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Results for “host:pathogen interactions”

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PubMed2000

Enteropathogenic Escherichia coli (EPEC) attachment to epithelial cells: exploiting the host cell cytoskeleton from the outside.

Enteropathogenic Escherichia coli (EPEC), a leading cause of human infantile diarrhoea, is the prototype for a family of intestinal bacterial pathogens that induce attaching and effacing (A/E) lesions on host cells. A/E lesions are characterized by localized effacement of the brush border of enterocytes, intimate bacterial attachment and pedestal formation beneath the adherent bacteria. As a result of some recent breakthrough discoveries, EPEC has now emerged as a fascinating paradigm for the study of host-pathogen interactions and cytoskeletal rearrangements that occur at the host cell membrane. EPEC uses a type III secretion machinery to attach to epithelial cells, translocating its own receptor for intimate attachment, Tir, into the host cell, which then binds to intimin on the bacterial surface. Studies of EPEC-induced cytoskeletal rearrangements have begun to provide clues as to the mechanisms used by this pathogen to subvert the host cell cytoskeleton and signalling pathways. These findings have unravelled new ways by which pathogenic bacteria exploit host processes from the cell surface and have shed new light on how EPEC might cause diarrhoea.

Adhesins, Bacterial↗

PubMed2025

Understanding Mycobacterium tuberculosis through its genomic diversity and evolution.

Pathogen evolution and genomic diversity are shaped by specific host immune pressures and therapeutic interventions. Analysis of the extant genomes of circulating strains of Mycobacterium tuberculosis, a leading cause of infectious mortality that has co-evolved with humans for thousands of years, can provide new insights into host-pathogen interactions that underlie specific aspects of pathogenesis and onward transmission. With the explosion in the number of fully sequenced M. tuberculosis strains that are now paired with detailed clinical data, there are new opportunities to understand the evolutionary basis for and consequences of M. tuberculosis strain diversity. This review examines mechanistic findings that have emerged from pairing whole genome sequencing data and evolutionary analysis with functional dissection of specific bacterial variants. These include improved understanding of secreted effectors that modulate the properties and migratory behavior of infected macrophages as well as bacterial genetic alterations important for survival within hypoxic microenvironments. Genomic, evolutionary, and functional analyses across diverse M. tuberculosis strains will identify prominent bacterial adaptations to their human hosts and shape our understanding of TB disease biology and the host immune response.

Mycobacterium tuberculosis↗

PubMed2006

Sialic acid-binding immunoglobulin-like lectin 7 mediates selective recognition of sialylated glycans expressed on Campylobacter jejuni lipooligosaccharides.

siglecs are a family of sialic-acid binding immunoglobulin-like lectins mostly expressed by cells of the immune system that have the potential to interact with sialylated glycans expressed not only on host cells but also on certain pathogens. Campylobacter jejuni is a common pathogen of humans that expresses surface lipooligosaccharides (LOS) that can be modified with ganglioside-like terminal structures in the core oligosaccharides. In this study, we examined the interaction of 10 siglecs with LOS purified from four different C. jejuni isolates expressing GM1-like, GD1a-like, GD3-like, and GT1a-like oligosaccharides. Of all siglecs examined, only Siglec-7 exhibited specific, sialic acid-dependent interactions with C. jejuni LOS in solid-phase binding assays. Binding was especially prominent with LOS from the HS:19(GM1(+) GT1a(+)) isolate, with weaker binding with LOS from the HS:19(GD3(+)) isolate. Binding of Siglec-7 was also observed with intact bacteria expressing these LOS structures. Specific binding of HS:19(GM1(+) GT1a(+)) bacteria was demonstrated with Siglec-7 expressed on transfected Chinese hamster ovary cells and with peripheral blood leukocytes, among which HS:19(GM1(+) GT1a(+)) bacteria bound selectively to both natural killer cells and monocytes which naturally express Siglec-7. These results raise the possibility that, in addition to their role in generating autoimmune antibody responses, C. jejuni LOS could interact with Siglec-7 expressed by leukocytes, modulate the host-pathogen interaction, and contribute to the clinical outcome and the development of secondary complications such as Guillain-Barré syndrome.

