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PubMed2026

Structure-resolved virus-host interactomics by cross-linking mass spectrometry.

Viruses depend on host protein networks to replicate, assemble progeny, and spread between cells and organisms. Defining these virus-host protein interactions is challenging because they are highly dependent on infection stage, cell type, species, and because mechanistic interpretation requires information about structural interfaces and conformational states. Cross-linking mass spectrometry (XL-MS) addresses these challenges by adding a spatial and structural dimension to virus-host interactomics in native systems. In this review, we discuss how XL-MS has advanced from targeted analysis of viral protein complexes to structure-resolved mapping of virion architecture and infected-cell virus-host interactomes. We highlight how XL-MS complements AP-MS, cryo-EM/cryo-ET, quantitative proteomics, genetic perturbation, and structure prediction to connect physical proximity with molecular mechanisms. Finally, we discuss current limitations in sensitivity, chemical coverage, temporal resolution, and model interpretation, and outline how future quantitative and integrative XL-MS workflows may enable systems-level structural virology.

Mass Spectrometry↗

PubMed2005

Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients.

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction.

APACHE↗

PubMed2003

Host and microbial constituents influence Helicobacter pylori-induced cancer in a murine model of hypergastrinemia.

BACKGROUND & AIMS: Helicobacter pylori cag(+) strains and high-expression host interleukin 1beta (IL-1beta) polymorphisms augment the risk for intestinal-type gastric adenocarcinoma, a malignancy that predominates in males. We examined the effects of an H. pylori cancer-associated determinant (cagE), IL-1beta, and host gender in a transgenic hypergastrinemic (INS-GAS) murine model of gastric carcinogenesis. METHODS: Male and female INS-GAS mice infected with wild-type H. pylori, an H. pylori cagE(-) mutant, or H. felis were killed 2-24 weeks postchallenge. Gastric injury was scored from 0 to 4, and mucosal IL-1beta levels were quantified by ELISA. RESULTS: Male INS-GAS mice infected with H. pylori uniformly developed atrophy, intestinal metaplasia, and dysplasia by 6 weeks and carcinoma by 24 weeks. Mucosal IL-1beta concentrations increased 12 weeks following Helicobacter challenge, but levels then decreased by 24 weeks. Inactivation of cagE delayed the progression to carcinoma, but neoplasia ultimately developed in all males infected with the H. pylori mutant. In contrast, none of the H. pylori-infected female mice developed cancer, and injury scores, but not IL-1beta levels, were significantly higher in males compared with females. CONCLUSIONS: H. pylori infection induces gastric adenocarcinoma in an experimental mouse model of disease. Cancer is restricted to males and loss of cagE temporally retards but does not abrogate pathologic progression. Mucosal levels of IL-1beta increase prior to the development of gastric cancer but are not related to gender. The INS-GAS model is effective for investigating discrete host-microbial interactions that culminate in gastric cancer within the context of biologic conditions induced by H. pylori.

Adenocarcinoma↗

PubMed2002

Helicobacter pylori and gastrointestinal tract adenocarcinomas.

Although gastric adenocarcinoma is associated with the presence of Helicobacter pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial-cell physiology. Understanding the host-microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.

Adenocarcinoma↗

PubMed2025

Genome assembly and annotation of the parasitoid jewel wasp Nasonia oneida.

The jewel wasp, Nasonia (Hymenoptera: Pteromalidae), is a well-established model system for evolutionary genetics and host-microbial interactions. Here, we present the genome of N. oneida, a species lacking prior genomic characterization, using 10× Genomics linked-read (400× coverage), Illumina short-read (120× coverage), and transcriptome data (30× coverage). The assembled genome size is 267 Mb, comprising 4,675 scaffolds, with a scaffold N50 of 1 Mb and 98.40% Benchmarking Universal Single-Copy Orthologues (BUSCOs) completeness score. Annotation revealed 32.29% (86.46 Mb) of repetitive sequences and 14,221 protein-coding genes. Comparative genomics of N. oneida with 15 other hymenopteran species validated the presence of 5,939 gene families shared among them, including 3643 single-copy and 2296 multicopy gene families. This study provides the first de novo assembly of N. oneida, providing a significant addition to the growing repertoire of molecular tools for comparative genomics and functional studies to understand the evolution of closely related species as well as the evolution of parasitic wasps.

Animals↗

PubMed2001

Helicobacter pylori infection in children.

