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Results for “host:pathogen interactions”

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PubMed2026

Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in Cryptococcus neoformans.

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved PP2A-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell-cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11Δ strains were avirulent, whereas far9Δ mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent in vitro fitness advantage. In contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3Δ cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal and cell-cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely, mob3Δ mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.

Journal Article↗

PubMed2006

A review of an emerging enteric pathogen: enteroaggregative Escherichia coli.

Enteroaggregative Escherichia coli (EAEC) is an increasingly recognized enteric pathogen. It is a cause of both acute and persistent diarrhoea among children, adults and HIV-infected persons, in both developing and developed countries. In challenge studies, EAEC has caused diarrhoeal illness with the ingestion of 10(10) c.f.u. Outbreaks of diarrhoeal illness due to EAEC have been reported, and linked to the ingestion of contaminated food. Diarrhoeal illness due to EAEC is the result of a complex pathogen-host interaction. Some infections due to EAEC result in diarrhoeal illness and elicit an inflammatory response, whereas other infections do not result in a symptomatic infection. Many putative virulence genes and EAEC strains that produce biofilm have been identified; however, the clinical significance of these genes and of biofilm production has yet to be defined. A -251 AA single nucleotide polymorphism (SNP) in the interleukin (IL)-8 promoter region is reported to increase host susceptibility to EAEC diarrhoea. Ciprofloxacin and rifaximin continue to be an effective treatment in persons infected with EAEC. This review is intended to provide an updated review for healthcare workers on EAEC, an emerging enteric pathogen.

Adult↗

PubMed2006

Diacyltrehalose of Mycobacterium tuberculosis inhibits lipopolysaccharide- and mycobacteria-induced proinflammatory cytokine production in human monocytic cells.

The lipids located in the outer layer of Mycobacterium tuberculosis, which include sulfolipid, phthiocerol dimycocerosate (PDIM), diacyltrehalose, and polyacyltrehalose, may play a role in host-pathogen interactions. These lipids were purified using thin-layer chromatography, and their ability to induce proinflammatory cytokines in human monocytes and in a human acute monocytic leukemia cell line (THP-1) was examined. None of the lipids tested induced significant interleukin (IL)-12p40 or tumor necrosis factor (TNF)-alpha production in monocytic cells. Diacyltrehalose significantly inhibited lipopolysaccharide- and M. tuberculosis-induced IL-12p40, TNF-alpha, and IL-6 productions in human monocytes, whereas other lipids had no effect. However, diacyltrehalose was unable to inhibit peptidoglycan-induced IL-12p40 production. These results suggest that diacyltrehalose is a mycobacterial factor capable of modulating host immune responses.

Cell Line, Tumor↗

PubMed2005

Wall-associated kinase WAK1 interacts with cell wall pectins in a calcium-induced conformation.

Wall-associated kinase 1 (WAK1) is a transmembrane protein containing a cytoplasmic Ser/Thr kinase domain and an extracellular domain in contact with the pectin fraction of the plant cell walls. In order to characterize further the interaction of WAK1 with pectin, a 564 bp DNA sequence corresponding to amino acids 67-254 of the extracellular domain of WAK1 from Arabidopsis thaliana was cloned and expressed as a soluble recombinant peptide in yeast. Using enzyme-linked immunosorbent assays (ELISA), we show that peptide WAK(67-254) binds to polygalacturonic acid (PGA), oligogalacturonides, pectins extracted from A. thaliana cell walls and to structurally related alginates. Our results suggest that both ionic and steric interactions are required to match the relatively linear pectin backbone. Binding of WAK(67-254) to PGA, oligogalacturonides and alginates occurred only in the presence of calcium and in ionic conditions promoting the formation of calcium bridges between oligo-and polymers (also known as 'egg-boxes'). The conditions inhibiting the formation of calcium bridges (EDTA treatment, calcium substitution, high NaCl concentrations, depolymerization and methylesterification of pectins) also inhibited the binding of WAK(67-254) to calcium-induced egg-boxes. The relevance of this non-covalent link between WAK(67-254) and cell wall pectins is discussed in terms of cell elongation, cell differentiation and host-pathogen interactions.

Arabidopsis↗

PubMed2005

Threat of infection: microbes of high pathogenic potential--strategies for detection, control and eradication.

