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PubMed2005

Targets for human encoded microRNAs in HIV genes.

MicroRNAs (miRNAs) are increasingly being shown to play vital roles in development, apoptosis, and oncogenesis by interfering with gene expression at the post-transcriptional level. miRNAs, in principle, can contribute to the repertoire of host pathogen interactions during HIV-1 infection. Using a consensus scoring approach, high scoring miRNA-target pairs were selected which were identified by four well-established target prediction softwares. While hsa-mir-29a and 29b target the nef gene, hsa-mir-149 targets the vpr gene, hsa-mir-378 targets env, and hsa-mir-324-5p targets the vif gene. Not only were the minimum free energy values lowest for the bound complex, but also, the rules so far observed for microRNA-target pairing, viz., a continuous stretch of 6-7 base pairing towards the 5' end of the miRNA and incomplete complementarity with the target sequence, were found to be valid. The target regions were highly conserved across the various clades of HIV-1. microRNA expression profiles from previously reported microarray based experiments show that the five human miRNAs are expressed in T-cells, the normal site of infection of HIV-1 virus. This is the first report of human microRNAs which can target crucial HIV-1 genes including the nef gene, which plays an important role in delayed disease progression.

Base Pairing↗
PubMed2005

Modification of iron regulation by the inflammatory response.

Iron is an essential compound for immunosurveillance because of its growth-promoting and differentiation-inducing properties for immune cells and its interference with cell-mediated immune effector pathways and cytokine activities. Thus, the reticuloendothelial system has generated sophisticated strategies to control iron metabolism in general and the handling of the metal within immune cells. Cytokines, immune-cell-derived radicals, and acute-phase proteins affect the regulation of iron homeostasis at different levels ranging from transcriptional interference with iron genes to modulation of iron transport capacities of transmembrane iron channels. Thus, under inflammatory conditions a diversion of iron traffic from the circulation to storage sites of the reticuloendothelial system occurs. This results in an iron-restricted erythropoiesis and the development of anemia, termed 'anemia of chronic disease'. The development of hypoferremia and hyperferritinemia under chronic inflammatory conditions may also harbor some positive effects: first, by limiting the availability of the essential nutrient and growth factor iron to invading microbes and tumor cells, thus blocking their proliferation, and secondly by strengthening cell-mediated immune effector pathways directed against invading pathogens. Studying iron metabolism under inflammatory conditions will extend our knowledge and improve our understanding of regulatory pathways in host-pathogen interactions during infection and cancer, and may hold the key for future therapeutic developments for the treatment of such diseases as well as for anemia of chronic disease.

Acute-Phase Proteins↗
PubMed2026

Construction of circRNA-miRNA-mRNA regulatory networks in the intestine of turbot (Scophthalmus maximus) following Vibrio anguillarum infection.

Circular RNAs (circRNAs) play pivotal roles in post-transcriptional regulation by acting as molecular sponges for microRNAs (miRNAs) within the competitive endogenous RNA (ceRNA) network. However, the regulatory mechanisms in teleost immune responses remain poorly understood. In this study, circRNA-miRNA-mRNA networks were investigated in turbot (Scophthalmus maximus) following Vibrio anguillarum infection to elucidate host-pathogen interactions. Through high-throughput sequencing of intestinal tissues, a total of 50 differentially expressed circRNAs (DE-circRNAs) (18 at 2 hpi, 16 at 12 hpi, 16 at 48 hpi), 212 DE-miRNAs (11 at 2 hpi, 70 at 12 hpi, 15 at 48 hpi), and 1774 DE-mRNAs were identified. Functional enrichment analyses (GO/KEGG) revealed significant associations with immune pathways, including the MAPK signaling pathway and gap junction. An integrated circRNA-miRNA-mRNA regulatory network was constructed, highlighting key interactions including novel_circ_0002573/DE-miR-27a-3p/FGB and novel_circ_0002423/novel_347/GNE, which may regulate inflammatory and antibacterial responses. The expression patterns of selected circRNAs, miRNAs and mRNAs were validated using qRT-PCR, confirming the reliability of the sequencing results. Importantly, fibrinogen beta chain (FGB) and CXCR4/CXCL12 signaling were identified as critical immune modulators. These findings provide insights of the ceRNA regulatory networks involved in teleost intestinal immunity and provide potential molecular targets for selective breeding of disease resistance in this species.

