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Results for “host:pathogen interactions”

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PubMed1999

In vivo genetic analysis of bacterial virulence.

In vitro assays contribute greatly to our understanding of bacterial pathogenesis, but they frequently cannot replicate the complex environment encountered by pathogens during infection. The information gained from such studies is therefore limited. In vivo models, on the other hand, can be difficult to use, and this has to some extent diminished the incentive to perform studies in living animals. However, several recently developed techniques permit in vivo examination of many genes simultaneously. Most of these methods fall into two broad classes: in vivo expression technology and signature-tagged mutagenesis. In vivo expression technology is a promoter-trap strategy designed to identify genes whose expression is induced in a specific environment, typically that encountered in a host. Signature-tagged mutagenesis uses comparative hybridization to isolate mutants unable to survive specified environmental conditions and has been used to identify genes critical for survival in the host. Both approaches have so far been used exclusively for investigating pathogen-host interactions, but they should be easily adaptable to the study of other processes.

Animals↗

PubMed2004

Tobacco mosaic virus: a model system for plant biology.

Tobacco mosaic virus (TMV) has had an illustrious history for more than 100 years, dating to Beijerinck's description of the mosaic disease of tobacco as a contagium vivum fluidum and the modern usage of the word "virus." Since then, TMV has been acknowledged as a preferred didactic model and a symbolic model to illuminate the essential features that define a virus. TMV additionally emerged as a prototypic model to investigate the biology of host plants, namely tobacco. TMV also exemplifies how a model system furthers novel, and often unexpected, developments in biology and virology. Today, TMV is used as a tool to study host-pathogen interactions and cellular trafficking, and as a technology to express valuable pharmaceutical proteins in tobacco. The history of TMV illustrates how pragmatic strategies to control an economically important disease of tobacco have had unexpected and transforming effects across platforms that impinge on plant health and public health.

Agriculture↗

PubMed2006

Evolution of plant pathogenicity in Streptomyces.

Among the multitude of soil-inhabiting, saprophytic Streptomyces species are a growing number of plant pathogens that cause economically important diseases, including potato scab. Streptomyces scabies is the dominant pathogenic species worldwide, but is only one of many that cause very similar disease symptoms on plants. Molecular genetic analysis is beginning to identify the mechanisms used by plant pathogenic species to manipulate their hosts. The nitrated dipeptide phytotoxin, thaxtomin, inhibits cellulose biosynthesis in expanding plant tissues, stimulates Ca2+ spiking, and causes cell death. A secreted necrogenic protein, Nec1, contributes to virulence on diverse plant species. The thaxtomin biosynthetic genes and nec1 lie on a large mobilizable PAI, along with other putative virulence genes including a cytokinin biosynthetic pathway and a saponinase homolog. The PAI is mobilized during conjugation and site-specifically inserts in the linear chromosome of recipient species, accounting for the emergence of new pathogens in agricultural systems. The recently available genome sequence of S. scabies will accelerate research on host-pathogen interactions.

Biological Evolution↗

PubMed2006

The dawn of fungal pathogen genomics.

Recent advances in sequencing technologies have led to a remarkable increase in the number of sequenced fungal genomes. Several important plant pathogenic fungi are among those that have been sequenced or are being sequenced. Additional fungal pathogens are likely to be sequenced in the near future. Analysis of the available genomes has provided useful information about genes that may be important for plant infection and colonization. Genome features, such as repetitive sequences, telomeres, conserved syntenic blocks, and expansion of pathogenicity-related genes, are discussed in detail with Magnaporthe oryzae (M. grisea) and Fusarium graminearum as examples. Functional and comparative genomic studies in plant pathogenic fungi, although still in the early stages and limited to a few pathogens, have enormous potential to improve our understanding of the molecular mechanisms involved in host-pathogen interactions. Development of advanced genomics tools and infrastructure is critical for efficient utilization of the vast wealth of available genome sequence information and will form a solid foundation for systems biology studies of plant pathogenic fungi.

Fungi↗

PubMed2000

Public health genetics: an emerging interdisciplinary field for the post-genomic era.