Infectious diseases due to microbes of high pathogenic potential remain a constant and variable threat for human and animal health. The emergence of new diseases or the re-emergence of diseases that were previously under control complicates the situation to date. Infectious disease research, which has undergone a dramatic progress in understanding disease mechanisms such as host-pathogen interactions, is now focusing increasingly on new strategies for prevention and therapy. Significant progress has been achieved in the development of delivery systems for protective heterologous protein antigens and in veterinary vaccinology. A landmark of infectious diseases research is the chemical synthesis of genomes, a major new field of research referred to as "synthetic biology", that to date has resulted in the chemical synthesis of the poliovirus and of phage phiX174 genomes and their expression as infectious viruses. On the molecular level the evolution of pathogens and mechanisms of genome flexibility, which account for several pathogenic properties of infectious agents, have received increased attention. Bacterial toxins are an additional threat to human health and their interference with host cells and cellular functions is receiving more attention.

Animals↗

PubMed2005

Replication dynamics of Mycobacterium tuberculosis in chronically infected mice.

The dynamics of host-pathogen interactions have important implications for the design of new antimicrobial agents to treat chronic infections such as tuberculosis (TB), which is notoriously refractory to conventional drug therapy. In the mouse model of TB, an acute phase of exponential bacterial growth in the lungs is followed by a chronic phase characterized by relatively stable numbers of bacteria. This equilibrium could be static, with little ongoing replication, or dynamic, with continuous bacterial multiplication balanced by bacterial killing. A static model predicts a close correspondence between "viable counts" (live bacteria) and "total counts" (live plus dead bacteria) in the lungs over time. A dynamic model predicts the divergence of total counts and viable counts over time due to the accumulation of dead bacteria. Here, viable counts are defined as bacterial CFU enumerated by plating lung homogenates; total counts are defined as bacterial chromosome equivalents (CEQ) enumerated by using quantitative real-time PCR. We show that the viable and total bacterial counts in the lungs of chronically infected mice do not diverge over time. Rapid degradation of dead bacteria is unlikely to account for the stability of bacterial CEQ numbers in the lungs over time, because treatment of mice with isoniazid for 8 weeks led to a marked reduction in the number of CFU without reducing the number of CEQ. These observations support the hypothesis that the stable number of bacterial CFU in the lungs during chronic infection represents a static equilibrium between host and pathogen.

Animals↗

PubMed2004

Intravital fluorescence microscopy: a novel tool for the study of the interaction of Staphylococcus aureus with the microvascular endothelium in vivo.

BACKGROUND: The ability of Staphylococcus aureus to adhere to endothelial cells is a major prerequisite for the tissue-invasive stage of bacterial infection. METHODS: To develop a model for the study of endothelial attachment and detachment kinetics of S. aureus within the host's microvasculature in vivo, we labeled inactivated staphylococci with fluorescein isothiocyanate and investigated their interaction with the vascular endothelium of arterioles, capillaries, and venules in the dorsal skin-fold chamber of untreated and tumor necrosis factor (TNF)-alpha-treated hamsters by use of intravital fluorescence microscopy. RESULTS: During the first 20 min after injection, >99% of the bacteria were removed from the microvascular bloodstream. In parallel, single bacteria and bacterial clusters adhered to the endothelial lining of postcapillary venules and to nutritive capillaries. Bacterial adherence to the endothelium of arterioles was only rarely observed. TNF-alpha treatment significantly accelerated bacterial clearance and resulted in a significant increase of venular, but not arteriolar and capillary, bacterial adherence, indicating the venular endothelium to be the target structure for bacterial recruitment. CONCLUSION: The insights into host-pathogen interaction gained with this new in vivo model offer highly promising novel aspects of the understanding of infections caused by S. aureus.

Animals↗

PubMed2002

Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism.

Nramp2 is a widely expressed metal-ion transporter that is involved in dietary iron absorption in the duodenum and iron uptake from transferrin in peripheral tissues. Nramp1 is a related gene involved in regulation of host pathogen interaction. Nramp2 has at least two alternatively spliced isoforms, one of which contains an iron-responsive element in its 3'-untranslated region. In this study, we investigated the regulation of both isoforms of Nramp2 in activated primary macrophages from mouse strains with wild-type (Bcg(r)) or mutant (Bcg(s)) alleles. The Nramp2-IRE and/or -nonIRE transcripts were up-regulated in all mouse strains analyzed after treatment with interferon-gamma and lipopolysaccharide. cDNA microarray analysis revealed that Nramp2 regulation is controlled discordantly from other iron-regulated genes and classical macrophage-activation genes in different mouse strains. We suggest that Nramp2 is regulated independently of known iron-responsive genes in macrophages, and its function in host defense is unrelated to Nramp1.

Animals↗

PubMed2005

Pathogenesis of bovine tuberculosis: the role of experimental models of infection.