A number of scientific breakthroughs since H pylori first became recognized as a human pathogen have increased our understanding of the pathogenesis of gastroduodenal disease. In particular, advances in molecular bacteriology and the complete sequencing of the H pylori genome in 1999, and soon thereafter the human genome, provide tools allowing better delineation of the pathogenesis of disease. These molecular tools for both bacteria and host should now be applied to multicenter pediatric studies that evaluate disease outcome. More recent developments indicate that a better understanding of the microbial-host interaction is critical to furthering knowledge with respect to H pylori-induced diseases. Studies are needed to evaluate either DNA-based or more traditional protein-based vaccines, to evaluate more specific antimicrobials that confer minimal resistance, and to evaluate probiotics for the management of H pylori infection. Multicenter multinational studies of H pylori infection in the pediatric population, which include specific, randomized controlled eradication trials, are essential to extend current knowledge and develop better predictors of disease outcome.

Abdominal Pain↗

PubMed1994

Use of genetic recombination as a reporter of gene expression.

An understanding of the patterns of gene expression in response to specific environmental signals can yield insight into a variety of complex biological systems such as microbial-host interactions, developmental cycles, cellular differentiation, ontogeny, etc. To extend the utility of the reporter gene fusion approach to such studies, we have constructed a gene expression reporter cassette that permits the generation of transcriptional fusions to tnpR encoding resolvase, a site-specific recombinase of the transposable element gamma delta. Induction of the transcriptional fusions results in production of resolvase, which in turn, catalyzes excision of a linked tetracycline-resistance reporter gene flanked by direct repeats of res, the DNA sequences at which resolvase functions. The loss of tetracycline resistance in descendant bacteria serves as a permanent and heritable marker of prior gene expression. This gene fusion approach will allow us to assay the induction of gene expression in as few as one cell. Additionally, gene expression can be assayed at a later time and/or different place from the inducing environment facilitating the study of gene expression in complex environments such as animal tissues.

Alkaline Phosphatase↗

PubMed1999

Dynamics of Helicobacter pylori colonization in relation to the host response.

The dynamics of Helicobacter pylori colonization from its acquisition through the development of steady-state are examined through a mathematical model that includes the host response. The model encompasses both host and microbiological variation. The individual capacity of the host response is shown to be a key model parameter, leading to either transient or persistent colonization, whereas the growth rate of that response has little effect. Analyses of competing strains indicate that each must occupy a specific niche, otherwise exclusion occurs. The model implies that there exists a lower bound on the host response to the indigenous microflora that is consistent with current biological views of H. pylori. Parallel models may be useful in understanding other persistent host-microbial interactions.

Cell Division↗

PubMed1997

Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice.

The Paneth cell lineage is one of four epithelial lineages derived from the adult mouse small intestine's multipotent stem cell. Mature Paneth cells secrete antimicrobial peptides (cryptdins), growth factors, as well as two gene products, a secreted phospholipase A2 and matrilysin, that has been implicated as modifiers of adenoma formation in mice containing a mutation in the tumor suppressor Apc. Immature Paneth cells are located just above and below the cell layer, in intestinal crypts, that has been proposed to contain the multipotent stem cell. Paneth cells differentiate during a downward migration to the crypt base. The location and direction of Paneth cell migration, their high density and long residency time at the crypt base, and the nature of their secreted gene products, suggest that they may influence the structure and/or function of the stem cell niche. Paneth cell ablation can therefore be viewed as an experimental manipulation of the cellular microenvironment that purportedly contains the stem cell and its immediate descendants. Two types of ablation experiments were performed in transgenic mice. Nucleotides -6500 to +34 of the mouse cryptdin-2 gene (CR2) were used to express an attenuated diphtheria toxin A fragment. Light and electron microscopic immunohistochemical analyses of several pedigrees of postnatal day 28 to 180 animals established that ablation of Paneth cells is accompanied by an increase in the proportion of undifferentiated crypt base columnar cells. These cells normally co-exist with Paneth cells. The ablation does not produce a detectable effect on the proliferation or terminal differentiation programs of the other three lineages or on host-microbial interactions. The last conclusion is based on the ability of crypts to remain free of microbes detectable by Gram and Warthin-Starry stains and by retention of the normal crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue. CR2-directed expression of simian virus 40 large T antigen also results in a loss of mature Paneth cells but produces a marked amplification of crypt cells having a morphology intermediate between Paneth and granule goblet cells. EM immunohistochemical analyses suggest that intermediate cells can differentiate to mature goblet cells but not to Paneth cells, as they migrate up the crypt-villus axis. Our findings suggest that (i) stemness in the crypt is not defined by instructive interactions involving the Paneth cell; (ii) expressing a Paneth cell fate may require that precursors migrate to the crypt base; (iii) antimicrobial factors produced by Paneth cells are not required to prevent colonization of small intestinal crypts; and (iv) this lineage does not function to maintain the asymmetric crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue.