Animals↗

PubMed2026

Upsurge of pneumococcal clade I-α/CC180 serotype 3 and its association with a LytA mutation linked to immune evasion and disease potential: an observational and experimental study.

BACKGROUND: Streptococcus pneumoniae serotype 3 is one of the most prevalent serotypes that cause invasive pneumococcal disease (IPD) in children and adults worldwide. Serotype 3 is associated with vaccine failures and breakthrough episodes in children vaccinated with 13-valent pneumococcal conjugate vaccine (PCV13). In this study, we aimed to investigate potential genetic mechanisms that could explain the increase in cases of serotype 3 IPD in Spain. METHODS: We analysed the epidemiology of serotype 3 causing IPD in Spain, during 2009-23, in different age groups. Molecular characterisation was performed by whole-genome sequencing. Host-pathogen interactions of the different lineages were evaluated in terms of interaction with lung epithelial cells, biofilm formation, and capsular polysaccharide production, using opsonophagocytosis assays and mouse models of pneumonia. We used Poisson regression models to compare incidence and chi-square test calculations to identify clonal variations across vaccine periods. FINDINGS: Genomic analyses confirmed the predominance of clade I-α/clonal complex (CC) 180 in Spain, which shows increased resistance to complement-mediated immunity and phagocytosis and enhanced potential to infect lung cells. In all isolates of this lineage, we observed a single amino acid substitution (166His→Tyr) in the crucial virulence factor LytA, which increased its enzymatic activity. On evaluating the phagocytosis of mutants without LytA of the two major lineages of serotype 3 (CC180 and CC260), LytA was responsible for the increased phagocytosis-evasion pattern of clade I-α/CC180. Evaluation of individuals with IPD caused by different serotype 3 genotypes confirmed a significant (p<0·05) association between cardiac and respiratory comorbidities and infection by sequence type 180/CC180, which showed the importance of CC180 in IPD. INTERPRETATION: Our findings confirm that PCV13 reduced IPD cases caused by the susceptible CC260 lineage until CC260 was replaced by the clade I-α/CC180 lineage, which has a higher potential to cause IPD and divert the host immune system. A key mutation on LytA protein was associated with this hypervirulent phenotype. Emerging lineages jeopardise the effectiveness of pneumococcal conjugate vaccines. FUNDING: Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, and PubMLST.

Animals↗

PubMed2004

The influence of mutation, recombination, population history, and selection on patterns of genetic diversity in Neisseria meningitidis.

Patterns of genetic diversity within populations of human pathogens, shaped by the ecology of host-microbe interactions, contain important information about the epidemiological history of infectious disease. Exploiting this information, however, requires a systematic approach that distinguishes the genetic signal generated by epidemiological processes from the effects of other forces, such as recombination, mutation, and population history. Here, a variety of quantitative techniques were employed to investigate multilocus sequence information from isolate collections of Neisseria meningitidis, a major cause of meningitis and septicemia world wide. This allowed quantitative evaluation of alternative explanations for the observed population structure. A coalescent-based approach was employed to estimate the rate of mutation, the rate of recombination, and the size distribution of recombination fragments from samples from disease-associated and carried meningococci obtained in the Czech Republic in 1993 and a global collection of disease-associated isolates collected globally from 1937 to 1996. The parameter estimates were used to reject a model in which genetic structure arose by chance in small populations, and analysis of molecular variation showed that geographically restricted gene flow was unlikely to be the cause of the genetic structure. The genetic differentiation between disease and carriage isolate collections indicated that, whereas certain genotypes were overrepresented among the disease-isolate collections (the "hyperinvasive" lineages), disease-associated and carried meningococci exhibited remarkably little differentiation at the level of individual nucleotide polymorphisms. In combination, these results indicated the repeated action of natural selection on meningococcal populations, possibly arising from the coevolutionary dynamic of host-pathogen interactions.