Public health genetics is an exciting interdisciplinary area that brings all the public health sciences to bear on the emerging challenge of interpreting the medical and public health significance of genetic variation within populations. Sequencing of the human genome will generate an avalanche of genetic information to be linked with information about microbial, chemical, and physical exposures; nutrition, metabolism, lifestyle behaviors, and medications. The public health genetics mini-symposium in this volume includes articles dealing with educational innovations, host-pathogen interactions in infectious diseases, nutrition/genetic interactions in cancers, and population screening for hemochromatosis. Additional topics addressed here are ecogenetics and risk assessment, the genetics of unhealthful behaviors, and ethical and policy issues. Finally, a set of principles for community-based health research in populations is presented as a public health-oriented counterpart to the principle of autonomy and the practice of informed consent that have become key elements of ethics in medical care and medical research with individuals.

Ethics, Medical↗

PubMed2006

Cortactin: the gray eminence of the cytoskeleton.

Cortactin, an actin filament-binding protein and target of multiple kinases, has emerged as a central element connecting signaling pathways with cytoskeleton restructuring. It is involved in a perplexingly diverse array of cellular processes, including cell motility, invasiveness, synaptogenesis, endocytosis, intercellular contact assembly, and host-pathogen interactions, where the common denominator appears to be a role in the coordination of membrane dynamics with cytoskeletal remodeling. Although in recent years our knowledge about cortactin has increased exponentially, the exact mechanisms underlying its fundamental roles remain to be defined.

Animals↗

PubMed2006

Serine threonine protein kinases of mycobacterial genus: phylogeny to function.

Serine/threonine protein kinases (STPKs) are known to act as sensors of environmental signals that thereby regulate developmental changes and host pathogen interactions. In this study, we carried out comparative genome analysis of six completely sequenced pathogenic and nonpathogenic mycobacterial species to systematically characterize the STPK complement of mycobacterium. Our analysis revealed that while Mycobacterium tuberculosis strains have 11 conserved kinases, this number varies from 4 to 24 in other mycobacterial species. pknA, an essential STPK encoding gene, was found to be truncated in the initial analysis of M. avium subsp. paratuberculosis (Map) and M. tuberculosis C genomes. However, resequencing of pknA gene in Map confirmed that the truncation was due to a sequencing error. The conservation of division and cell wall gene cluster involved in cell envelope biosynthesis and cell division, in the vicinity of pknL locus, implicates a possible role of PknL in cell division and envelop biosynthesis. We identified a cyclophilin domain as part of a mycobacterial kinase in Map that suggests a plausible regulation of cyclophilins by phosphorylation. The co-inheritance of pknA, pknB, pknG, and pknL loci across genomes and some unique repertoire of pathogen-specific kinases such as pknI and pknJ of Mtb complex suggest similitude and divergence between pathogenic and nonpathogenic signaling. This study would add another dimension toward identification of physiological substrates and thereby function, while resolving the existing complexities in signaling network between the two domains of life, pathogen and nonpathogen.

Bacterial Proteins↗

PubMed2003

Proteomics in Vaccinology and Immunobiology: An Informatics Perspective of the Immunone.

The postgenomic era, as manifest, inter alia, by proteomics, offers unparalleled opportunities for the efficient discovery of safe, efficacious, and novel subunit vaccines targeting a tranche of modern major diseases. A negative corollary of this opportunity is the risk of becoming overwhelmed by this embarrassment of riches. Informatics techniques, working to address issues of both data management and through prediction to shortcut the experimental process, can be of enormous benefit in leveraging the proteomic revolution. In this disquisition, we evaluate proteomic approaches to the discovery of subunit vaccines, focussing on viral, bacterial, fungal, and parasite systems. We also adumbrate the impact that proteomic analysis of host-pathogen interactions can have. Finally, we review relevant methods to the prediction of immunome, with special emphasis on quantitative methods, and the subcellular localization of proteins within bacteria.

Journal Article↗

PubMed2004

Early predictors of in-hospital death in infective endocarditis.

BACKGROUND: Data on early determinants of outcome in infective endocarditis (IE) are limited. We evaluated the prognostic significance of early clinical characteristics in a large, prospective cohort of patients with IE. METHODS AND RESULTS: Two hundred sixty-seven consecutive patients with definite or possible IE by modified Duke criteria and echocardiography performed within 7 days of presentation were evaluated. Acute physiology was assessed by the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score at the time of presentation, and early heart failure was diagnosed by Framingham criteria. In-hospital mortality rate in the cohort was 19% and similar for patients with definite or possible IE (20% versus 16%, respectively; P=0.464). Independent predictors of death determined by logistic regression modeling were diabetes mellitus (OR 2.48; 95% CI, 1.24 to 4.96), Staphylococcus aureus as causative organism (OR, 2.06; 95% CI, 1.01 to 4.20), APACHE II score (OR, 1.07; 95% CI, 1.01 to 1.12), and embolic event (OR, 2.79; 95% CI, 1.15 to 6.80). Early echocardiographic findings of the Duke criteria were not predictive of death. CONCLUSIONS: Early in the course of IE, readily available clinical characteristics that reflect the host-pathogen interaction are predictive of in-hospital death. These factors may identify those patients with IE for more aggressive treatment.

