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Results for “host:pathogen interactions”

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PubMed2004

Probing Trypanosoma cruzi biology with DNA microarrays.

The application of genome-scale approaches to study Trypanosoma cruzi-host interactions at different stages of the infective process is becoming possible with sequencing and assembly of the T. cruzi genome nearing completion and sequence information available for both human and mouse genomes. Investigators have recently begun to exploit DNA microarray technology to analyze host transcriptional responses to T. cruzi infection and dissect developmental processes in the complex T. cruzi life-cycle. Collectively, information generated from these and future studies will provide valuable insights into the molecular requirements for establishment of T. cruzi infection in the host and highlight the molecular events coinciding with disease progression. While the field is in its infancy, the availability of genomic information and increased accessibility to relatively high-throughput technologies represents a significant advancement toward identification of novel drug targets and vaccine candidates for the treatment and prevention of Chagas' disease.

Animals↗

PubMed2026

Rasputin/G3BP mediates subversion of antiviral immunity by o'nyong-nyong virus in Anopheles coluzzii.

Cellular G3BP proteins are essential for alphavirus infection in both vertebrate and mosquito hosts, but the underlying mechanism of their proviral activity is poorly understood in any host. Whether the mosquito G3BP ortholog, Rasputin (Rin), interacts with host immunity to influence alphavirus infection has not been investigated, and anopheline mosquito interactions with arboviruses have been little studied. Here, we find that Rin silencing in Anopheles mosquitoes results in decreased ONNV infection levels, indicating a proviral activity for Anopheles Rin. We find that Rin function is required to maintain basal activity of the antiviral Imd and JAK/STAT pathways in uninfected mosquitoes. However, during ONNV infection, the control of the Imd pathway by Rin activity appears corrupted because Rin silencing leads to overexpression of the Imd positive regulator, Rel2. Thus, silencing of Rin both augments Rel2 transcript abundance and decreases ONNV load. Co-silencing of Rel2 with Rin restores normal ONNV infection levels, indicating that Rin activity is required to inhibit Imd function during ONNV infection, and which explains most of the Rin proviral phenotype. In addition, we show that the ONNV non-structural protein 3 (nsP3), which binds to Rin, strongly alters the pattern of Anopheles cellular protein partners interacting with Rin. In the presence of ONNV nsP3, 48 Rin-binding host proteins are unchanged but seven binding proteins are excluded and eight new cellular proteins bind Rin. The altered cellular protein partners are candidate host factors involved in viral subversion of Rin control over Imd activity. Overall, these results reveal a molecular mechanism in which ONNV, probably through nsP3, co-opts the normal Rin function for basal cellular immune activity by subverting the Imd antiviral pathway to promote infection. These results may be generalizable for Rin function during alphavirus infection of other mosquitoes, as well as for G3BP function in the mammalian host, and could offer a target for development of vector-based genetic control tools against arbovirus transmission.

Animals↗

PubMed2026

EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Despite the availability of a vaccine in China, no direct-acting antivirals are approved, and host factors required for HEV replication remain poorly defined. Here, using a genome-wide CRISPR/Cas9 knockout screen in a replicon system, we identified Eukaryotic Translation Initiation Factor 4H (EIF4H) and Y-Box Binding Protein 1 (YBX1) as essential host factors for HEV replication and pathogenesis. Knockout of either factor markedly impaired replication of HEV genotypes 1, 3, and 4, as well as HEV infection and production in hepatocellular carcinoma cells and human induced pluripotent stem cell-derived hepatocyte-like cells, while leaving SARS-CoV-2, hepatitis B virus, hepatitis C virus, and Zika virus unaffected, underscoring their HEV-specific roles. Mechanistically, EIF4H interacts with ORF1 via its methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1-associated replication complex. By contrast, YBX1 is dispensable for ORF1 translation and RNA binding but is specifically required for ORF1 proteolytic processing, a prerequisite for assembling a functional replication machinery. EIF4H knockout rats and liver-specific YBX1 knockout rats were largely resistant to rat HEV-C1 infection, showing profound reductions in viral shedding, suppressed hepatic and intestinal viral loads, and protection from liver pathology. Together, our findings establish EIF4H and YBX1 as essential host factors for HEV infection and pathogenesis and reveal potential targets for antiviral intervention.