In many countries, test-and-slaughter policies based on tuberculin skin testing have made a significant impact on the control of bovine tuberculosis (caused by infection with Mycobacterium bovis). However, in some countries these policies have not proved as effective and improved disease control strategies are required (including improved diagnostic tests and development of vaccines). The host pathogen interactions in bovine tuberculosis are very complex. While studies of the disease in naturally infected field cases of bovine tuberculosis have provided valuable information, detailed knowledge can also be gained through studies of disease models. A number of studies have developed M. bovis infection models employing a range of routes and challenge doses. An early objective was assessment of vaccine efficiency, and models of infection remain central to current work in this area. Development of the intra-nasal and intra-tracheal models have also advanced our understanding of the kinetics of the immune response. In many of these studies, understanding of pathogenesis has been improved by definition of the cells that respond to infection and those that are instrumental in modulation of host responses. Experimental models of infection have been adapted to study cattle to cattle transmission, modeling one of the fundamental routes of infection. This review provides a historical perspective on the types of experimental models used in over 100 years of research and outlines new opportunities to refine those methods for bovine and human tuberculosis and to contribute to improved diagnostics, advanced understanding of immunology and vaccine design.

Aerosols↗

PubMed2004

Focusing light on infection in four dimensions.

The fusion of cell biology with microbiology has bred a new discipline, cellular microbiology, in which the primary aim is to understand host-pathogen interactions at a tissue, cellular and molecular level. In this context, we require techniques allowing us to probe infection in situ and extrapolate quantitative information on its spatiotemporal dynamics. To these ends, fluorescent light-based imaging techniques offer a powerful tool, and the state-of-the-art is defined by paradigms using so-called multidimensional (multi-D) imaging microscopy. Multi-D imaging aims to visualize and quantify biological events through time and space and, more specifically, refers to combinations of: three (3D, volume), four (4D, time) and five (5D, multiwavelength)-dimensional recordings. Successful multi-D imaging depends upon understanding the available technologies and their limitations. This is especially true in the field of microbiology where visualization of infectious/pathogenic activities inside living host systems presents particular technical challenges. Thus, as multi-D imaging rapidly becomes a common bench tool to the cellular microbiologist, this review provides the new user with some of the necessary technical insight required to get the best from these methods.

Animals↗

PubMed2026

Influence of Major Histocompatibility Complex (MHC) Diversity on Immune Modulation, Pathogenesis, and Control of Lumpy Skin Disease Virus.

INTRODUCTION: Lumpy Skin Disease Virus (LSDV), a member of the genus Capripoxvirus within the family Poxviridae, is an economically important transboundary viral pathogen affecting cattle and water buffalo. The disease causes severe production losses through decreased milk yield, infertility, hide damage, reduced growth performance, and occasional mortality. The rapid geographic spread of LSDV, together with its vectorborne transmission and emerging recombinant strains, has intensified the need for improved understanding of viral pathogenesis, host immune responses, and effective prevention strategies. In particular, the role of the bovine Major Histocompatibility Complex (BoLA/MHC) in regulating antiviral immunity, disease susceptibility, and vaccine responsiveness has gained increasing scientific attention. METHODS: This review summarises the published literature related to the epidemiology, transmission, structure, pathogenesis, diagnosis, prevention, and control of LSDV, with special emphasis on the immunological and molecular role of bovine MHC molecules. Relevant studies concerning BoLA-mediated antigen presentation, immunoinformaticsbased epitope prediction, vaccine development, antiviral drug repurposing, molecular docking, genomic surveillance, and diagnostic approaches, including PCR- and ELISAbased assays, were critically evaluated. Recent advances in computational biology, molecular virology, and host-pathogen interaction studies were also reviewed. RESULTS: The reviewed studies demonstrate that Lumpy Skin Disease Virus (LSDV) possesses a complex double-stranded DNA genome enabling immune modulation and efficient transmission through arthropod vectors such as mosquitoes, ticks, and biting flies. Disease progression involves systemic viral replication, vascular injury, dermal necrosis, and inflammatory skin lesions. Real-time PCR remains the most sensitive diagnostic method for early detection, while ELISA supports surveillance. Evidence highlights the central role of bovine Major Histocompatibility Complex (BoLA) molecules in antigen presentation and T-cell activation. Computational studies identified promising BoLA-binding epitopes and repurposed antiviral candidates, including ivermectin, theaflavin, canagliflozin, and tepotinib, for future therapeutic development. DISCUSSION: Current evidence indicates that effective LSDV control requires integration of molecular diagnostics, vector management, vaccination, and host immunogenetics. BoLAguided immunoinformatics provides promising opportunities for developing multi-epitope vaccines, although experimental validation remains essential. Similarly, repurposed antiviral candidates require comprehensive in vivo and pharmacological evaluation before clinical application. Future research should focus on elucidating viral immune-evasion mechanisms, validating predicted epitopes, and translating computational findings into practical vaccines and therapeutics for sustainable disease control. CONCLUSION: Lumpy Skin Disease continues to pose a major threat to global cattle health and livestock economies. Advances in molecular diagnostics, genomic surveillance, antiviral drug discovery, and BoLA-guided vaccine design provide promising opportunities for improved disease control. Understanding the interaction between LSDV and the bovine MHC system is essential for developing next-generation vaccines, immunotherapeutics, and precision disease-management strategies. Future research should prioritise experimental validation of predicted epitopes, large-scale vaccine trials, and mechanistic studies on host-virus immune interactions to establish effective and sustainable global control programs for LSDV.

