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PubMed2005

The biology of Phytophthora infestans at its center of origin.

The central highlands of Mexico are considered to be a center of genetic diversity for both the potato late blight pathogen and for tuber-bearing Solanum spp. Recent work conducted in Mexico and South America sheds new light on the biology and evolution of Phytophthora infestans and other related Phytophthora pathogens. It now appears that Mexican Solanum species, which coevolved with P. infestans and were previously known for providing a source of R-genes, also provide a source of quantitative, rate-reducing resistance that is highly effective, stable, and durable. It is now apparent that Mexico is the center of origin not only of the potato late blight pathogen P. infestans, but also of several related Phytophthora species including P. mirabilis, P. ipomoeae, and possibly P. phaseoli. We close with the hypothesis that these Phytophthora species evolved sympatrically from one ancestral host through adaptive radiation onto their respective four host families.

Mexico↗

PubMed2006

Pivotal advance: activation of cell surface Toll-like receptors causes shedding of the hemoglobin scavenger receptor CD163.

The hemoglobin scavenger receptor (HbSR) CD163 is a monocyte/macrophage-specific glycoprotein that binds and facilitates uptake of haptoglobin-hemoglobin (Hp-Hb) complexes, which are rapidly formed in the circulation upon hemolysis of red blood cells. Hemolysis can be caused by a diverse range of infectious agents and provides pathogens a source of iron to enhance their survival and replication. Previous work demonstrated that lipopolysaccharide (LPS) activates monocytes to cleave cell-bound HbSR into a soluble mediator that retains the capacity to bind Hp-Hb complexes. We report that blocking LPS activation of Toll-like receptor 4 prevents LPS-mediated shedding of CD163. Furthermore, activation of two other cell surface Toll-like receptors (TLR), TLR2 and TLR5, induces shedding of the HbSR from human monocytes. In contrast, treatment of monocytes with intracellular TLR3, TLR7, and TLR9 agonists failed to cause HbSR shedding, suggesting that this shedding event is selective to cell surface TLR activation. These data demonstrate that the soluble HbSR is released from monocytic cells in response to TLR signaling as an acute innate immune response to extracellular pathogen infections.

Antigens, CD↗

PubMed2026

Parkinson Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation.

BACKGROUND AND OBJECTIVES: Known pathogenic variants (PVs) in Parkinson disease (PD) contribute to disease development but have yet to be fully explored by arrays on a large scale. This study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of PVs across ancestries. METHODS: We analyzed the presence and allele frequency of PVs in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson's Genetics Program (GP2) data set. Cluster plots were used to assess the quality of PVs genotyped on NBA. RESULTS: Genes previously predicted to have high or very high confidence of causing PD tend to have more PVs and are present across ancestry groups. Of 34 known PD gene PVs assessed, 25 were typed by NBA and classified as "good" (n = 12), "medium" (n = 4), or "bad" (n = 9) quality variants. DISCUSSION: Our results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for the genotyping of rare variants of PD.

Journal Article↗

PubMed2000

Rational empiric antibiotic prescription in the ICU.

The prescribing of antibiotics in the ICU is usually empiric, given the critical nature of the conditions of patients hospitalized there. Appropriate antibiotic utilization in this setting is crucial not only in ensuring an optimal outcome, but in curtailing the emergence of resistance and containing costs. We propose that research in the ICUs is vitally important in guiding antibiotic prescription practices and, therefore, the achievement of above-stated goals. There is wide institutional diversity in the relative prevalence of predominant pathogens and their antimicrobial susceptibilities, and within individual ICUs there exist unique patient populations with varying risks for and susceptibilities to infections and specific pathogens. Appropriate antibiotic prescription practices should be formulated based on surveillance studies and research at individual ICUs; these goals can be accomplished utilizing existing resources.

Anti-Bacterial Agents↗

PubMed2006

Angioedema without urticaria: a large clinical survey.

BACKGROUND: Angioedema without major urticarial flares (hives) is poorly understood. Its causes are diverse, and little is known about its pathogenic mechanisms. We report on our 11 years of experience with this condition and propose a classification of patients affected by angioedema unaccompanied by urticaria. METHODS: From 1993 through 2003 at our outpatient clinic, 929 consecutive patients were examined for recurrent angioedema unaccompanied by urticaria. A detailed history was taken to identify known causes of angioedema, with special attention to external allergenic agents. Each patient underwent a complete physical examination, routine laboratory tests (blood cell count, protein electrophoresis, erythrosedimentation rate, examination of stool for ova and parasites, pharyngeal and urine cultures, sinus and dental radiography, and measurements of antitissue autoantibodies and rheumatoid factor in plasma), and complement parameters (C1 inhibitor, C4 and C1q). Further testing was done when pertinent, based on clinical findings. When all results were negative, response to H1-antihistamine was considered. RESULTS: Angioedema could not be classified in 153 patients who were lost to follow-up (16.4%). Among the 776 cases with adequate data, these types of angioedema were identified: 124 (16%) related to external agents such as a drug, insect bite or foodstuff; 85 (11%) related to treatment with angiotensin-converting enzyme inhibitor; 55 (7%) associated with an autoimmune disease or infection; and 197 (25%) caused by C1 inhibitor deficiency. In the other 315 cases (41%), the etiology was undiscovered: 254 cases (33% of the study sample) were idiopathic histaminergic; 40 (5%) were idiopathic nonhistaminergic; and 21 (3%) had other causes of peripheral or generalyzed edema. INTERPRETATION: Our data indicated that angioedema without urticaria could be classified according to specific clinical and pathogenic characteristics, and we have suggested a work-up for patients experiencing this condition.