Virus Replication↗

PubMed2025

UHRF1 restricts HCoV-229E infection through epigenetic silencing of the viral receptor APN.

The emergence of SARS-CoV-2 has posed significant threats to global health, particularly for the older population. Similarly, common human coronaviruses, such as HCoV-229E, which typically cause mild cold-like symptoms, can lead to severe diseases, underscoring the need to understand virus-host interactions and identify host factors contributing to viral pathogenesis and disease progression. In this study, we perform a genome-wide CRISPR knockout screen using HCoV-229E and identify UHRF1 as a potent restriction factor. Mechanistically, UHRF1 suppresses HCoV-229E infection by downregulating the expression of its cell entry receptor, APN, through promoter hypermethylation. Focused CRISPR activation screens of UHRF1-downregulated genes confirm the critical role of APN in HCoV-229E infection and identify additional genes (e.g., SIGLEC1, PLAC8, and heparan sulfate biosynthesis genes) contributing to the restrictive functions of UHRF1. Transcriptomic and single-cell RNA sequencing analysis reveal that UHRF1 expression decreases with age, negatively correlating with increased APN expression. This age-related decline in UHRF1 is validated in primary alveolar macrophages from elderly individuals, which exhibit heightened susceptibility to HCoV-229E compared to those from younger individuals. Our findings highlight UHRF1 as a key age-related host defense factor against coronavirus and provide insights into the epigenetic regulation of viral entry receptors.

Animals↗

PubMed2026

Infection cycles of viruses of the phylum Nucleocytoviricota.

The phylum Nucleocytoviricota, formerly known as nucleocytoplasmic large DNA viruses (NCLDVs), comprises evolutionarily related viruses with remarkably diverse genome sizes, coding capacities and virion morphologies. These viruses infect hosts across the eukaryotic tree of life, from protists to humans, and are believed to have emerged during the early stages of eukaryotic evolution. How the basic aspects of virus-host interaction have evolved in different lineages and whether they share a conserved infection cycle remain unclear. In this Review, we synthesize the information on the infection cycles of model representatives from the major orders within the phylum, revealing both shared traits and lineage-specific innovations. We compare the information available for the extensively studied poxviruses, asfiviruses, iridoviruses and chloroviruses with insights from the rapidly expanding literature on the mimiviruses, pandoraviruses, marseilleviruses and pithoviruses. We provide an overview of the molecular details underlying the key stages of Nucleocytoviricota infection cycles: entry via membrane fusion, formation of viral factories organized via phase separation, genome replication, virion morphogenesis through a crescent intermediate, and egress. We highlight outstanding questions in the field, unify concepts across traditionally separated research areas, and provide a conceptual framework to guide future cell biology studies on large double-stranded DNA viruses.

DNA Viruses↗

PubMed2025

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity.

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.IMPORTANCEEmerging coronaviruses like SARS-CoV, SARS-CoV-2, and MERS-CoV cause a range of disease outcomes in humans from an asymptomatic, moderate, and severe respiratory disease that can progress to death but the factors causing these disparate outcomes remain unclear. Understanding host responses to mild and life-threatening infections provides insight into virus-host networks within and across organ systems that contribute to disease outcomes. We used multi-omics approaches to comprehensively define the host response to moderate and severe MERS-CoV infection. Severe respiratory disease was associated with dysregulation of the immune response. Key lung epithelial cell populations that are essential for lung function get infected and die. Mice lacking key immune cell populations experienced greater virus replication but decreased disease severity implicating the immune system in both protective and pathogenic roles in response to MERS-CoV. These data could be utilized to design new therapeutic strategies targeting specific pathways that contribute to severe disease.

Animals↗

PubMed2026

A small viral protein suppresses immune amplification by two distinct mechanisms.