APACHE↗

PubMed2006

Haemophilus influenzae forms biofilms on airway epithelia: implications in cystic fibrosis.

RATIONALE: Nontypeable Haemophilus influenzae (NTHi) commonly infects patients with cystic fibrosis (CF), especially early in childhood. Bacteria biofilms are increasingly recognized as contributing to bacterial persistence and disease pathogenesis in CF. OBJECTIVES: This study investigated ability of NTHi to form biofilms and its impact on airway epithelia using in vivo and in vitro analyses. METHODS: We evaluated bronchoalveolar lavage fluid from young patients with CF for evidence of NTHi biofilms. To further investigate the pathogenesis of NTHi in respiratory infections, we developed a novel in vitro coculture model of NTHi biofilm formation on polarized human airway epithelial cells grown at the air-liquid interface. MEASUREMENTS AND MAIN RESULTS: In bronchoalveolar lavage fluid samples from young, asymptomatic patients with CF, we found morphologic evidence suggestive of NTHi biofilm formation. In addition, 10 clinical NTHi isolates from patients with CF formed biofilms on plastic surfaces. NTHi formed biofilms on the apical surface of cultured airway epithelia. These biofilms exhibited decreased susceptibility to antibiotics and were adherent to epithelial surfaces. Airway epithelial cells remained viable throughout 4 d of coculture, and responded to NTHi with nuclear factor-kappaB signaling, and increased chemokine and cytokine secretion. CONCLUSIONS: NTHi formed adherent biofilms on the apical surface airway epithelia with decreased susceptibility to antibiotics, and respiratory cells exhibited inflammatory and host defense responses-evidence of a dynamic host-pathogen interaction. The data presented here have implications both for understanding early CF lung disease pathogenesis and for the treatment of early, asymptomatic colonization of patients with CF with H. influenzae.

Biofilms↗

PubMed2026

Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.

Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.

Humans↗

PubMed1997

Inactivation of Streptococcus pyogenes extracellular cysteine protease significantly decreases mouse lethality of serotype M3 and M49 strains.

Cysteine proteases have been implicated as important virulence factors in a wide range of prokaryotic and eukaryotic pathogens, but little direct evidence has been presented to support this notion. Virtually all strains of the human bacterial pathogen Streptococcus pyogenes express a highly conserved extracellular cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB). Two sets of isogenic strains deficient in SpeB cysteine protease activity were constructed by integrational mutagenesis using nonreplicating recombinant plasmids containing a truncated segment of the speB gene. Immunoblot analyses and enzyme assays confirmed that the mutant derivatives were deficient in expression of enzymatically active SpeB cysteine protease. To test the hypothesis that the cysteine protease participates in host mortality, we assessed the ability of serotype M3 and M49 wild-type strains and isogenic protease-negative mutants to cause death in outbred mice after intraperitoneal inoculation. Compared to wild-type parental organisms, the serotype M3 speB mutant lost virtually all ability to cause mouse death (P < 0.00001), and similarly, the virulence of the M49 mutant was detrimentally altered (P < 0.005). The data unambiguously demonstrate that the streptococcal enzyme is a virulence factor, and thereby provide additional evidence that microbial cysteine proteases are critical in host-pathogen interactions.

Animals↗

PubMed2004

Characterization of a wild-type strain of Francisella tularensis isolated from a cat.

Francisella tularensis type A is the primary cause of tularemia in animals and humans in North America. The majority of research on F. tularensis has been done with the attenuated live vaccine strain (LVS), which is a type B, but very few wild-type F. tularensis strains have been characterized. A gram-negative coccobacillus that was isolated in pure culture from the lungs of a cat that died after being lost for 5 days was received for identification at the Virginia-Maryland Regional College of Veterinary Medicine Teaching hospital. The isolate (strain TI0902) was not identified (or was misidentified) by commercial identification systems; however, it was identified as F. tularensis subspecies tularensis (type A) by sequencing a portion of the 16S ribosomal RNA gene. Furthermore, repetitive extragenic palindromic sequences-polymerase chain reaction amplified a 4-kb DNA fragment from TI0902 that was characteristic of F. tularensis type A but not type B. The electrophoretic profile of the lipopolysaccharide of strain TI0902 was identical to that of the LVS by Western blotting with antiserum to LVS. The protein-enriched outer membrane of strain TI0902 contained 6-8 proteins, which were similar in molecular size to those from the LVS. Electron microscopy of negatively stained and alcian blue-stained LVS and TI0902 cells showed that both strains were coccobacillary in shape and may be encapsulated. However, after mouse challenge, the TI0902 strain was clearly more virulent than the LVS strain. Results of this study indicate that the genotype and phenotype of wild-type F. tularensis type A strain TI0902 is similar, but not identical, to that of the LVS strain. Further studies will help determine whether pathogenesis and host-pathogen interactions are also similar between the 2 strains.