Adolescent↗

PubMed2006

Toll-like receptor modulation in cardiovascular disease: a target for intervention?

Toll-like receptors (TLRs) form a family of pattern recognition receptors that have emerged as key mediators of innate immunity. These receptors sense invading microbes and initiate the immune response. TLR-mediated inflammation is an important pathogenic link between innate immunity and a diverse panel of clinical disorders. Among the processes in which TLRs play a role are cardiovascular disorders such as cardiac ischaemia, coronary artery disease, ventricular remodelling, cancer angiogenesis or transplant rejection. From these, many important opportunities for disease modification through TLR signalling manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated and this article reviews the current status of these treatment strategies for cardiovascular disease.

Animals↗

PubMedDate not supplied

Integrated genetic epidemiology of infectious diseases: the Chagas model.

Genetic typing of pathogenic agents and of vectors has known impressive developments in the last 10 years, thanks to the progresses of molecular biology, and to the contribution of the concepts of evolutionary genetics. Moreover, we know more and more on the genetic susceptibility of man to infectious diseases. I propose here to settle a new, synthetic field of research, which I call 'integrated genetic epidemiology of infectious diseases' (IGEID). I aim at evaluating, by an evolutionary genetic approach, the respective impact, on the transmission and pathogenicity of infectious diseases, of the host's, the pathogen's and the vector's genetic diversity, and their possible interactions (co-evolution phenomena). Chagas' disease constitutes a fine model to develop the IGEID methodology, by both field and experimental studies.

Animals↗

PubMed1998

Biological principles of heredity of and resistance to disease.

Understanding the biological principles of disease heredity and resistance to disease is a prerequisite for the incorporation of these factors into multi-trait breeding programmes. Mutations represent an evolutionary aspect of disease. The author reviews patterns of Mendelian inheritance and possible causes of non-Mendelian inheritance, such as multifactorial inheritance, expansion of trinucleotide repeats, mitochondiral inheritance and genomic imprinting, in relation to diseases of domestic animals. Host-pathogen interactions underlie genetic variability in resistance to disease. Infectious pathogens endowed with a high potential for evolutionary change use this potential to evade various host defence mechanisms. This interaction may have a competitive or co-evolutionary character. The host immune system copes with the variability of pathogens by using the potential of genetic diversity of lymphocytes in immunoglobulin, T-cell receptor and major histocompatibility complex genes. Possible mechanisms for maintenance of this diversity are discussed in the context of selection for disease resistance.

Animals↗

PubMed1998

Interleukin-10 as a regulatory cytokine induced by cellular stress: molecular aspects.

Interleukin-10 is an ubiquitous cytokine which plays a major regulatory role in the course of inflammatory responses by downregulating the synthesis of cytokines. In this paper, we summarize the major biological properties of IL-10 and the current knowledge of the molecular mechanisms by which IL-10 inhibits the expression of genes encoding proinflammatory cytokines. We then review the factors upregulating IL-10 synthesis and we present the concept that IL-10 is a stress cytokine produced not only in response to microbial pathogens but also to cellular injuries of diverse origins.

Animals↗

PubMed1995

A subgroup of human VH3 germline genes that encode a high-avidity synovial rheumatoid factor.

We have previously derived and identified a highly avid monoclonal IgM rheumatoid factor (mRF), C6, from unstimulated rheumatoid synovial cells (RSC). At the time, the closet VH germline gene, VH26, demonstrated only 88% homology with C6. To identify the germline counterpart of C6, genomic DNA from the same rheumatoid arthritis (RA) patient from whom C6 was derived was used in the polymerase chain reaction (PCR). Four of the six closely related germline genes that we sequenced had exonic regions that were identical with the VH region of C6 cDNA. These six germline sequences differed in their intronic regions, suggesting that they were distinct, but closely related genomic sequences. To further evaluate the extent of these related genes we identified nine additional germline genes having VH-encoding exons that were 86-97% identical to the C6 cDNA sequence. Furthermore, we examined the polymorphic nature of the C6 VH gene using single strand conformation polymorphism (SSCP), and identified two peaks, confirming the existence of highly homologous genes. The sequence and polymorphism data suggest that: (1) the VH region of the high avidity mRF C6 was derived from an unmutated germline gene; (2) C6 was encoded by a VH gene belonging to a set of homologous genes within the larger VH3 family; and (3) in addition to somatic rearrangements of B-cell genes and antigen-driven somatic mutation, gene duplication and conversion events of germline genes could be important in generating diversity and polyclonality among high-affinity pathogenic autoantibodies.