BoLA↗

PubMed2004

IsdA of Staphylococcus aureus is a broad spectrum, iron-regulated adhesin.

As an important facet of host-pathogen interaction, Staphylococcus aureus has the ability to adhere to human extracellular matrix (ECM) components via a range of surface proteins. Here we have shown that IsdA has broad-spectrum ligand-binding activity, including fibrinogen and fibronectin. Mapping studies revealed a distinct domain responsible for ligand binding. This domain is present in a number of iron-regulated proteins of S. aureus and in other Gram-positive organisms. The isdA gene is only expressed in iron-limited conditions under the control of Fur and not in standard laboratory media. Such conditions occur in serum in vitro and during infection. Whole cell binding and clumping assays revealed that when the bacteria are grown under iron-limited conditions, IsdA constitutes a physiologically relevant adhesin to both fibrinogen and fibronectin. Thus for S. aureus, iron is an important marker for the host environment, to which the bacterium responds by differential regulation of at least one element of its adhesive strategy.

Adhesins, Bacterial↗

PubMed2004

Antigen-specific gene expression profiles of peripheral blood mononuclear cells do not reflect those of T-lymphocyte subsets.

Advances in microarray technology have allowed for the monitoring of thousands of genes simultaneously. This technology is of particular interest to immunologists studying infectious diseases, because it provides tremendous potential for investigating host-pathogen interactions at the level of immune gene expression. To date, many studies have focused either on cell lines, where the physiological relevance is questionable, or on mixed cell populations, where the contributions of individual subpopulations are unknown. In the present study, we perform an intrasubject comparison of antigen-stimulated immune gene expression profiles between a mixed population of peripheral blood mononuclear cells (PBMC) and the two predominant cell types found in PBMC, CD4+ and CD8+ T lymphocytes. We show that the microarray profiles of CD4+ and CD8+ T lymphocytes differ from each other as well as from that of the mixed cell population. The independence of the gene expression profiles of different cell types is demonstrated with a ubiquitous antigen (Candida albicans) as well as with a disease-specific antigen (human immunodeficiency virus p24). This study has important implications for microarray studies of host immunity and underscores the importance of profiling the expression of specific cell types.

Antigens↗

PubMed2006

Exacerbation of group B streptococcal sepsis and arthritis in diabetic mice.

Group B streptococci (GBS) have been recognised as an ever-growing cause of serious invasive infections in non-pregnant adults, in particular in association with severe underlying diseases such as diabetes mellitus. In the present study we used mice rendered diabetic to gain further insights into host-pathogen interaction during induced GBS sepsis and septic arthritis. Type I diabetes was induced in adult CD-1 mice by low-dose streptozotocin treatment. Mice were then infected with different doses of GBS, and mortality, appearance of arthritis, growth of microorganisms in the organs and cytokine and chemokine profile were assessed in diabetic and control animals. The LD50 was significantly lower in diabetics than in controls, while both incidence and severity of arthritis were higher. A significantly higher number of microorganisms were recovered from the organs of diabetic mice than in controls. The worsening of sepsis and arthritis was associated with a significant increase in systemic and local production of IL-6, IL-1 beta, TNF-alpha, IL-10, macrophage inflammatory protein 1 alpha (MIP-1alpha), and MIP-2 and with a decrease in IFN-gamma production. Taken together, our results indicate an impaired host resistance to GBS infection in diabetics, likely due to a dysregulation of the cytokine network and prolonged local inflammatory response.

Animals↗

PubMed2004

Inactivation of transcription factor gene ACE2 in the fungal pathogen Candida glabrata results in hypervirulence.

