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PubMed2006

The weapon potential of human pathogenic fungi.

With the exception of Coccidioides spp., human pathogenic fungi are not found among lists of microbes with potential for biological warfare and bioterrorism against humans. However, many human pathogenic fungi are easily obtainable from the environment, are highly dispersible and can cause significant disease after inhalation with relatively low inocula. When the biological and pathogenic attributes of certain human pathogenic fungi are considered using a formula for calculating the relative weapon potential of a microbe it is as apparent that some organisms such as Coccidioides spp. are comparable to other microbes for which there is significant concern. Our analysis suggests that the current indifference to fungi as potential biological weapons against human populations is probably a perception engendered by their non-communicability, lack of history of use or development as biological weapons, and a relatively low incidence of symptomatic disease following natural infection. Awareness of the weapon potential of human pathogenic fungi is an important consideration for greater preparedness against the threat posed by biowarfare and bioterrorism.

Biological Warfare↗

PubMed1964

PORCINE CONTAGIOUS PLEUROPNEUMONIA. II. STUDIES OF THE PATHOGENICITY OF THE ETIOLOGICAL AGENT, HEMOPHILUS PLEUROPNEUMONIAE.

Hemophilus pleuropneumoniae is highly pathogenic for swine when given intranasally. As few as 100 organisms induce characteristic porcine contagious pleuropneumonia (PCP) and, when as many as one-half million are given, the infection usually proceeds to a fatal termination. While the organism is highly pathogenic when introduced by way of the respiratory tract, it is innocuous when given subcutaneously even in large numbers. Swine that have been inoculated subcutaneously are rendered solidly immune to infection with H. pleuropneumoniae intranasally. The marked pathogenicity of H. pleuropneumoniae for swine has been contrasted with the lack of pathogenicity of another swine Hemophilus, H. influenzae suis. It has been pointed out that, in its high degree of pathogenicity, in its pneumotropism, and in its immunogenicity by a non-respiratory route of inoculation, H. pleuropneumoniae appears to resemble certain viruses more than it does a bacterium.

Actinobacillus pleuropneumoniae↗

PubMed1990

Characterization of an immuno-dominant variable surface antigen from pathogenic and nonpathogenic Entamoeba histolytica.

A 125-kD surface antigen of Entamoeba histolytica is recognized by 73% of immune sera from patients with amoebic liver abscesses. Using pooled human immune sera a cDNA clone (lambda cM17) encoding this antigen (M17) has been isolated from a lambda gt11 expression library of the virulent stain E. histolytica HM1:IMSS. Monospecific antibodies, purified by binding to phage lysate of lambda cM17, and mAb FA7 reacted exclusively with the 125-kD antigen by Western blot analysis. Surface binding and cap formation are observed with patient sera, purified monospecific antiserum, and mAb FA7. Corresponding genomic clones (pBSgM17-1/2/3) were isolated by hybridization with the cDNA clone. These contained an open-reading frame of 3345 bp, which is in good agreement with the mRNA size of approximately 3.0 kb as revealed by Northern hybridization with lambda cM17. The inferred amino acid sequence predicts a 125,513 dalton protein that contains 17 potential N-linked glycosylation sites and is unusually rich in tyrosine and asparagine residues. A distinctly hydrophobic NH2-terminal region may serve as membrane anchor or signal sequence. In contrast to conservation of an immunodominant epitope recognized in pathogenic and nonpathogenic strains by monoclonal FA7 and human immune sera, amplification and sequence analysis of a 1,4000-bp fragment of this gene from a fresh nonpathogenic isolate by use of the PCR demonstrate regions of significant sequence divergence in this antigen. A 1% sequence variability among different isolates of the pathogenic strain HM1:IMSS and a 12-13% variability between pathogenic and nonpathogenic strains are revealed by comparison to published partial amino acid sequences (Tannich, E., R.D. Horstmann, J. Knobloch, and H.H. Arnold. 1989. Proc. Natl. Acad. Sci. USA. 86:5118). Some restriction enzymes were found that allowed PCR diagnosis of nonpathogenic and pathogenic isolates with the exclusion of E. histolytica-like Laredo, suggesting that a detailed study of nonpathogenic and pathogenic isolates in relation to the M17 antigen sequence will provide a basis of differentiating isolates.