Amino Acid Sequence↗

PubMed2000

Unprecedented polymorphism of Mhc-DRB region configurations in rhesus macaques.

The rhesus macaque is an important model in preclinical transplantation research and for the study of chronic and infectious diseases, and so extensive knowledge of its MHC (MhcMamu) is needed. Nucleotide sequencing of exon 2 allowed the detection of 68 Mamu-DRB alleles. Although most alleles belong to loci/lineages that have human equivalents, identical Mhc-DRB alleles are not shared between humans and rhesus macaques. The number of -DRB genes present per haplotype can vary from two to seven in the rhesus macaque, whereas it ranges from one to four in humans. Within a panel of 210 rhesus macaques, 24 Mamu-DRB region configurations can be distinguished differing in the number and composition of loci. None of the Mamu-DRB region configurations has been described for any other species, and only one of them displays major allelic variation giving rise to a total of 33 Mamu-DRB haplotypes. In the human population, only five HLA-DRB region configurations were defined, which in contrast to the rhesus macaque exhibit extensive allelic polymorphism. In comparison with humans, the unprecedented polymorphism of the Mamu-DRB region configurations may reflect an alternative strategy of this primate species to cope with pathogens. Because of the Mamu-DRB diversity, nonhuman primate colonies used for immunological research should be thoroughly typed to facilitate proper interpretation of results. This approach will minimize as well the number of animals necessary to conduct experiments.

Animals↗

PubMed1999

Nonrandom tissue distribution of mutant mtDNA.

Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of inherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect. Marked variation in the level of mutant mtDNA among tissues is thought to be responsible for the diverse clinical phenotypes associated with the same pathogenic mtDNA mutation. This study was designed to determine whether the percentage level of a pathogenic mtDNA molecule is determined by a purely random process. The tissue distribution of the A3243G MELAS point mutation was analyzed in five individuals who were members of a family with maternally inherited diabetes and deafness. The level of mutant mtDNA was measured in four tissues in three individuals and three tissues in two individuals. The highest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocyte/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 x 10(-5). These results indicate that the distribution of the A3243G mutation is not solely determined by random processes.

Adult↗

PubMed1999

Antibiotic resistance: genetic mechanisms and mobility.

Based on the current knowledge, resistance genes seems mainly to originate in the organisms which produce antibiotics (Davies 1994). We lack considerably in the understanding of how these genes were transferred to pathogenic bacteria, and due to the enormous diversity of e.g. the soil flora, it is doubtful that we will ever obtain more that a faint picture of this. In Gram negative bacteria, more and more resistance genes are demonstrated to be located in integrons (e.g. beta-lactamase and streptomycin resistance genes in Salmonella Typhimurium DT104 (Sandvang et al. in press)). Integrons seem primarily to act as insertion sites for resistance genes. The origin of integrons as well as the resistance gene cassettes that are the other essential element of this system, is largely unknown (Hall & Collis 1995). Integrons can be located in the chromosome, in transposons, which have the ability to copy them themselves to other DNA molecules, or on plasmids. The emergence of resistant bacteria normally happens because of selection for a resistant clone of bacteria. Several mechanisms, however, exists by which the resistance genes can be transferred from one bacteria to another. Conjugation, mediated by plasmids or conjugative transposons, is currently the most well established of these mechanisms. Still, however, the selection pressure created by the use of antibiotics determines whether bacteria that have newly acquired a resistance gene expand to dominate in the population or remains a blink in history.

Drug Resistance, Microbial↗

PubMed2000

[Asthma and aspirin intolerance].

Undesirable reactions to aspirin and other non-steroidal antiinflammatory drugs compose a diverse group of clinical manifestations with different pathogenic mechanisms. In this review we describe one particular type of manifestation: aspirin-induced asthma. This syndrome describes a straightforward situation with typical clinical signs. The distinctive sign is asthma triggered by aspirin and NSAID. Data has accumulated over recent years concerning the interference of these drugs with arachidonic acid metabolism in the bronchi and lungs. In patients sensitive to aspirin inhibition of cyclooxygenase is accompanied by overproduction of cysteinyl leucotrienes. The clinical course of this condition, the pathogenic mechanisms of the undesirable reactions to aspirin, and treatment are discussed.