Diverse viral suppressors of RNA interference (RNAi) and RNA silencing (VSRs) interact directly with core protein and/or RNA components of the host RNAi pathway. However, the specific counter-defense function of any VSR biochemical activity is fully validated only when it is shown as essential for viral infection in the wild-type but not mutant hosts defective in antiviral RNAi. Here, we investigated the role of VSR activities for direct binding to small-interfering RNA duplexes (siRNA), long double-stranded RNA (dsRNA), or RNA-dependent RNA polymerase 1 (RDR1) during plant infection by wild-type and mutant cucumber mosaic virus (CMV), a positive-strand RNA virus expressing the 110-residue 2b protein as its VSR. We demonstrate that a C-terminally truncated 2b mutant (2b1-93) active in direct binding to siRNA and dsRNA, but not RDR1, was able to suppress the amplification of virus-derived siRNAs (vsiRNA) and antiviral RNAi mediated by RDR6, but not RDR1. By contrast, an N-terminally truncated 2b mutant (2b18-110) inactive in direct binding to siRNA or dsRNA was able to suppress vsiRNA amplification and antiviral RNAi mediated by RDR1, but not RDR6, and was less effective to promote systemic CMV infection and disease development than 2b1-93. Together, our results show that whereas RDR1 suppression requires direct binding of VSR-2b to RDR1, but not siRNA or dsRNA, RDR6 suppression depends on direct binding to siRNA and dsRNA, but not RDR1. Therefore, CMV, through its VSR-2b, suppresses two parallel vsiRNA amplification pathways by distinct molecular mechanisms, and this unique property may account for the unusually wide host range of CMV.IMPORTANCEHost amplification of antiviral immunity is essential for robust control of viral infections. However, little is known about the mechanisms that viruses have evolved to suppress immune amplification in plants. Here, we characterized whole plant infection by cucumber mosaic virus (CMV) with its viral suppressor of RNA interference (RNAi) mutated to become inactive in direct binding to small-interfering RNA duplexes (siRNA), long double-stranded RNA (dsRNA), or RNA-dependent RNA polymerase 1 (RDR1). We demonstrate maximal suppression of both RDR1- and RDR6-mediated antiviral RNAi amplification by the CMV 2b protein, a viral suppressor of RNAi (VSR). Notably, whereas RDR1 suppression requires direct binding of 2b to RDR1 but not siRNA or dsRNA, RDR6 suppression depends on direct binding to siRNA and dsRNA, but not RDR1. Our findings reveal a novel counter-defense strategy evolved by a wide host range positive-strand RNA virus to suppress two pathways of immune amplification by distinct mechanisms.

Cucumovirus↗

PubMed2025

Modulation of Cell Cycle Kinases by Kaposi's Sarcoma-Associated Herpesvirus.

The cell cycle is governed by kinase activity that coordinates progression through a series of regulatory checkpoints, preventing the division of damaged cells. The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple genes that modulate or co-opt the activity of these kinases, shaping the cellular environment to promote viral persistence. By advancing the cell cycle, KSHV facilitates latent replication and subsequent transmission of viral genomes to daughter cells, while also contributing to the establishment of multiple cancer types. Conversely, during viral lytic replication, KSHV extends the resting phase of the cell cycle to prevent cellular DNA synthesis that would otherwise compete for essential replication precursors. This review will examine the mechanisms KSHV has evolved to control the kinase activity regulating host cell cycle progression.

Herpesvirus 8, Human↗

PubMed2025

An Evolutionary Framework Exploiting Virologs and Their Host Origins to Inform Poxvirus Protein Functions.

Poxviruses represent evolutionary successful infectious agents. As a family, poxviruses can infect a wide variety of species including humans, fish, and insects. While many other viruses are species-specific, an individual poxvirus species is often capable of infecting diverse hosts and cell types. For example, the prototypical poxvirus, vaccinia, is well known to infect numerous human cell types but can also infect cells from divergent hosts like frog neurons. Notably, poxvirus infections result in both detrimental human and animal diseases. The most infamous disease linked to a poxvirus is smallpox caused by variola virus. Poxviruses are large double-stranded DNA viruses, which uniquely replicate in the cytoplasm of cells. The model poxvirus genome encodes ~200 nonoverlapping protein-coding open reading frames (ORFs). Poxvirus gene products impact various biological processes like the production of virus particles, the host range of infectivity, and disease pathogenesis. In addition, poxviruses and their gene products have biomedical application with several species commonly engineered for use as vaccines and oncolytic virotherapy. Nevertheless, we still have an incomplete understanding of the functions associated with many poxvirus genes. In this chapter, we outline evolutionary insights that can complement ongoing studies of poxvirus gene functions and biology, which may serve to elucidate new molecular activities linked to this biomedically relevant class of viruses.