Animals↗

PubMed1998

Epithelial antimicrobial peptides: review and significance for oral applications.

Epithelial tissues provide the first line of defense between an organism and the environment. Disruption of this barrier leads to bacterial invasion and subsequent inflammation. This is precisely the situation existing in the human oral cavity, where tissues are constantly exposed to a variety of microbial challenges that can lead to bacterially induced periodontal diseases, and to infections of the oral mucosa by bacteria, fungi, and viruses. With the recent discoveries of host-derived peptide antibiotics in mammalian mucosal epithelium, a new line of investigation is emerging to test the hypothesis that one class of these peptides, called "beta-defensins", functions to protect the host against microbial pathogenesis at these critical, confrontational sites. In that light, impairment of beta-defensin activity has recently been implicated in chronic bacterial infections in cystic fibrosis patients. The first direct evidence of expression of defensin peptides in the oral mucosa was the identification of a novel epithelial beta-defensin in mammalian tongue. It was shown to be upregulated in inflammation, suggesting that it participates in host defense. It is theorized that epithelial cell-derived antimicrobial peptides function to keep the natural flora of micro-organisms in a steady state in different niches such as the skin, the intestines, the airway, the endocervix, and the mouth. There is now evidence indicating that normal gingival epithelial cells and tissues express two beta-defensins, hBD-1 and the newly described hBD-2. In addition, a cathelin-class antimicrobial peptide, designated LL-37 and found in human neutrophils, is also expressed in skin and gingiva. It is highly likely that these and/or other epithelial antimicrobial peptides play an important role in determining the outcome of the host-pathogen interaction at the oral mucosal barrier, and that they may have important future applications in antibiotic treatment.

Amino Acid Sequence↗

PubMed2003

Genetic and molecular characterization of a dental pathogen using genome-wide approaches.

Actinobacillus actinomycetemcomitans causes periodontitis, a costly chronic infection that affects a large number of patients. The pathogenesis of this dental infection is a multifactorial process that results in a serious degenerative disease of the periodontium. Although significant progress has been achieved after the identification of this Gram-negative bacterium as the etiological agent of this infection, much remains to be done to understand in detail the bacterial factors and host-pathogen interactions involved in the pathogenesis of this disease. Classic research approaches have resulted in the identification of important virulence factors and cellular processes, although they have provided a rather narrow picture of some of the steps of this complex process. In contrast, a much wider picture could be obtained with the application of tools such as bioinformatics and genomics. These tools will provide global information regarding the differential expression of genes encoding factors and processes that lead to the pathogenesis of this disease. Furthermore, comparative genomics has the potential of helping us to understand the emergence and evolution of this human pathogen. This genome-wide approach should provide a more complete picture of the pathogenesis process of this disease, and will facilitate the development of efficient diagnostic, preventive, and therapeutic measures for this disease.

Actinobacillus Infections↗

PubMed1986

Ultrastructural localization of glycoconjugates in the fungus Ascocalyx abietina, the Scleroderris canker agent of conifers, using lectin-gold complexes.

Different glycoconjugates were revealed in the fungus Ascocalyx abietina (Lagerberg.) Schlaepfer-Bernhard, by using various lectin-gold complexes. N-acetylglucosamine, N-acetylgalactosamine, and D-mannose were specifically localized in cell walls of fungal cells. N-acetylneuraminic acid (sialic acid) and L-fucose were detected in structures corresponding to lipid bodies, whereas they were totally absent in the cell wall. This is the first report on the occurrence of sialic acid in fungi and of fucose in Ascomycetes. The great advantage of using lectin-gold complexes for ultrastructural localization of sugars in phytopathogenic fungi, as well as in studies concerning host-pathogen interactions, is discussed.