Animals↗
PubMed2026

Transcriptomic analysis provides molecular insights into the innate immune defense of Mactra veneriformis against Vibrio alginolyticus infection.

Mactra veneriformis is an economically important bivalve mollusc in China, but its aquaculture is frequently threatened by Vibrio infections, particularly Vibrio alginolyticus. To investigate the molecular immune response of M. veneriformis to V. alginolyticus, we performed RNA-seq analysis of hepatopancreatic tissues collected at 48 h post-infection, the peak mortality time point, with PBS-injected individuals used as controls. Infection with V. alginolyticus caused severe histopathological damage in the hepatopancreas and resulted in a cumulative mortality of 53.3% over 14 d, compared with 3.3% in the control group. Transcriptomic analysis identified 2623 differentially expressed genes (DEGs), including 1585 significantly up-regulated genes and 1038 down-regulated genes. KEGG enrichment analysis demonstrated that DEGs were significantly enriched in immune related and metabolism pathways, including the JAK-STAT signaling pathway, RIG-I-like receptor (RLR) signaling pathway, and cytochrome P450 (CYP450) signaling pathway. Collectively, these findings revealed candidate immune related genes (tlr3, tlr5, myd88, nfkb1, il-17d, and ifi44l), a putative TLR-MyD88-NF-κB signaling axis, and KEGG signaling pathways, including JAK-STAT, RLR and CYP450, that may be involved in the innate immune response of M. veneriformis to V. alginolyticus infection. These results provide a transcriptomic basis for understanding host-pathogen interactions in this species and highlight candidate genes and pathways for future functional validation and potential application in disease-resistance breeding.

Animals↗
PubMed2004

Visualizing the immune response to pathogens.

Advances in immune visualization have enabled the physical tracking of immune responses in vivo. The adaptation of such technology to models of infectious disease holds the promise of a more detailed analysis of host-pathogen interactions in a natural setting. However, the visualization of pathogen-specific immune responses in vivo confronts challenges that are inherent to the study of infectious disease systems. Recent attempts to track pathogen-specific immune responses in vivo validate the usefulness and underline the complexity of this experimental strategy.

Animals↗
PubMed2006

Identification of critical genes in microarray experiments by a Neuro-Fuzzy approach.

Gene expression profiling by microarray technology is usually difficult to interpret into a simpler pattern. One approach to resolve the complexity of gene expression profiles is the application of artificial neural networks (ANNs). A potential difficulty in this strategy, however, is that the non-linear nature of ANN makes it essentially a 'black-box' computation process. Addition of a fuzzy logic approach is useful because it can complement ANN by explicitly specifying membership function during computation. We employed a hybrid approach of neural network and fuzzy logic to further analyze a published microarray study of gene responses to eight bacteria in human macrophages. The original analysis by hierarchical clustering found common gene responses to all bacteria but did not address individual responses. Our method allowed exploration of the gene response of the host to individual bacterium. We implemented a two-layer, feed-forward neural network containing the principle of 'competitive learning' (i.e. 'winner-take-all'). The weights of the trained neural network were fed into a fuzzy logic inference system. A new measurement, called the impact rating (IR) was also introduced to explore the degree of importance of each gene. To assess the reliability of the IR value, a bootstrap re-sampling method was applied to the dataset and a confidence level for each IR was obtained. Our approach has successfully uncovered the unique features of host response to individual bacterium. Further, application of gene ontology (GO) annotation to the genes of high IR values in each response has suggested new biological pathways for individual host-pathogen interactions.

Algorithms↗
PubMed2004

Jonathan Hodgkin.

Jonathan Hodgkin graduated from Oxford in 1971 and then did a PhD with Sydney Brenner at MRC LMB in Cambridge, studying behavioural genetics in the nematode Caenorhabditis elegans. Later, after a couple of years working with myxobacteria as a postdoc in Dale Kaiser's lab at Stanford, he returned to LMB as a staff member, where he remained for most of the subsequent two decades. In the year 2000, he moved to Oxford as Professor of Genetics in the Department of Biochemistry, switching his major research interests from developmental genetics and sex determination to the study of host-pathogen interactions in the worm. For the past ten years, he has acted as curator of the C. elegans genetic map and gene nomenclature, and he is currently President of the Genetics Society of Great Britain.