Amebiasis↗

PubMed1994

Mutational analysis of an autoantibody: differential binding and pathogenicity.

We have used site-directed mutagenesis to change amino acid residues in the heavy chain of the pathogenic R4A anti-double-stranded DNA (dsDNA) antibody and have looked for resultant alterations in DNA binding and in pathogenicity. The data demonstrate that single amino acid substitutions in both complementarity determining and framework regions alter antigen binding. Changes in only a few amino acids entirely ablate DNA specificity or cause a 10-fold increase in relative binding. In vivo studies in mice of the pathogenicity of the mutated antibodies show that a single amino acid substitution leading to a loss of dsDNA binding leads also to a loss of glomerular sequestration. Amino acid substitutions that increase relative affinity for dsDNA cause a change in localization of immunoglobulin deposition from glomeruli to renal tubules. These studies demonstrate that small numbers of amino acid substitutions can dramatically alter antigen binding and pathogenicity, and that the pathogenicity of anti-DNA antibodies does not strictly correlate with affinity for DNA.

Amino Acid Sequence↗

PubMed1998

Characterization of a hemoglobin protease secreted by the pathogenic Escherichia coli strain EB1.

Many pathogenic bacteria can use heme compounds as a source of iron. Pathogenic Escherichia coli strains are capable of using hemoglobin as an iron source. However, the mechanism of heme acquisition from hemoglobin is not understood for this microorganism. We present the first molecular characterization of a hemoglobin protease (Hbp) from a human pathogenic E. coli strain. The enzyme also appeared to be a heme-binding protein. Affinity purification of this bifunctional protein enabled us to identify the extracellular gene product, and to clone and analyze its gene. A purification procedure developed for Hbp allowed us to perform functional studies. The protein interacted with hemoglobin, degraded it and subsequently bound the released heme. These results suggest that the protein is involved in heme acquisition by this human pathogen. Hbp belongs to the so-called IgA1 protease-like proteins, as indicated by the kinetics of its membrane transfer and DNA sequence similarity. The gene of this protein appears to be located on the large pColV-K30 episome, that only has been isolated from human and animal pathogens. All these characteristics indicate that Hbp may be an important virulence factor that may play a significant role in the pathogenesis of E. coli infections.

Bacterial Proteins↗

PubMed2004

Population dynamics of pathogens with multiple host species.

Pathogens that can infect multiple host species will have different dynamics than pathogens that are restricted to a single species of host. This article examines the conditions for establishment and long-term population dynamic behavior of pathogens that infect multiple species of hosts. The article attempts to address three major questions in this area: First, under which conditions will increases in the diversity of host species buffer infectious disease outbreaks, and under which conditions will host diversity amplify disease outbreaks? Second, under what conditions is it possible to control an infectious agent by focusing control against only one host species? Third, what role does host species diversity play in maintaining pathogen persistence? The answers to these questions supply some important general insights into the role that biodiversity plays in buffering humans and other species against new and emerging pathogens.

Animals↗

PubMed2005

The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209L region.

The innate immunity system constitutes the first line of host defense against pathogens. Two closely related innate immunity genes, CD209 and CD209L, are particularly interesting because they directly recognize a plethora of pathogens, including bacteria, viruses, and parasites. Both genes, which result from an ancient duplication, possess a neck region, made up of seven repeats of 23 amino acids each, known to play a major role in the pathogen-binding properties of these proteins. To explore the extent to which pathogens have exerted selective pressures on these innate immunity genes, we resequenced them in a group of samples from sub-Saharan Africa, Europe, and East Asia. Moreover, variation in the number of repeats of the neck region was defined in the entire Human Genome Diversity Panel for both genes. Our results, which are based on diversity levels, neutrality tests, population genetic distances, and neck-region length variation, provide genetic evidence that CD209 has been under a strong selective constraint that prevents accumulation of any amino acid changes, whereas CD209L variability has most likely been shaped by the action of balancing selection in non-African populations. In addition, our data point to the neck region as the functional target of such selective pressures: CD209 presents a constant size in the neck region populationwide, whereas CD209L presents an excess of length variation, particularly in non-African populations. An additional interesting observation came from the coalescent-based CD209 gene tree, whose binary topology and time depth (approximately 2.8 million years ago) are compatible with an ancestral population structure in Africa. Altogether, our study has revealed that even a short segment of the human genome can uncover an extraordinarily complex evolutionary history, including different pathogen pressures on host genes as well as traces of admixture among archaic hominid populations.

