conserve these viral genes is somewhat lower.

3' Untranslated Regions↗
PubMed2005

Methionine sulfoxide reductases in prokaryotes.

In living organisms, most methionine residues exposed to reactive oxygen species (ROS) are converted to methionine sulfoxides. This reaction can lead to structural modifications and/or inactivation of proteins. Recent years have brought a wealth of new information on methionine sulfoxide reductase A (MsrA) and B (MsrB) which makes methionine oxidation a reversible process. Homologs of msrA and msrB genes have been identified in most living organisms and their evolution throughout different species led to different genetic organization and different copy number per organism. While MsrA and MsrB had been the focus of multiple biochemical investigations, our understanding of their physiological role in vivo remains scarce. Yet, the recent identification of a direct link between protein targeting and MsrA/MsrB repair offers a best illustration of the physiological importance of this pathway. Repeatedly identified as a potential "virulence factor", contribution of msrA to pathogenicity is also discussed. It remains, however, unclear whether reduced virulence results from overall viability loss or relates to specific oxidized virulence factors left unrepaired. We speculate that a major issue towards assessing the in vivo role of the MsrA/MsrB repair pathway in the next future will be to decipher the interrelations, if any, between MsrA/MsrB-mediated repair and chaperone-assisted folding and/or protease-assisted degradation.

Escherichia coli↗
PubMed1994

Selfish DNA as a method of pest control.

The inheritance of most genes is tightly controlled, governed by the rules of mendelian inheritance if nuclear or uniparental inheritance if cytoplasmic. A few notable genes and cytoplasmic genomes have escaped this regulation. Such genes may spread by increasing their own rate of transmission despite reducing host fitness and may be regarded as 'selfish'. Their population genetics are described and it appears they may impose a significant genetic load on the host population. Modern molecular techniques may enable similar loads to be imposed on pest species either by transferring selfish genes between species, or by linking deleterious genes to a selfish locus. Alternatively, 'modifier' genes that eliminate the virulent, or disease vectorial capacity, of the pest population may be introduced by linkage to a selfish locus. Selfish elements present in multiple copies may be preferable to single-copy elements as the former are capable of a larger reduction in host fitness. The practical application of these agents depends on five factors: (i) the rate of 'reversion' to a non-selfish form; (ii) the evolution of host repressor systems; (iii) their effect on host fitness, which determines their rate of invasion; (iv) the mechanism regulating host population size in the field; and (v) their ease of manipulation in the laboratory. The first two factors are the most uncertain in most systems, but should be amenable to experimental analysis. It is proposed that the development of such techniques may result in powerful new methods of population control which may be applied to both agricultural pests and disease vectors.

Alleles↗
PubMed2006

Multiple seropathotypes of verotoxin-producing Escherichia coli (VTEC) disrupt interferon-gamma-induced tyrosine phosphorylation of signal transducer and activator of transcription (Stat)-1.

Verotoxin-producing Escherichia coli (VTEC) O157:H7 inhibits interferon-gamma-stimulated tyrosine phosphorylation of signal transducer and activator of transcription (Stat)-1 in epithelial cells, independent of Verotoxins and the locus of enterocyte effacement pathogenicity island. Although E. coli O157:H7 is the major cause of disease in humans, non-O157:H7 VTEC also cause human disease. However, the virulence properties of non-O157:H7 VTEC are less well characterized. The aims of this study were to define the ability of VTEC strains of differing seropathotypes (classified as A-E) to inhibit interferon-gamma stimulated Stat1-phosphorylation and to further characterize the bacterial-derived inhibitory factor. Confluent T84 and HEp-2 cells were infected with VTEC strains (MOI 100:1, 6h, 37 degrees C), and then stimulated with interferon-gamma (50 ng/mL) for 0.5h at 37 degrees C. Whole-cell protein extracts of infected cells were collected and prepared for immunoblotting to detect tyrosine phosphorylation of Stat1. The effects of E. coli O55 strains, the evolutionary precursors of VTEC, on Stat1-tyrosine phosphorylation were also determined. The effects of isogenic mutants of O-islands 47 and 122 were tested to determine the role of genes encoded on these putative pathogenicity islands in mediating VTEC inhibition of the interferon-gamma-Stat1 signaling cascade. To evaluate potential mechanism(s) of inhibition, VTEC O157:H7-infected cells were treated with pharmacological inhibitors, including, wortmannin and LY294002. Relative to uninfected cells, Stat1-tyrosine phosphorylation was significantly reduced after 6h infection of both T84 and HEp-2 cells by VTEC strains of all five seropathotypes. E. coli O55 strains, but not enteropathogenic E. coli (EPEC), also caused inhibition of Stat1-tyrosine phosphorylation, suggesting that this effect was acquired early in the evolution of VTEC. Stat1-activation did not recover in epithelial cells infected with isogenic mutants of O-islands 47 and 122, indicating that the inhibitory factor was not contained in these genomic regions. Stat1-phosphorylation remained intact when VTEC-infected cells were treated with wortmannin (0-100 nM), but not by treatment with the more specific PI3-kinase inhibitor, LY294002. Inhibition of interferon-gamma stimulated Stat1-tyrosine phosphorylation by VTEC of multiple seropathotypes indicates the presence of a common inhibitory factor that is independent of bacterial virulence in humans. The results of treatment with wortmannin suggest that the bacterial-derived inhibitory factor employs host cell signal transduction to mediate inhibition of Stat1-activation.