Animals↗
PubMed2004

Cytidine deamination of retroviral DNA by diverse APOBEC proteins.

The human cytidine deaminase APOBEC3G edits both nascent human immunodeficiency virus (HIV) and murine leukemia virus (MLV) reverse transcripts, resulting in loss of infectivity. The HIV Vif protein is able to protect both viruses from this innate restriction to infection. Here, we demonstrate that a number of other APOBEC family members from both humans and rodents can mediate anti-HIV effects, through cytidine deamination. Three of these, rat APOBEC1, mouse APOBEC3, and human APOBEC3B, are able to inhibit HIV infectivity even in the presence of Vif. Like APOBEC3G, human APOBEC3F preferentially restricts vif-deficient virus. Indeed, the mutation spectra and expression profile found for APOBEC3F indicate that this enzyme, together with APOBEC3G, accounts for the G to A hypermutation of proviruses described in HIV-infected individuals. Surprisingly, although MLV infectivity is acutely reduced by APOBEC3G, no other family member tested here had this effect. It is especially interesting that although both rodent APOBECs markedly diminish wild-type HIV infectivity, MLV is resistant to these proteins. This implies that MLV may have evolved to avoid deamination by mouse APOBEC3. Overall, our findings show that although APOBEC family members are highly related, they exhibit significantly distinct antiviral characteristics that may provide new insights into host-pathogen interactions.

APOBEC-1 Deaminase↗
PubMed2004

Alveolar epithelial cells type II are major target cells for C. pneumoniae in chronic but not in acute respiratory infection.

Pulmonary presence of Chlamydia pneumoniae is associated with acute and chronic infections. We show that unapparent chlamydial infection in four out of 31 chronic obstructive pulmonary disease (COPD) patients (12.9%) is characterized by a significant increase in infected alveolar epithelial cells type II (18.2 +/- 3.5% vs. 2.3 +/- 0.9; IHC/ISH) compared to a newly established model of acute chlamydial infection (ACIM) in vital lung specimens from pulmonary lobectomy. Expression of cHSP60 demonstrated pathogen viability and virulence in the ACIM. We conclude that target cells differ in acute and chronic chlamydial infection and suggest the ACIM as a novel tool to analyze the host-pathogen-interactions in acute respiratory infections.

Acute Disease↗
PubMed2004

In vivo induced antigenic determinants of Actinobacillus actinomycetemcomitans.

Actinobacillus actinomycetemcomitans is a Gram-negative capnophilic rod and the etiological agent of localized aggressive periodontitis. The genome-wide survey of A. actinomycetemcomitans using in vivo induced antigen technology (IVIAT) has previously resulted in the discovery of antigenic determinants expressed specifically in diseased patients. The present study evaluated the potential of these antigens as putative disease markers, and investigating their contribution to the pathogenesis of the microorganism. Sera from patients had a significantly greater antibody titer than sera from healthy controls against six antigens, which supports the in vivo expression of these antigens, and suggests their usefulness as disease markers. A. actinomycetemcomitans invasion of epithelium-derived HeLa cells resulted in the induction of all three genes tested, as evidenced by real-time PCR. Isogenic mutants of these three genes were constructed and the adhesion and intracellular survival of the mutants was assayed in a competition assay with the wild-type strain. A significant defect in the intracellular survival of two of these mutant strains (orf1402 and orf859) was found. This defect could not be attributed to an adhesion defect. In contrast, a mutation in vapA, a homologue of a novel putative transcriptional regulator, out-competed the wild-type strain in the same assay. The virulent phenotype was restored for a mutant strain in orf859 upon complementation. This data provided new insight into the pathogenic personality of A. actinomycetemcomitans in vivo and supported the use of HeLa cells as a valid in vitro host-pathogen interactions model for that microorganism. IVIAT is applicable to most pathogens and will undoubtedly lead to the discovery of novel therapies, antibiotics and diagnostic tools.

Actinobacillus Infections↗
PubMed2005

Transmission of Chlamydia pneumoniae infection from blood monocytes to vascular cells in a novel transendothelial migration model.