Bacterial Infections↗

PubMed1992

Rapid inactivation of infectious pathogens by chlorhexidine-coated gloves.

OBJECTIVE: Gloves containing chlorhexidine gluconate in an instant-release matrix on their inner surface (CHG gloves) were tested to determine their ability to rapidly inactivate infectious pathogens that may permeate or leak through the latex surface. DESIGN: CHG gloves were exposed for 1 to 10 minutes to blood or media containing infectious pathogens (e.g., bacteria, fungi, parasites, and viruses) as well as to lymphocytes and macrophages that are known to be the primary carriers of human immunodeficiency virus (HIV). Inactivation of pathogens was determined either by in vitro assay or in vivo infectivity. Stressed control and CHG glove fingers were submerged in a viral pool (retrovirus or bacteriophage) and after a set time, the glove interiors were checked for presence of permeated virions. RESULTS: CHG gloves rapidly inactivate all the pathogens tested including retrovirus and hepatitis B virus (90% to 100%). In the stressed glove fingers, live virus was detected in 26% of the control group but not in any of the CHG group. CONCLUSIONS: The use of CHG gloves may reduce the risk of exposure to infectious fluid-borne pathogens should the integrity of the latex barrier be compromised by overt failure or by permeation of viruses. Rapid destruction of lymphocytes and macrophages may facilitate inactivation of HIV associated with these cells. Tests have shown that CHG coating does not alter physical properties of the glove, and, furthermore, CHG gloves do not show potential for dermal irritation or sensitization.

Animals↗

PubMed2004

Antimicrobial resistance among gram-negative foodborne bacterial pathogens associated with foods of animal origin.

Antimicrobial-resistant foodborne pathogens are acquired primarily through consumption of contaminated food of animal origin or water. While there is much disagreement on the health burden imposed by resistance in foodborne bacterial pathogens, it is generally agreed that the use of antimicrobials, whether for growth promotion, prevention, or treatment, can select for resistant bacterial pathogens, and that these pathogens can be transmitted on food originating from sites processing treated animals. Information on the evolution and dissemination of antimicrobial resistance in foodborne pathogens shows that the situation is complex and differs by organism and antimicrobial. A clearer understanding of the ecology of resistance is needed in order to support science-based assessments of the public health risks due to the use of antimicrobials in the animal husbandry environment.

Animal Husbandry↗

PubMed1995

Primate erythrocyte (E) complement receptor (CR1) as an anchor site for bispecific-based therapies to clear pathogens or autoantibodies safely from the circulation.

We have prepared cross-linked, bispecific complexes [heteropolymers (HP) and antigen-based heteropolymers (AHP)] that facilitate complement-independent binding of target model pathogens or autoantibodies to primate erythrocytes (E) via complement receptors (CR1). The method is based on using monoclonal antibodies (mAb) specific for CR1 that either are cross-linked to an mAb specific for a prototype pathogen (e.g., IgE) or are cross-linked to an autoantigen (e.g., dsDNA) that is recognized by circulating pathogenic autoantibodies in the autoimmune disease systemic lupus erythematosus (SLE). The underlying assumption in this research is that complexed ligands containing IgG bound to primate E CR1 should be recognized and processed via the same mechanism by which complement-opsonized immune complexes bound to E CR1 are cleared from the circulation and phagocytosed in the liver and spleen. Our work in experimental monkey models has demonstrated that binding of substrates to primate E via this method does indeed lead to the safe and rapid clearance of the target pathogens or autoantibodies from the circulation, without any lysis or loss of the E. Although a number of questions must still be resolved, it may be possible to generalize these findings and use this CR1-based approach to develop a simple noninvasive bispecific therapy that can be used to clear pathogens or autoantibodies from the circulation.

Animals↗

PubMed2006

Host defense mechanisms against pathogens.