Acetylgalactosamine↗

PubMed2005

Airway epithelial cell tolerance to Pseudomonas aeruginosa.

BACKGROUND: The respiratory tract epithelium is a critical environmental interface that regulates inflammation. In chronic infectious airway diseases, pathogens may permanently colonize normally sterile luminal environments. Host-pathogen interactions determine the intensity of inflammation and thus, rates of tissue injury. Although many cells become refractory to stimulation by pathogen products, it is unknown whether the airway epithelium becomes either tolerant or hypersensitive in the setting of chronic infection. Our goals were to characterize the response of well-differentiated primary human tracheobronchial epithelial cells to Pseudomonas aeruginosa, to understand whether repeated exposure induced tolerance and, if so, to explore the mechanism(s). METHODS: The apical surface of well-differentiated primary human tracheobronchial epithelial cell cultures was repetitively challenged with Pseudomonas aeruginosa culture filtrates or the bacterial media control. Toxicity, cytokine production, signal transduction events and specific effects of dominant negative forms of signaling molecules were examined. Additional experiments included using IL-1beta and TNFalpha as challenge agents, and performing comparative studies with a novel airway epithelial cell line. RESULTS: An initial challenge of the apical surface of polarized human airway epithelial cells with Pseudomonas aeruginosa culture filtrates induced phosphorylation of IRAK1, JNK, p38, and ERK, caused degradation of IkappaBalpha, generation of NF-kappaB and AP-1 transcription factor activity, and resulted in IL-8 secretion, consistent with activation of the Toll-like receptor signal transduction pathway. These responses were strongly attenuated following a second Pseudomonas aeruginosa, or IL-1beta, but not TNFalpha, challenge. Tolerance was associated with decreased IRAK1 protein content and kinase activity and dominant negative IRAK1 inhibited Pseudomonas aeruginosa--stimulated NF-kappaB transcriptional activity. CONCLUSION: The airway epithelial cell response to Pseudomonas aeruginosa entails adaptation and tolerance likely mediated, in part, by down-regulation of IRAK1.

Cell Line↗

PubMed2004

A plant natriuretic peptide-like gene in the bacterial pathogen Xanthomonas axonopodis may induce hyper-hydration in the plant host: a hypothesis of molecular mimicry.

BACKGROUND: Plant natriuretic peptides (PNPs) are systemically mobile molecules that regulate homeostasis at nanomolar concentrations. PNPs are up-regulated under conditions of osmotic stress and PNP-dependent processes include changes in ion transport and increases of H2O uptake into protoplasts and whole tissue. PRESENTATION OF THE HYPOTHESIS: The bacterial citrus pathogen Xanthomonas axonopodis pv. Citri str. 306 contains a gene encoding a PNP-like protein. We hypothesise that this bacterial protein can alter plant cell homeostasis and thus is likely to represent an example of molecular mimicry that enables the pathogen to manipulate plant responses in order to bring about conditions favourable to the pathogen such as the induced plant tissue hyper-hydration seen in the wet edged lesions associated with Xanthomonas axonopodis infection. TESTING THE HYPOTHESIS: We found a Xanthomonas axonopodis PNP-like protein that shares significant sequence similarity and identical domain organisation with PNPs. We also observed a significant excess of conserved residues between the two proteins within the domain previously identified as being sufficient to induce biological activity. Structural modelling predicts identical six stranded double-psi beta barrel folds for both proteins thus supporting the hypothesis of similar modes of action. No significant similarity between the Xanthomonas axonopodis protein and other bacterial proteins from GenBank was found. Sequence similarity of the Xanthomonas axonopodis PNP-like protein with the Arabidopsis thaliana PNP (AtPNP-A), shared domain organisation and incongruent phylogeny suggest that the PNP-gene may have been acquired by the bacteria in an ancient lateral gene transfer event. Finally, activity of a recombinant Xanthomonas axonopodis protein in plant tissue and changes in symptoms induced by a Xanthomonas axonopodis mutant with a knocked-out PNP-like gene will be experimental proof of molecular mimicry. IMPLICATION OF THE HYPOTHESIS: If the hypothesis is true, it could at least in part explain why the citrus pathogen Xanthomonas campestris that does not contain a PNP-like gene produces dry corky lesions while the closely related Xanthomonas axonopodis forms lesions with wet edges. It also suggests that genes typically found in the host, horizontally transferred or heterologous, can help to explain aspects of the physiology of the host-pathogen interactions.

Amino Acid Sequence↗