Animals↗

PubMed1995

Omega-3 fatty acids in respiratory diseases: a review.

The health benefits of dietary omega-3 fatty acids have been investigated in a variety of conditions but there have been few studies of their effects in human respiratory diseases. Although many of the physiological changes associated with omega-3 polyunsaturate ingestion have been attributed to alterations in endogenous eicosanoid production, effects on blood rheology, host-microbial interactions and lung surfactant production have also been described. In reviewing the literature, there is little evidence that these polyunsaturates have beneficial effects in allergic disorders, but they may have potential as modulators of respiratory diseases involving chronic inflammatory and infectious processes or impaired pulmonary blood flow. Further work on the effects of omega-3 fatty acids in several chronic pulmonary syndromes, for which there are currently no effective therapies, appears to be warranted.

Asthma↗

PubMed1995

The PapG-adhesin at the tip of P-fimbriae provides Escherichia coli with a competitive edge in experimental bladder infections of cynomolgus monkeys.

Human urinary tract infection is an infectious disease that depends on a series of host-microbial interactions. The bacteria first colonize the colon and then the periurethral/vaginal areas; they ascend to and infect first the bladder and then the kidneys. Expression of Escherichia coli P-fimbriae constitutes the strongest correlation to renal pathogenicity, but is also related to first-time cystitis in children. The role of P-fimbriae in the preceding steps in the infectious process is unknown. To examine this, we constructed, from a P-fimbriated E. coli strain with a class II G-adhesin preferentially binding to globoside, one isogenic mutant lacking the G-adhesin and another isogenic mutant in which we replaced the papG class II allele with a class III adhesin preferentially binding to the Forssman antigen. We report here the comparison of the adhesin knockout mutant (DS17-8) and the class-switch mutant (DS17-1) with the wild-type (DS17) for in vivo colonization of the gut, vagina, and bladder of cynomolgus monkeys. It was recently shown that the class II tip G-adhesin is a prerequisite for acute pyelonephritis to occur in the monkey model in the absence of other kidney-specific adhesins or obstruction of the urinary flow. Here we show that it is not required for bladder infection but gives a competitive advantage in mixed infections. In the vagina and colon, the G-adhesin gives no competitive advantage.

Adhesins, Escherichia coli↗

PubMed2003

Immunologic regulation of toll-like receptors in gut epithelium.

PURPOSE OF REVIEW: In response to the presence of pathogens in the environment, the innate immune system has evolved to provide a rapid defense against microbes. This response involves the recognition of molecular patterns present in diverse microbes by a series of receptors termed toll-like receptors. The focus of this article is the regulation of toll-like receptor signaling in the intestinal epithelium. The intestinal epithelium is continually exposed to a high concentration of diverse bacteria. In spite of the density of commensal bacteria, the normal intestine is not inflamed. Idiopathic inflammatory bowel disease in humans and animals is characterized by aberrant host-microbial interactions. RECENT FINDINGS: Several studies demonstrate that intestinal epithelial cells are poorly responsive to microbial products. The reason for this hyporesponsiveness is decreased or polarized expression of toll-like receptor molecules. Inflammatory cytokines upregulate expression of toll-like receptors. SUMMARY: The intestinal epithelium has evolved under the pressure of the microbiota to mute a response to commensal bacteria while maintaining the ability to respond to pathogens. In inflammatory bowel disease, the loss of tolerance to the normal flora may be due in part to inappropriate toll-like receptor signaling.

Journal Article↗

PubMed2004

New developments in experimental models of inflammatory bowel disease.

PURPOSE OF REVIEW: To consider new data and directions coming from experimental models of inflammatory bowel diseases. RECENT FINDINGS: Advances are discussed in the areas of microbial-host interactions in the intestine, the role of cytokines like IL-23, chemokines like IP-10, and various costimulatory molecules in disease pathogenesis. Multiple regulatory cells have been identified as well as the mechanisms they use to inhibit pathogenic responses to the microbiota in the intestine. New data is available on how the intestine heals after inflammatory insults. SUMMARY: These data are providing fundamental insights into the pathogenesis of IBD and thus are forming the basis of new therapeutic approaches, many of which will be translated to the clinic in the near future.

Journal Article↗

PubMed2005

Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota.

There are now many experimental models of inflammatory bowel disease (IBD), most of which are due to induced mutations in mice that result in an impaired homeostasis with the intestinal microbiota. These models can be clustered into several broad categories that, in turn, define the crucial cellular and molecular mechanisms of host microbial interactions in the intestine. The first of these components is innate immunity defined broadly to include both myeloid and epithelial cell mechanisms. A second component is the effector response of the adaptive immune system, which, in most instances, comprises the CD4+ T cell and its relevant cytokines. The third component is regulation, which can involve multiple cell types, but again particularly involves CD4+ T cells. Severe impairment of a single component can result in disease, but many models demonstrate milder defects in more than one component. The same is true for both spontaneous models of IBD, C3H/HeJBir and SAMPI/Yit mice. The thesis is advanced that 'multiple hits' or defects in these interacting components is required for IBD to occur in both mouse and human.