Animals↗

PubMed2006

The host acts as a genetic bottleneck during serial infections: an insect-fungal model system.

The genetic variation of a pathogen population is a pivotal component of pathogen evolution, having important implications for emerging diseases, nosocomial infections, and laboratory subculturing practices. Furthermore, it is undoubtedly altered during infection of a host. We address this issue using an insect-fungal model system to examine the influence of serial host passage on the genetic variation of a pathogen population. Using amplified fragment length polymorphism, a strain of the opportunistic fungus, Aspergillus flavus, showing initially 98% genetic similarity, was assessed for changes in genetic diversity during repeated passage through Galleria mellonella larvae and compared to that of a parallel population serially subcultured on artificial media. In two independent trials, the genetic diversity of the population passed through the insect dropped significantly, while the genetic variation of the population subcultured on media increased or remained unchanged. However, there were no changes in virulence or the production of protease or aflatoxin, indicating an apparent lack of selection. We suggest that the insect acted as a genetic bottleneck, reducing the genetic diversity of the A. flavus population. The ability of a host to produce a genetic bottleneck in a pathogen population impacts our understanding of emerging diseases, nosocomial infections, and laboratory subculturing practices.

Animals↗

PubMed2005

Characterization of a porcine intestinal epithelial cell line for in vitro studies of microbial pathogenesis in swine.

In vitro studies on the pathogenesis in swine have been hampered by the lack of relevant porcine cell lines. Since many bacterial infections are swine-specific, studies on pathogenic mechanisms require appropriate cell lines of porcine origin. We have characterized the permanent porcine intestinal epithelial cell line, IPEC-J2, using a variety of methods in order to assess the usefulness of this cell line as an in vitro infection model. Electron microscopic analyses and histochemical staining revealed the cells to be enterocyte-like with microvilli, tight junctions and glycocalyx-bound mucin. The functional integrity of monolayers was determined by transepithelial electrical resistance (TEER) measurements. Both commensal bacteria and important bacterial pathogens were chosen for study based on their principally different infection mechanisms: obligate extracellular Escherichia coli, facultative intracellular Salmonella and obligate intracellular Chlamydia. We determined the colonization and proliferation of the bacteria on and within the host cells and monitored the host cell response. We verified the expression of mRNAs encoding the cytokines IL-1alpha, -6, -7, -8, -18, TNF-alpha and GM-CSF, but not TGF-beta or MCP-1. IL-8 protein expression was enhanced by Salmonella invasion. We conclude that the IPEC-J2 cell line provides a relevant in vitro model system for porcine intestinal pathogen-host cell interactions.

Animals↗

PubMed2026

Uncovering host transcriptional responses to tilapia lake virus (TiLV) through De novo RNA-seq assembly in Nile tilapia, Oreochromis niloticus.

Tilapia lake virus (TiLV) has emerged as an important pathogen that negatively impacts tilapia farming globally. Using RNA sequencing technology, this study investigated the liver transcriptomic profile of apparently healthy and TiLV-infected Oreochromis niloticus from wild. RNA sequence libraries generated 3,356 differentially expressed genes (DEGs), with 1,726 genes that were upregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified 680 different pathways with differential regulation of the metabolic and immune-related pathways indicating that TiLV may interfere in host metabolism and replicate to establish the infection. This study provides transcriptomic insights into the liver responses of naturally TiLV-infected wild O. niloticus and highlights key immune and metabolic pathways associated with viral infection.

Animals↗

PubMed2004

Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases.

This review outlines some of the many factors a clinician must consider when selecting an antimicrobial dosing regimen for the treatment of infection. Integration of the principles of antimicrobial pharmacology and the pharmacokinetic parameters of an individual patient provides the most comprehensive assessment of the interactions between pathogen, host, and antibiotic. For each class of agent, appreciation of the different approaches to maximize microbial killing will allow for optimal clinical efficacy and reduction in risk of development of resistance while avoiding excessive exposure and minimizing risk of toxicity. Disease states with special considerations for antimicrobial use are reviewed, as are situations in which pathophysiologic changes may alter the pharmacokinetic handling of antimicrobial agents.