Androstadienes↗
PubMed1997

PfEMP1, polymorphism and pathogenesis.

The virulence of Plasmodium falciparum relative to the other species of malarial parasite which infect humans is thought to be due to this parasite's ability to adhere to endothelial cells lining small blood vessels and, in some cases, to its ability to form rosettes with uninfected erythrocytes. The latter phenotype has been found more frequently in cases of severe disease. The former property means that only the younger, asexual, intra-erythrocytic forms circulate whereas the more mature developmental stages are sequestered in the vasculature of a variety of organs. When large numbers of parasites accumulate in a vulnerable target organ such as the brain, the the life-threatening condition of cerebral malaria may result. While the factors that control whether or not cerebral malaria develops are not clearly defined, one crucial determinant my be the endothelial receptors utilised by the infecting isolate. Many such receptors have been identified, including CD36, thrombospondin, ICAM-1, VCAM, E-selectin and chondroitin-4-sulphate. The results of laboratory, field, post-mortem and direct receptor-binding studies indicate that, of the receptors currently identified, ICAM-1 binding is more likely to be associated with the development of cerebral malaria. The molecule expressed on the surface of the infected erythrocyte which mediates adherence to endothelium belongs to a large family of clonally variable antigens encoded by the var genes. The evidence for this conclusion and progress in defining the regions of var-gene products responsible to receptor-specific binding are discussed. Finally, the organization of the var genes within and between parasites is discussed in relation to the evolution of the var-gene family and its functions of antigenic variation and endothelial adhesion.

Animals↗
PubMed2003

Helicobacter pylori tissue tropism: mouse-colonizing strains can target different gastric niches.

Studies with the mouse-adapted Helicobacter pylori strain SS1 had supported an idea that infections by this pathogen start in the gastric antrum and spread to the corpus after extensive mucosal damage. This paper shows that the unrelated strain X47 colonizes the corpus preferentially. Differences between strains in preferred gastric region were detected by co-inoculating mice with a mixture of SS1 and X47, and genotyping H. pylori recovered after 2-8 weeks of infection by vacA s allele PCR and RAPD fingerprinting. Mixed infections were found in each of 59 co-inoculated young C57BL/6J mice. On average, however, SS1 was fourfold more abundant than X47 in the antrum and X47 was threefold more abundant than SS1 in the corpus. Similar results were obtained in mice inoculated first with one strain and then the other strain 2 weeks later. SS1 was even more abundant in the antrum of elderly (>1 year old) mice (97 % of isolates). Qualitatively similar SS1 and X47 tissue distributions were seen using unrelated mouse lines (AKR/J, A/J, DBA/2J, BALB/cJ, LG/J, SM/J), but with significantly different SS1 : X47 ratios in some cases. These results suggest the existence of at least two distinct gastric niches whose characteristics may be affected by host genotype and age (physiology), and indicate that strains differ in how effectively they colonize each niche. Differences among gastric regions and the mixed infections that these allow may contribute to H. pylori diversity and genome evolution.

Aging↗
PubMed2005

Decreased virus population diversity in p53-null mice infected with weakly oncogenic Abelson virus.