During an infection, the coordinated orchestration of many factors by the invading organism is required for disease to be initiated and to progress. The elucidation of the processes involved is critical to the development of a clear understanding of host-pathogen interactions. For Candida species, the inactivation of many fungal attributes has been shown to result in attenuation. Here we demonstrate that the Candida glabrata homolog of the Saccharomyces cerevisiae transcription factor gene ACE2 encodes a function that mediates virulence in a novel way. Inactivation of C. glabrata ACE2 does not result in attenuation but, conversely, in a strain that is hypervirulent in a murine model of invasive candidiasis. C. glabrata ace2 null mutants cause systemic infections characterized by fungal escape from the vasculature, tissue penetration, proliferation in vivo, and considerable overstimulation of the proinflammatory arm of the innate immune response. Compared to the case with wild-type fungi, mortality occurs much earlier in mice infected with C. glabrata ace2 cells, and furthermore, 200-fold lower doses are required to induce uniformly fatal infections. These data demonstrate that C. glabrata ACE2 encodes a function that plays a critical role in mediating the host-Candida interaction. It is the first virulence-moderating gene to be described for a Candida species.

Alleles↗

PubMed2005

Concerted evolution in the repeats of an immunomodulating cell surface protein, SOWgp, of the human pathogenic fungi Coccidioides immitis and C. posadasii.

Genome dynamics that allow pathogens to escape host immune responses are fundamental to our understanding of host-pathogen interactions. Here we present the first population-based study of the process of concerted evolution in the repetitive domain of a protein-coding gene. This gene, SOWgp, encodes the immunodominant protein in the parasitic phase of the human pathogenic fungi Coccidioides immitis and C. posadasii. We sequenced the entire gene from strains representing the geographic ranges of the two Coccidioides species. By using phylogenetic and genetic distance analyses we discovered that the repetitive part of SOWgp evolves by concerted evolution, predominantly by the mechanism of unequal crossing over. We implemented a mathematical model originally developed for multigene families to estimate the rate of homogenization and recombination of the repetitive array, and the results indicate that the pattern of concerted evolution is a result of homogenization of repeat units proceeding at a rate close to the nucleotide point mutation rate. The release of the SOWgp molecules by the pathogen during proliferation may mislead the host: we speculate that the pathogen benefits from concerted evolution of repeated domains in SOWgp by an enhanced ability to misdirect the host's immune system.

Antigens, Fungal↗

PubMed2006

Development of a novel three-dimensional in vitro model of oral Candida infection.

Oropharyngeal candidiasis is emerging as a serious health problem in the elderly as well as other chronically immunosuppressed patient populations. Several approaches have been used to study the interactions between Candida and the oral mucosa in vitro. Recently, three-dimensional organotypic systems of the oral mucosa have been developed, which provide an organizational complexity that is between the culture of single cell types and organ cultures in vivo. In this report we describe the development of a novel three-dimensional system of the human oral mucosa based on an immortalized oral keratinocyte cell line. Unlike the commercially available cell line systems, this system also contains a connective tissue cell component, which ensures the quality and resemblance of the tissue model to the human oral masticatory mucosa and submucosa. Using a panel of Candida albicans strains with variable virulence in vivo, we showed that the extent of tissue damage, fungal invasion and host inflammatory response in this system was proportional to the well-documented in vivo virulence potential of these strains. Therefore, this investigation has added another useful tool in the study of host pathogen interactions in oral candidiasis.

Candida albicans↗

PubMed2001

Two novel insect defensins from larvae of the cupreous chafer, Anomala cuprea: purification, amino acid sequences and antibacterial activity.

A humoral immune response in larvae of the coleopteran insect, Anomala cuprea has been examined for exploring the molecular basis of host-pathogen interactions. The antibacterial activity against the Gram-positive strain, Micrococcus luteus was detected at a low level in absence of injection. The activity increased strikingly in the hemolymph of the larvae challenged with Escherichia coli, showing the fluctuating profile through a time course, which consists of the static induction phase, the production phase rising to a maximum level, and the reduction phase extending over a long duration. Two peptides were purified and characterized by reverse-phase HPLC, Edman degradation and mass spectrometry. They were isoforms, composed of similar sequences with two amino acid substitutions in 43 residues, and novel members of the insect defensins, cysteine-rich antibacterial peptides. Anomala defensins A and B showed potent activity against Gram-positive bacteria, with slight differences in activity against a few strains of tested bacteria. Anomala defensin B was active at high concentration of 40 microM against the Gram-negative strain, Xenorhabdus japonicus, a pathogen toward the host, A. cuprea larvae.

Amino Acid Sequence↗