Adolescent↗

PubMed2003

Reactive oxygen intermediates in plant-microbe interactions: who is who in powdery mildew resistance?

Reactive oxygen intermediates (ROIs) such as hydrogen peroxide (H(2)O(2)) and the superoxide anion radical (O*(2)(-)) accumulate in many plants during attack by microbial pathogens. Despite a huge number of studies, the complete picture of the role of ROIs in the host-pathogen interaction is not yet fully understood. This situation is reflected by the controversially discussed question as to whether ROIs are key factors in the establishment and maintenance of either host cell inaccessibility or accessibility for fungal pathogens. On the one hand, ROIs have been implicated in signal transduction as well as in the execution of defence reactions such as cell wall strengthening and a rapid host cell death (hypersensitive reaction). On the other hand, ROIs accumulate in compatible interactions, and there are reports suggesting a function of ROIs in restricting the spread of leaf lesions and thus in suppressing cell death. Moreover, in situ analyses have demonstrated that different ROIs may trigger opposite effects in plants depending on their spatiotemporal distribution and subcellular concentrations. This demonstrates the need to determine the particular role of individual ROIs in distinct stages of pathogen development. The well-studied interaction of cereals with fungi from the genus Blumeria is an excellent model system in which signal transduction and defence reactions can be further elucidated in planta. This review article gives a synopsis of the role of ROI accumulation, with particular emphasis on the pathosystem Hordeum vulgare L.- Blumeria graminis.

Disease Susceptibility↗

PubMed2002

To sialylate, or not to sialylate: that is the question.

Most oropharyngeal pathogens express sialic acid units on their surfaces, mimicking the sialyl-rich mucin layer coating epithelial cells and the glycoconjugates present on virtually all host cell surfaces and serum proteins. Unlike the host's cells, which synthesize sialic acids endogenously, several microbial pathogens use truncated sialylation pathways. How microorganisms regulate sialic acid metabolism to ensure an adequate supply of free sugar for surface remodeling is a new area of research interest to basic scientists and those focused on the clinical outcome of the host-pathogen interaction.

Host-Parasite Interactions↗

PubMed1997

Strong density- and diversity-related effects help to maintain tree species diversity in a neotropical forest.

Intraspecific density-dependent effects in the Barro Colorado Island (Panama) study area are far stronger, and involve far more species, than previously had been suspected. Significant effects on recruitment, many extremely strong, are seen for 67 out of the 84 most common species in the plot, including the 10 most common. Significant effects on the intrinsic rate of increase are seen in 54 of the 84 species. These effects are far more common than interspecific effects, and are predominantly of the type that should maintain tree diversity. As a result, the more diverse an area in the forest is, the higher is the overall rate of increase of the trees in that area, although sheer crowding has by itself a negative effect. These findings are consistent with, but do not prove, an important role for host-pathogen interactions (defined broadly) in the maintenance of diversity. Ways are suggested by which to test host-pathogen models and competing models.

Journal Article↗

PubMedDate not supplied

The use of DNA array technology in studies of ocular viral pathogenesis.

DNA arrays can be used to simultaneously analyze the expression of hundreds of genes and permit systematic approaches to biological discovery with a potentially profound impact on genomics, pharmacogenomics, and proteomics. Microarrays have been used to study host-pathogen interactions, and recently this technology has been applied to investigate host-virus interactions. DNA arrays are used to monitor host alterations in several virus-induced cancers and upon infection with wild-type or modified viruses, or viral gene products. Alternatively, viral chips are used to characterize the transcriptional program of pathogenic viruses and in antiviral drug screening and drug resistance. With an aim to extend the use of this technology to ocular research, and specifically to study changes in host cell transcription in ocular adenovirus infection, we used a commercial array to compare adenovirus-infected human corneal cells to mock-infected cells. Of the 1176 genes analyzed, 72 genes associated with cell cycle regulation, apoptosis, oncogenesis, transcription, signaling, and inflammation were differentially regulated. In this review we summarize the use of DNA arrays in the study of viral infections and suggest potential uses of the technology in ocular viral pathogenesis research.