Chlamydia pneumoniae uses blood monocytes (PBMC) for systemic dissemination, persists in atherosclerotic lesions, and has been implicated in the pathogenesis of atherosclerosis. During transmigration in a newly developed transendothelial migration model (TEM) C. pneumoniae-infected PBMC spread their infection to endothelial cells. Transmigrated PBMC retained their infectivity and transmitted the pathogen to smooth muscle cells in the lower chamber of the TEM. Detection of chlamydial HSP60 mRNA proved pathogen viability and virulence. We conclude that PBMC can spread chlamydial infection to vascular wall cells and we suggest the TEM as a novel tool to analyze host-pathogen interactions in vascular chlamydial infections.

Arteriosclerosis↗
PubMed2005

Whole-genome analysis of Leptospira interrogans to identify potential vaccine candidates against leptospirosis.

Leptospirosis is an important global human and veterinary health problem. Humans can be infected by exposure to chronically infected animals and their environment. An important focus of the current leptospiral research is the identification of outer membrane proteins (OMPs). Due to their location, leptospiral OMPs are likely to be relevant in host-pathogen interactions, hence their potential ability to stimulate heterologous immunity. The existing whole-genome sequence of Leptospira interrogans serovar Copenhageni offers a unique opportunity to search for cell surface proteins. Predicted genes encoding potential surface proteins were amplified from genomic DNA by PCR methodology and cloned into an Escherichia coli expression system. The partially purified recombinant proteins were probed by Western blotting with sera from human patients diagnosed with leptospirosis. Sixteen proteins, out of a hundred tested, were recognized by antibodies present in human sera. Four of these proteins were conserved among eight serovars of L. interrogans and absent in the non-pathogenic Leptospira biflexa. These proteins might be useful for the diagnosis of the disease as well as potential vaccine candidates.

Antigens, Bacterial↗
PubMed2005

Siderophore accumulation and phytopathogenicity in Microbotryum violaceum.

We investigated the role of the siderophore rhodotorulic acid (RA) accumulation in the host-pathogen interaction of Microbotryum violaceum and Silene latifolia. While the wild-type M. violaceum accumulated RA in the culture medium in response to iron stress, the monogenic mutant 45 of M. violaceum did not accumulate detectable amounts of RA under limiting iron supply. Genetic analysis showed the mutant 45 locus to be 3.8 cM from the centromere, endorsing the pericentric gene clustering of M. violaceum. Crosses of mutant and wild-type strains demonstrated that the lack of siderophore accumulation in mutant 45 did not preclude pathogenesis, hence fungal reproduction.

Basidiomycota↗
PubMed2006

Homologous recombination and the pattern of nucleotide substitution in Ehrlichia ruminantium.

Patterns of nucleotide substitution at orthologous loci were examined between three genomes of Ehrlichia ruminantium, the causative agent of heartwater disease of ruminants. The most recent common ancestor of two genomes (Erwe and Erwo) belonging to the Welgevonden strain was estimated to have occurred 26,500-57,000 years ago, while the most recent common ancestor of these two genomes and the Erga genome (Gardel strain) was estimated to have occurred 2.1-4.7 million years ago. The search for genes showing extremely high values of the number of synonymous substitutions per site was used to identify genes involved in past homologous recombination. The most striking case involved the map1 gene, encoding major antigenic protein-1; evidence for homologous recombination is consistent with previous phylogenetic analysis of map1 alleles. At this and certain other loci, homologous recombination may have contributed to the evolution of host-pathogen interactions. In addition, comparison of the patterns of synonymous and nonsynonymous substitution provided evidence for positive selection favoring a high level of amino acid change between the Welgevonden and Gardel strains at a locus of unknown function (designated Erum4340 in the Erwo genome).

Computational Biology↗
PubMed2006

Transcriptome analysis of the salivary glands of Dermacentor andersoni Stiles (Acari: Ixodidae).