Animals↗

PubMed1995

Volatile fatty acids, metabolic by-products of periodontopathic bacteria, inhibit lymphocyte proliferation and cytokine production.

Short-chain fatty acids are a major by-product of anaerobic metabolism and can be detected in gingival fluid from periodontal pockets. Since most T cells are present subjacent to the pocket epithelium in conjunction with the plasma cells, it is important to know how these T cells are affected by short-chain fatty acids produced by subgingival plaque. The purpose of this study is to examine the effects of extracellular metabolites from periodontopathic bacteria on the proliferation and cytokine production of mouse splenic cells as a potential mechanism of imbalance among host-microbial interactions. A low-molecular-weight, heat-stable agent present in the two-day culture filtrate of Porphyromonas gingivalis, Prevotella loescheii, and Fusobacterium nucleatum significantly depressed Con A- and LPS- induced cell proliferation. To determine whether short-chain fatty acids present in the filtrate could account for the depression, we tested extracted volatile and non-volatile fatty acids for their effects on mitogenic activity. The volatile fatty acids extracted from immunosuppressive supernatants greatly inhibited T- and B- cell proliferation. Among these volatile fatty acids, butyric, propionic, valeric, and isovaleric acids impaired cell proliferation dose-dependently. From gas-liquid chromatographic analysis data, it is suggested that immuno-inhibitory activities in culture filtrates are mainly attributable to butyric and isovaleric acids in P. gingivalis, to propionic, butyric, and isovaleric acids in P. loescheii, and to butyric acid in F. nucleatum. Furthermore, these fatty acids significantly depressed interleukin 2 (IL-2), IL-4, IL-5, IL-6, and IL-10 production by Con A-stimulated splenic-T cells dose-dependently.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Anti-neutrophil cytoplasmic autoantibodies: a renewed paradigm in periodontal disease pathogenesis?

In the past, various models including the autoimmunity model have been proposed to explain the pathogenesis of periodontal diseases. The aim of this review is to introduce the pathogenic role of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in various autoimmune diseases and compare these conditions with periodontal disease to elucidate common pathogenic mechanisms. Also, a novel model to explain the pathogenesis of periodontal disease based on the concept of ANCA-associated autoimmunity is proposed. This encompasses a wide array of biochemical mediators that range from direct and indirect initiators of ANCA production and eventual release of proinflammatory mediators and free radicals, all of which have been implicated in periodontal tissue destruction in the past. In addition, specific links between the typical ANCA-associated diseases and periodontal disease are discussed. Finally, a new paradigm in the periodontal disease-associated destruction is proposed that includes the currently accepted mechanism, namely, the genetic-microbial-host interactions.

Antibodies, Antineutrophil Cytoplasmic↗

PubMedDate not supplied

[Infection and inflammation of the urinary tract: various cases of urinary tract infections investigated with the Thomas' test during forced water loading].

We simultaneously employed the Water-Loading Test and the ABU Test in three patients suffering from UTI, when the commonly recommended diagnostic tests did not give explanatory results. Two different bacterial strains were discovered in two cases; in one case the strain responsible of the renal involvement was identified, in the other cases the results induced to perform further invasive procedures not recommended on the basis of the routine laboratory techniques. If the clinical interest of this approach is limited to selected cases, the results obtained induce to discuss about the various problems related to the host-microbial interactions in the pathogenesis of UTI.

Child↗

PubMed1996

The gut in critical illness: evidence from human studies.

Data from a large number of published human studies support the hypothesis that the gastrointestinal tract of the critically ill patient is an important factor in ICU morbidity and mortality. Changes in proximal gut flora in the critically ill patient predict nosocomial infection with the same organism, while gut-directed therapeutic measures clearly reduce rates of nosocomial infection and may have an impact on mortality Modulation of the systemic inflammatory response through gut derived measures has been no more successful than modulation of that response through more conventional systemic forms of mediator-directed therapy. But if the gastrointestinal tract is an important factor in nosocomial ICU-acquired infection, the bigger unanswered question is, to what extent does infection per se alter outcome in critical illness? Current articulations of the gut hypothesis challenge long-held and probably outmoded views of host-microbial interactions. The challenge to replace them is no less compelling and no less treacherous than it was in the era of Metchnikoff, Lane, or their ancient forebears.

Animals↗