Animals↗

PubMed2003

Deficiency in mycolipenate- and mycosanoate-derived acyltrehaloses enhances early interactions of Mycobacterium tuberculosis with host cells.

Lipids that are uniquely found in the cell envelope of pathogenic mycobacteria, such as those containing multiple methyl-branched long-chain fatty acids, have long been thought to play a role in host-pathogen interactions. The recent construction by Dubey et al. (2002) Mol Microbiol 45: 1451-1459, of a Mycobacterium tuberculosis mutant that is deficient in the synthesis of the di- and tri-methylbranched fatty acids, mycolipenates and mycosanoates, found in some forms of diacyltrehaloses (DAT) and polyacyltrehaloses (PAT) provided the opportunity to assess the contribution of these complex lipids to pathogenesis directly. We provide evidence that DAT/PAT deficiency affects the surface global composition of the mycobacterial cell envelope improving the efficiency with which M. tuberculosis binds to and enters phagocytic and non-phagocytic host cells. Interestingly, this property did not affect the overall replication and persistence of the tubercle bacillus in the lungs, spleen and liver of mice infected via the respiratory or intravenous route.

Animals↗

PubMedDate not supplied

Gene array technology to determine host responses to Salmonella.

Gene expression array technology is a powerful new tool that has already been used to expand our understanding of host-pathogen interactions. There has been a rapid increase in published reports describing use of this approach to profile host responses to pathogenic bacteria and viruses. The large number of array studies currently in progress coupled with increasing accessibility of this new technology promises a plethora of gene expression data on host response to infection in the near future. Recent insights into macrophage and epithelial cell responses to Salmonella infection garnered from array studies are outlined and used as a basis to discuss various future research directions using gene arrays that will advance the field of cellular microbiology. There is an exciting potential for the gene expression data generated in such studies to provide insights into host physiology, the pathophysiology of disease and novel therapeutics.

Animals↗

PubMed1999

Identification of the INO1 gene of Mycobacterium tuberculosis H37Rv reveals a novel class of inositol-1-phosphate synthase enzyme.

1L-myo-inositol (inositol) is vital for the biogenesis of mycothiol, phosphatidylinositol and glycosylphosphatidylinositol anchors linked to complex carbohydrates in Mycobacterium tuberculosis. All these cellular components are thought to play important roles in host-pathogen interactions and in the survival of the pathogen within the host. However, the inositol biosynthetic pathway in M. tuberculosis is not known. To delineate the pathways for inositol formation, we employed a unique combination of tertiary structure prediction and yeast-based functional assays. Here, we describe the identification of the gene for mycobacterial INO1 that encodes inositol-1-phosphate synthase distinct in many respects from the eukaryotic analogues.

Amino Acid Sequence↗

PubMed2003

Transfected Plasmodium knowlesi produces bioactive host gamma interferon: a new perspective for modulating immune responses to malaria parasites.

Transgenic pathogenic microorganisms expressing host cytokines such as gamma interferon (IFN-gamma) have been shown to manipulate host-pathogen interaction, leading to immunomodulation and enhanced protection. Expression of host cytokines in malaria parasites offers the opportunity to investigate the potential of an immunomodulatory approach by generating immunopotentiated parasites. Using the primate malaria parasite Plasmodium knowlesi, we explored the conditions for expressing host cytokines in malaria parasites. P. knowlesi parasites transfected with DNA constructs for expressing rhesus monkey (Macaca mulatta) IFN-gamma under the control of the heterologous P. berghei apical membrane antigen 1 promoter, produced bioactive IFN-gamma in a developmentally regulated manner. IFN-gamma expression had no marked effect on in vitro parasite development. Bioactivity of the parasite-produced IFN-gamma was shown through inhibition of virus cytopathic effect and confirmed by using M. mulatta peripheral blood cells in vitro. These data indicate for the first time that it is feasible to generate malaria parasites expressing bioactive host immunomodulatory cytokines. Furthermore, cytokine-expressing malaria parasites offer the opportunity to analyze cytokine-mediated modulation of malaria during the blood and liver stages of the infection.