BACKGROUND AND PURPOSE: The body is under constant assault by potentially harmful microbes. Both innate and adaptive immune responses counteract the action of pathogens. METHOD: Review of the pertinent literature. RESULTS: The innate response is focused mainly on physically eliminating the pathogens, mostly by phagocytosis, while the adaptive response reacts specifically to, and neutralizes, a given pathogen and maintains a memory of it for safer and faster elimination on subsequent encounters. CONCLUSION: The basic mechanisms of pathogen elimination by the immune system and some mechanisms of evasion of the immune response by pathogens are discussed.

Bacterial Infections↗

PubMed1994

The effects of nonclassic pediatric bacterial pathogens on the usefulness of the Directigen latex agglutination test.

Haemophilus influenzae type b, Escherichia coli, Neisseria meningitis, Streptococcus agalactiae, and Streptococcus pneumoniae are classically the predominant meningeal pathogens of children. The Directigen latex agglutination test identifies these pathogens by detecting specific antigens in cerebrospinal fluid (CSF) and urine. The authors tested 1151 specimens from 791 children with suspected meningeal infections. They found that the sensitivity of the Directigen test for detecting the five classic CSF pathogens of children was 83.3% with CSF and 60% with urine specimens. In detecting all pathogens, however, the sensitivity was only 50% with CSF and 37.5% with urine. Thus, an increased prevalence of nonclassic pathogens in a pediatric population adversely affects the efficacy of the Directigen test for confirming a diagnosis of meningitis and emphasizes the diagnostic importance of the clinical history and other routine CSF tests.

Antigens, Bacterial↗

PubMed2006

Antiviral effects on influenza viral transmission and pathogenicity: observations from household-based trials.

Four household-based, randomized clinical trials, two each of zanamivir and oseltamivir, were designed primarily to estimate the effect of postexposure prophylaxis on preventing influenza illness in household contacts. However, the effect of influenza antivirals on infectiousness as well as on the ability of the virus to cause disease--the pathogenicity--have important public health consequences. The authors show how such studies can provide estimates of pathogenicity, antiviral efficacy for pathogenicity, and the antiviral effect on infectiousness. Analysis of the four studies confirmed the high prophylactic efficacy against illness of both zanamivir (75%, 95% confidence interval (CI): 54, 86) and oseltamivir (81%, 95% CI: 35, 94). The effect on reducing infectiousness was 19% (95% CI: -160, 75) for zanamivir and 80% (95% CI: 43, 93) for oseltamivir. Pathogenicity in controls ranged from 44% (95% CI: 33, 55) to 66% (95% CI: 48, 72). Efficacy in reducing pathogenicity for zanamivir was 52% (95% CI: 19, 72) and 56% (95% CI: 14, 77) in the two studies; for oseltamivir, it was 56% (95% CI: 10, 73) and 79% (95% CI: 45, 92). Studies of influenza antivirals in transmission units would be improved if randomization schemes were used that allow estimation of the antiviral effect on infectiousness from individual studies.

Antiviral Agents↗

PubMed2026

TaxTriage: an open-source metagenomic sequencing data analysis pipeline enabling putative pathogen detection.

MOTIVATION: TaxTriage is a comprehensive pathogen identification workflow designed for both short- and long-read untargeted DNA and RNA sequencing data. Combining read classification, mapping, and de novo assembly approaches, putative pathogens are identified through comparisons to curated pathogens and abundance expectations from healthy cohort data. Flexible installation options are enabled using Nextflow™ (NF), including cloud deployment via NF Tower (Seqera Platform) and local installation on a variety of systems, including standalone installations without external internet access. Final analysis summaries are compiled into an Organism Discovery Report, which lists likely pathogens and supporting data, including a custom confidence score. RESULTS: Evaluation of published in silico, clinical, and outbreak datasets identified performance comparable to alternative cloud-based processing pipelines for expected pathogen and co-infection detection with similar sensitivity and increased specificity. To support both public health and veterinary diagnostics communities, customization options have been incorporated to enable improved performance for host species of interest. AVAILABILITY AND IMPLEMENTATION: Source code for TaxTriage is freely available at https://github.com/jhuapl-bio/taxtriage. TaxTriage v2.1.1 has been archived on Zenodo at https://zenodo.org/records/17081354 to permit reproducible analysis as described in this manuscript.