The Abelson murine leukemia virus (Ab-MLV), like other retroviruses that contain v-onc genes, arose following a recombination event between a replicating retrovirus and a cellular oncogene. Although experimentally validated models have been presented to address the mechanism by which oncogene capture occurs, very little is known about the events that influence emerging viruses following the recombination event that incorporates the cellular sequences. One feature that may play a role is the genetic makeup of the host in which the virus arises; a number of host genes, including oncogenes and tumor suppressor genes, have been shown to affect the pathogenesis of many murine leukemia viruses. To examine how a host gene might affect an emerging v-onc gene-containing retrovirus, we studied the weakly oncogenic Ab-MLV-P90A strain, a mutant that generates highly oncogenic variants in vivo, and compared the viral populations in normal mice and mice lacking the p53 tumor suppressor gene. While variants arose in both p53+/+ and p53-/- tumors, the samples from the wild-type animals contained a more diverse virus population. Differences in virus population diversity were not observed when wild-type and null animals were infected with a highly oncogenic wild-type strain of Ab-MLV. These results indicate that p53, and presumably other host genes, affects the selective forces that operate on virus populations in vivo and likely influences the evolution of oncogenic retroviruses such as Ab-MLV.

Abelson murine leukemia virus↗
PubMed2002

Molecular & evolutionary genetics & drug resistance of the gastric pathogen, Helicobacter pylori.

Helicobacter pylori colonizes the gastric mucosa of more than half of all people worldwide and is the major cause of peptic ulcer disease and an early risk factor for gastric cancer, even though most infections are asymptomatic. Infection occurs preferentially in early childhood and once established tends to persist for years or decades. Much of the pathology H. pylori causes probably results from the host response to infection, which is affected by bacterial genotype, human host characteristics and environmental conditions. H. pylori is one of the most genetically diverse of bacterial species, with different genotypes predominating in different parts of the world. In particular, strains from India differ from those of Europe and East Asia in DNA sequence of several diagnostic gene segments. This outcome invites speculation about H. pylori origins and the possibility of Indian-specific genes that might be uncommon in Western strains. Much has been learned from H. pylori genome sequences, along with epidemiological, mutational, molecular and immunologic analyses. Candidate bacterial colonization and virulence genes and host responses are being identified, and the hypotheses being developed are amenable to tests in cell culture and animal models. These research efforts, many of which are collaborative and international, provide insights into mechanisms of establishment and persistence of H. pylori infection and virulence, and should lead to new, far more potent and cost effective anti-Helicobacter therapies or vaccines, and thereby major improvement in human health worldwide.

Drug Resistance, Microbial↗
PubMed2001

Changes in the haemagglutinin and the neuraminidase genes prior to the emergence of highly pathogenic H7N1 avian influenza viruses in Italy.

Outbreaks of avian influenza due to an H7N1 virus of low pathogenicity occurred in domestic poultry in northern Italy from March 1999 until December 1999 when a highly pathogenic avian influenza (HPAI) virus emerged. Nucleotide sequences were determined for the HA1 and the stalk region of the neuraminidase (NA) for viruses from the outbreaks. The HPAI viruses have an unusual multibasic haemagglutinin (HA) cleavage site motif, PEIPKGSRVRRGLF. Phylogenetic analysis showed that the HPAI viruses arose from low pathogenicity viruses and that they are most closely related to a wild bird isolate, A/teal/Taiwan/98. Additional glycosylation sites were present at amino acid position 149 of the HA for two separate lineages, and at position 123 for all HPAI and some low pathogenicity viruses. Other viruses had no additional glycosylation sites. All viruses examined from the Italian outbreaks had a 22 amino acid deletion in the NA stalk that is not present in the N1 genes of the wild bird viruses examined. We conclude that the Italian HPAI viruses arose from low pathogenicity strains, and that a deletion in the NA stalk followed by the acquisition of additional glycosylation near the receptor binding site of HA1 may be an adaptation of H7 viruses to a new host species i.e. domestic poultry.

Amino Acid Motifs↗
PubMed2005

From bioremediation to biowarfare: on the impact and mechanism of type IV secretion systems.

Type IV secretion systems are employed by a wide variety of Gram-negative microorganisms for the translocation of macromolecules across the cell envelope. The translocated substrates (proteins, protein-DNA complexes and DNA) are as diverse as the organisms on the donor and recipient side of the translocation process. Over the course of evolution, these macromolecular transporters were adapted to many different purposes, but their basic mechanism was conserved. They impact human life in various ways, as there are driving forces of horizontal gene transfer, which spreads biodegradative capabilities of environmental bacteria as well as antibiotic resistance of pathogens in hospitals. Also, they translocate toxins and other effectors, which have an effect on host cell metabolism and are essential for the virulence of bacterial pathogens. We here present recent developments of research on the mechanism of type IV secretion focusing on the energetization of transport and assembly processes, formation of the translocation channel and of surface-exposed pili, which initiate host cell interactions.

Animals↗