Animals↗

PubMed2001

Depletion of rafts in late endocytic membranes is controlled by NPC1-dependent recycling of cholesterol to the plasma membrane.

In mammalian cells, cholesterol is thought to associate with sphingolipids to form lateral membrane domains termed rafts. Increasing evidence suggests that rafts regulate protein interactions, for example, during signalling, intracellular transport and host-pathogen interactions. Rafts are present in cholesterol-sphingolipid-enriched membranes, including early and recycling endosomes, but whether rafts are found in late endocytic organelles has not been analyzed. In this study, we analyzed the association of cholesterol and late endosomal proteins with low-density detergent-resistant membranes (DRMs) in normal cells and in cells with lysosomal cholesterol-sphingolipid accumulation. In normal cells, the majority of [(3)H]cholesterol released from [(3)H]cholesterol ester-LDL associated with detergent-soluble membranes, was rapidly transported to the plasma membrane and became increasingly insoluble with time. In Niemann-Pick C1 (NPC1) protein-deficient lipidosis cells, the association of LDL-cholesterol with DRMs was enhanced and its transport to the plasma membrane was inhibited. In addition, the NPC1 protein was normally recovered in detergent-soluble membranes and its association with DRMs was enhanced by lysosomal cholesterol loading. Moreover, lysosomal cholesterol deposition was kinetically paralleled by the sequestration of sphingolipids and formation of multilamellar bodies in late endocytic organelles. These results suggest that late endocytic organelles are normally raft-poor and that endocytosed LDL-cholesterol is efficiently recycled to the plasma membrane in an NPC1-dependent process. The cholesterol-sphingolipid accumulation characteristic to NPC disease, and potentially to other sphingolipidoses, causes an overcrowding of rafts forming lamellar bodies in the degradative compartments.

Androstenes↗

PubMed2005

Toxic shock syndrome in children: epidemiology, pathogenesis, and management.

Toxic shock syndrome (TSS) is an acute, toxin-mediated illness, like endotoxic shock, and is characterized by fever, rash, hypotension, multiorgan involvement, and desquamation. TSS reflects the most severe form of the disease caused by Staphylococcus aureus and Streptococcus pyogenes. A case definition for staphylococcal TSS was well established in the early 1980s and helped in defining the epidemiology. Since the late 1980s, a resurgence of highly invasive streptococcal infections, including a toxic shock-like syndrome, was noted worldwide and a consensus case definition for streptococcal TSS was subsequently proposed in 1993. Both TSS and the toxic shock-like syndrome occur at a lower incidence in children than in adults. Changes in the manufacturing and use of tampons led to a decline in staphylococcal TSS over the past decade, while the incidence of nonmenstrual staphylococcal TSS increased. Nonmenstrual TSS and menstrual TSS are now reported with almost equal frequency. The incidence of streptococcal TSS remains constant after its resurgence, but varies with geographic location. Streptococcal TSS occurs most commonly following varicella or during the use of NSAIDs. Sites of infection in streptococcal TSS are much deeper than in staphylococcal TSS, such as infection caused by blunt trauma, and necrotizing fasciitis. Bacteremia is more common in streptococcal TSS than in staphylococcal TSS. Mortality associated with streptococcal TSS is 5-10% in children, much lower than in adults (30-80%), and is 3-5% for staphylococcal TSS in children.TSS is thought to be a superantigen-mediated disease. Toxins produced by staphylococci and streptococci act as superantigens that can activate the immune system by bypassing the usual antigen-mediated immune-response sequence. The host-pathogen interaction, virulence factors, and the absence or presence of host immunity determines the epidemiology, clinical syndrome, and outcome. Early recognition of this disease is important, because the clinical course is fulminant and the outcome depends on the prompt institution of therapy. Management of a child with TSS includes hemodynamic stabilization and appropriate antimicrobial therapy to eradicate the bacteria. Supportive therapy, aggressive fluid resuscitation, and vasopressors remain the main elements. An adjuvant therapeutic strategy may include agents that can block superantigens, such as intravenous immunoglobulin that contains superantigen neutralizing antibodies.