Software↗

PubMed2004

PIML: the Pathogen Information Markup Language.

MOTIVATION: A vast amount of information about human, animal and plant pathogens has been acquired, stored and displayed in varied formats through different resources, both electronically and otherwise. However, there is no community standard format for organizing this information or agreement on machine-readable format(s) for data exchange, thereby hampering interoperation efforts across information systems harboring such infectious disease data. RESULTS: The Pathogen Information Markup Language (PIML) is a free, open, XML-based format for representing pathogen information. XSLT-based visual presentations of valid PIML documents were developed and can be accessed through the PathInfo website or as part of the interoperable web services federation known as ToolBus/PathPort. Currently, detailed PIML documents are available for 21 pathogens deemed of high priority with regard to public health and national biological defense. A dynamic query system allows simple queries as well as comparisons among these pathogens. Continuing efforts are being taken to include other groups' supporting PIML and to develop more PIML documents. AVAILABILITY: All the PIML-related information is accessible from http://www.vbi.vt.edu/pathport/pathinfo/

Bacteria↗

PubMed2002

Vaccines against dangerous pathogens.

Dangerous pathogens are defined by the UK Health and Safety Executive's advisory committee as category 3 (those which cause severe human disease for which prophylaxis or therapy is usually available) or category 4 (as for category 3, but for which prophylaxis or therapy is not available). Research and development of vaccines for such pathogens is challenging, due to the safety constraints in the manipulation of these pathogens. This chapter discusses the various approaches which can be taken to develop candidate vaccines for these pathogens, including the potential impact of genome sequencing on shortening the time required for R&D. For these pathogens, a direct test of the efficacy of the candidate vaccines in man is not ethical and, therefore, particular emphasis is placed on the demonstration of efficacy in animal models. Emphasis is also placed on the derivation of surrogate markers of efficacy and a demonstration that these correlate with protection in the animal model.

Animals↗

PubMedDate not supplied

Epidemiology of travelers' diarrhea and relative importance of various pathogens.

Each year 12 million persons travel from an industrialized country to a developing country in the tropics or subtropics. These travelers experience a high rate of diarrhea caused by a wide variety of enteric pathogens acquired by ingestion of contaminated food or water. One or more pathogens can be found in the stool of a majority of ill individuals. Enterotoxigenic Escherichia coli generally are the most frequently identified pathogens, having been found in a median of 42% of travelers' diarrheal episodes in studies in Latin America, 36% in Africa, and 16% in Asia. Other pathogens that cause diarrhea in a smaller fraction of ill travelers include Shigella species, Salmonella species, Campylobacter jejuni, Vibrio, Aeromonas hydrophila, Entamoeba histolytica, Giardia lamblia, rotavirus, and 27-nm viruses, including Norwalk virus. Other organisms that may cause a fraction of the episodes of travelers' diarrhea include Plesiomonas shigelloides, enteroadherent E. coli, adenovirus or other viruses, and Cryptosporidium. Mixed infections of two or more of these pathogens also occur.

Developing Countries↗

PubMed1997

The Salmonella selC locus contains a pathogenicity island mediating intramacrophage survival.

Pathogenicity islands are chromosomal clusters of horizontally acquired virulence genes that are often found at tRNA loci. The selC tRNA locus of Escherichia coli has served as the site of integration of two distinct pathogenicity islands which are responsible for converting benign strains into uro- and enteropathogens. Because virulence genes are targeted to the selC locus of E.coli, we investigated the homologous region of the Salmonella typhimurium chromosome for the presence of horizontally acquired sequences. At this site, we identified a 17 kb DNA segment that is both unique to Salmonella and necessary for virulence. This segment harbors a gene, mgtC, that is required for intramacrophage survival and growth in low Mg2+ media. The mgtC locus is regulated by the PhoP/PhoQ two-component system, a major regulator of virulence functions present in both pathogenic and non-pathogenic bacterial species. Cumulatively, our experiments indicate that the ability to replicate in low Mg2+ environments is necessary for Salmonella virulence, and suggest that a similar mechanism is responsible for the dissemination and acquisition of pathogenicity islands in enteric bacteria.

Adenosine Triphosphatases↗