Amongst blood-feeding arthropods, ticks of the family Ixodidae (hard ticks) are vectors and reservoirs of a greater variety of infectious agents than any other ectoparasite. Salivary glands of ixodid ticks secrete a large number of pharmacologically active molecules that not only facilitate feeding but also promote establishment of infectious agents. Genomic, proteomic and immunologic characterization of bioactive salivary gland molecules are, therefore, important as they offer new insights into molecular events occurring at the tick-host interface and they have implications for development of novel control strategies. The present work uses complementary DNA (cDNA) sequence analysis to identify salivary gland transcripts expressed by the Rocky Mountain wood tick, Dermacentor andersoni, a vector of the human pathogens causing Rocky Mountain spotted fever, Colorado tick fever, tularemia, and Powassan encephalitis as well as the veterinary pathogen Anaplasma marginale. Dermacentor andersoni is also capable of inducing tick paralysis. Automated single-pass DNA sequencing was conducted on 1440 randomly selected cDNA clones from the salivary glands of adult female D. andersoni collected during the early stages of feeding (18-24h). Analysis of the expressed sequence tags (ESTs) resulted in 544 singletons and 218 clusters with more than one quality read and attempts were made to assign putative functions to tick genes based on amino acid identity to published protein databases. Approximately 25.6% (195) of the sequences showed limited or no homology to previously identified gene products. A number of novel sequences were identified which presented significant sequence similarity to mammalian genes normally associated with extracellular matrix (ECM), regulation of immune responses, tumor suppression, and wound healing. Several coding sequences possessed various degrees of homology to previously described proteins from other tick species. Preliminary nucleotide variation analysis of these and other tick sequences suggests extensive nucleotide diversity, which has implications for evolution of tick feeding. Intra-species diversity studies can be a promising tool for identifying sequence variations potentially associated with phenotypic traits affecting vector-host-pathogen interactions.

Amino Acid Sequence↗
PubMed2026

The AAA+ chaperone ClpB contributes to stress tolerance and pathogenesis in Mycoplasma bovis.

ClpB, an ATP-dependent molecular chaperone belonging to the Hsp100/Clp subfamily of AAA+ ATPases, plays a crucial role in protein disaggregation, thereby enhancing bacterial survival under stress conditions. Despite its well-conserved function in prokaryotes, the specific contributions of ClpB to the pathogenesis of the ruminant pathogen Mycoplasma bovis remain largely unexplored. In this study, we identified and functionally characterized a ClpB homolog in M. bovis. Biochemical assays confirmed that the recombinant ClpB protein exhibits intrinsic ATPase activity and, in cooperation with the DnaK chaperone system, efficiently mediates protein disaggregation in vitro. Through genome-wide transposon mutagenesis of the M. bovis HB0801 strain, we generated ClpB-deficient mutants that maintained normal growth kinetics and morphology at 37 °C but exhibited significant growth defects under thermal and oxidative stress conditions. Phenotypic analysis demonstrated that ClpB disruption attenuated key virulence traits, including impaired adhesion to host cells, marked reduction in biofilm formation, diminished pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) expression in BoMac cells. Furthermore, the reduced virulence of the ClpB mutant was investigated by DIA proteomic analyses, which revealed that the ClpB mutant strain altered distinct protein expression patterns related to proteostasis, including phosphotransferase system, serine-type peptidase activity, serine hydrolase activity, and chaperone-mediated protein folding that contribute to the stress response and virulence. These findings collectively demonstrate that ClpB serves as a multifunctional virulence determinant in M. bovis, orchestrating stress adaptation, host-pathogen interactions, and pathogenic potential through modulation of both protein quality control systems and virulence-associated pathways.

Mycoplasma bovis↗
PubMed2004

Long-term collection and characterization of afferent lymph from the ovine small intestine.

Reliable methods for long-term collection of afferent lymph draining from the small intestine of sheep are described and validated. The procedure was used successfully in normal sheep, in animals infected experimentally with the parasitic intestinal nematode Trichostrongylus colubriformis and in animals infected naturally with Mycobacterium avium subsp. paratuberculosis, the causative agent of Johne's disease. Our approach enabled afferent lymph draining from the small intestine to be collected continuously for up to 4 months, without any detrimental effects on the animals. Based on cytokine gene expression profiles of afferent intestinal lymph cells, the two infections induced contrasting regional immune responses, namely, Th2-type immunity in the case of T. colubriformis infection and Th1-type immunity in natural cases of Johne's disease. Some immune parameters differed markedly between the two disease models, highlighting the potential value of this approach to gain real-time insights into distinctive host-pathogen interactions as they occur in vivo within the regional immune system of the gastrointestinal tract.

Animals↗