Adolescent↗

PubMed2005

Venezuelan equine encephalitis virus infection of spiny rats.

Enzootic strains of Venezuelan equine encephalitis virus (VEEV) circulate in forested habitats of Mexico, Central, and South America, and spiny rats (Proechimys spp.) are believed to be the principal reservoir hosts in several foci. To better understand the host-pathogen interactions and resistance to disease characteristic of many reservoir hosts, we performed experimental infections of F1 progeny from Proechimys chrysaeolus collected at a Colombian enzootic VEEV focus using sympatric and allopatric virus strains. All animals became viremic with a mean peak titer of 3.3 log10 PFU/mL, and all seroconverted with antibody titers from 1:20 to 1:640, which persisted up to 15 months. No signs of disease were observed, including after intracerebral injections. The lack of detectable disease and limited histopathologic lesions in these animals contrast dramatically with the severe disease and histopathologic findings observed in other laboratory rodents and humans, and support their role as reservoir hosts with a long-term coevolutionary relationship to VEEV.

Animals↗

PubMed2007

Separation of sequences from host-pathogen interface using triplet nucleotide frequencies.

The identification of genes involved in host-pathogen interactions is important for the elucidation of mechanisms of disease resistance and host susceptibility. A traditional way to classify the origin of genes sampled from a pool of mixed cDNA is through sequence similarity to known genes from either the pathogen or host organism or other closely related species. This approach does not work when the identified sequence has no close homologues in the sequence databases. In our previous studies, we classified genes using their codon frequencies. This method, however, explicitly required the prediction of CDS regions and thus could not be applied to sequences composed from the non-coding regions of genes. In this study, we show that the use of sliding-window triplet frequencies extends the application of the algorithm to both coding and non-coding sequences and also increases the prediction accuracy of a Support Vector Machine classifier from 95.6+/-0.3 to 96.5+/-0.2. Thus the use of the triplet frequencies increased the prediction accuracy of the new method by more than 20% compared to our previous approach. A functional analysis of sequences detected gene families having significantly higher or lower probability to be correctly classified compared to the average accuracy of the method is described. The server to perform classification of EST sequences using triplet frequencies is available at (URL: http://mips.gsf.de/proj/est3).

Algorithms↗

PubMed2006

Fitness consequences of infection of Arabidopsis thaliana with its natural bacterial pathogen Pseudomonas viridiflava.

Variation in plant resistance to pathogen infection is commonly observed in interactions between wild plants and their foliar pathogens. Models of host-pathogen interactions indicate that a large cost of infection is generally necessary to maintain this variation, yet there is limited evidence that foliar pathogens cause detectable fitness reductions in wild host plants. Most published work has focused on fungal pathogens. Pseudomonas viridiflava, a common bacterial pathogen of the annual weed Arabidopsis thaliana across its range, comprises two distinct genetic clades that cause disease symptoms of different severity. Here we measured the extent of infection of wild A. thaliana populations in the Midwest, USA, and examined the effect on seed production, in field and growth-chamber experiments, of experimental inoculation with isolates from the two clades. We found infection with P. viridiflava varied from 0 to 56% in Midwest A. thaliana populations, with the possibility of several leaves per plant infected later in the growing season. In the growth chambers, experimental inoculation reduced seed set by averages of 15 and 11% for clades A and B, respectively. In the field experiment, only clade A affected plant fitness significantly, reducing seed set by an average of 38%. Underlying these average effects we observed both negative and positive effects of infection, and variation in both fitness among plant genotypes and sensitivity to environmental conditions.

Arabidopsis↗