Aspirin↗

PubMed2005

[The research progress on molecular genetics of pathogenicity of rice blast fungus.].

Rice blast disease, caused by heterothallic ascomycete Magnaporthe grisea, is one of the most serious fungal diseases of rice throughout the world. The disease attacks rice plants throughout the season and causes severe yield losses. The pathogenesis of M. grisea is due to a complex process that spans the entire life cycle of the pathogen. The process including germination of conidia, formation of appressoria, differentiation of penetration pegs and proliferation of infectious hyphae is controlled by many genes. The interaction between M. grisea and rice is based on the gene-for-gene hypothesis and the defense responses are often activated by the action of the pathogen avirulence (Avr) gene and the host resistance (R) gene. The studies on molecular biology and genetic mechanism of pathogenicity of M. grisea has occupied pathologists and mycologists for several decades. This paper reviews the research progress related to molecular genetics of pathogenicity of the fungus and its genetic diversity and variation, and summarize research methods of the functional genes.

Genes, Fungal↗

PubMed1976

Complex surveillance of Streptococcus pyogenes. III. Immunological characteristics of streptococcal resistance in blood and new aspects of type nonspecific protection.

The influence of nonspecific immunity factors in indifferent human blood on the resistance of M non-typable field streptococci and collection M strains in the absence of anti-M antibodies was studied. The experimental results indicate that primary resistance is conditioned on balanced equipment of the strain with M protein and the nonspecific cofactor receptor [R]. Disbalanced strains were strongly phagocytized, with participation by nonspecific opsonins (complement C3 and nonspecific cofactor), irrespective of their M protein content. M + R--disbalance (selected collection strains) and M--R + disbalance (field strains on artificial media) were observed. The M and R resistance factor equipment of the streptococci probably represents plus and minus variants in the diverse process of the asymptomatic dissemination and pathogenic activity of streptococci in the human population. The given results are manifestly related to the general manner of existence of streptococci, to questions of conditional pathogenicity and to the concept of nonspecific defence against streptococci.

Antibody Specificity↗

PubMed1995

Babesiosis: new insights from phylogenetic analysis.

Piroplasms of the genus Babesia, along with their relatives to the Theileridae, comprise a genetically and antigenically diverse group of tick-transmitted intraerythrocytic pathogens that together have considerable veterinary, medical, and economic importance. Since the first description of a human case of babesiosis in 1957, this zoonotic infection has now attained a worldwide distribution. In the northeastern and upper midwestern United States, the transmission cycle of Babesia microti overlaps that of another well-known zoonotic agent, Borrelia burgdorferi, the causative agent of Lyme disease. Phylogenetic analysis of Babesia and Babesia-like piroplasms from human and animal sources has shown that many of the small Babesia spp., including B. microti, B. equi, B. gibsoni, and a recently described piroplasm infectious for humans known as WA1, may be phylogenetically related to Theileria. Implications of this observation may include the possible existence of an exoerythrocytic stage of parasite development and attendant features of chronicity, immune suppression, and perhaps lymphoproliferation. In this review, we provide a brief summary of recent developments in the study of Babesia and related piroplasms and speculate on the ramifications of chronic babesial infection in humans.

Adolescent↗

PubMed1996

Flanking residues alter antigenicity and immunogenicity of multi-unit CTL epitopes.

CD8+ CTL responses constitute a critical component for vaccines developed to eliminate intracellular pathogens. One approach to achieve broad CTL diversity is based on genetically linking immunogenic peptides from multiple proteins to form poly-epitope Ags. To address the influence of flanking residues on class I Ag presentation, H-2d-restricted HIV-1 and mouse hepatitis virus CTL epitopes were linked via various spacer residues. The resulting 20 to 31 amino acid peptides were expressed using recombinant vaccinia viruses to monitor both CTL recognition and induction. Our data indicate that recognition is profoundly influenced by the nature of intervening residues forming carboxyl-terminal flanks for one and amino-terminal flanks for the other epitope. Flanking amino acids with aromatic (tyrosine), basic (lysine), and small aliphatic side chains (alanine) supported efficient CTL recognition of both epitopes. By contrast, acidic and helix breaking residues (glycine, proline) specifically inhibited recognition of the adjacent amino-terminal epitope. Flanking residues inhibitory for recognition were also detrimental for CTL induction, suggesting similar processing mechanisms in vitro and in vivo. The ratios of peptide-specific CTL precursors primed by the tandem epitopes varied up to 50-fold depending on molecular context. These data demonstrate a substantial role of carboxyl-flanking residues in governing the efficiency of class I Ag presentation both in vitro and in vivo. The dramatic influence of flanking residues on the hierarchy of CTL responses indicates that CTL induction by poly-epitope Ags can be optimized by strategically linking epitopes via selection of appropriate spacer residues.

Animals↗