Anti-Bacterial Agents↗

PubMed2004

EST and microarray analyses of pathogen-responsive genes in hot pepper (Capsicum annuum L.) non-host resistance against soybean pustule pathogen (Xanthomonas axonopodis pv. glycines).

Large-scale single-pass sequencing of cDNA libraries and microarray analysis have proven to be useful tools for discovering new genes and studying gene expression. As a first step in elucidating the defense mechanisms in hot pepper plants, a total of 8,525 expressed sequence tags (ESTs) were generated and analyzed in silico. The cDNA microarray analysis identified 613 hot pepper genes that were transcriptionally responsive to the non-host soybean pustule pathogen Xanthomonas axonopodis pv. glycines ( Xag). Several functional types of genes, including those involved in cell wall modification/biosynthesis, transport, signaling pathways and divergent defense reactions, were induced at the early stage of Xag infiltration. In contrast, genes encoding proteins that are involved in photosynthesis, carbohydrate metabolism and the synthesis of chloroplast biogenetic proteins were down-regulated at the late stage of Xag infiltration. These expression profiles share common features with the expression profiles elicited by other stresses, such as fungal challenge, wounding, cold, drought and high salinity. However, we also identified several novel transcription factors that may be specifically involved in the defense reaction of the hot pepper. We also found that the defense reaction of the hot pepper may involve the deactivation of gibberellin. Furthermore, many genes encoding proteins with unknown function were identified. Functional analysis of these genes may broaden our understanding of non-host resistance. This study is the first report of large-scale sequencing and non-host defense transcriptome analysis of the hot pepper plant species. (The sequence data in this paper have been submitted to the dbEST and GenBank database under the codes 10227604-10236595 and BM059564-BM068555, respectively. Additional information is available at http://plant.pdrc.re.kr/ks200201/pepper.html).

Capsicum↗

PubMed2006

Modeling intercellular interactions in early Mycobacterium infection.

Infection with Mycobacterium tuberculosis (Mtb) is characterized by localized, roughly spherical lesions within which the pathogen interacts with host cells. Containment of the infection or progression of disease depends on the behavior of individual cells, which, in turn, depends on the local molecular environment and on contact with neighboring cells. Modeling can help us understand the nonlinear interactions that drive the overall dynamics in this system. Early events in infection are particularly important, as are spatial effects and inherently stochastic processes. We describe a model of early Mycobacterium infection using the CyCells simulator, which was designed to capture these effects. We relate CyCells simulations of the model to several experimental observations of individual components of the response to Mtb.

Computer Simulation↗

PubMed2024

Metagenomic Analysis of Gut Microbiome of Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is one of the most common diseases in the neonatal intensive care unit which severely affects neonatal survival. Gut microbes play an increasingly important role in human health, but there are rarely reported how gut microbiota contribute to PPHN. In our study, the metagenomic sequencing of feces from 12 PPHN's neonates and 8 controls were performed to expose the relation between neonatal gut microbes and PPHN disease. Firstly, we found that the abundance of Actinobacteria, Proteobacteria, Bacteroidetes were significantly increased in PPHN compared with controls, but the Firmicutes components was reduced. And some pathogenic strains (like Vibrio metschnikovii) were significantly enriched in the PPHN compared with controls. Secondly, functional annotation of genes found that PPHN up-regulated transmembrane transport, but down-regulated ribosome and ATP binding. Lastly, microbial metabolic pathway enrichment analysis indicated that some metabolic pathway in PPHN were conflicting and contradictory, showed that an abnormally increased metabolism, disturbed protein synthesis and genomic instability in the PPHN neonate. Our results contribute to understanding the changes in the species and function of gut microbiota in PPHN, thus providing a theoretical basis for the explanation and treatment of PPHN.

Gastrointestinal Microbiome↗

PubMed1994

Nearly right or precisely wrong? Natural versus laboratory studies of vector-borne diseases.

Recent studies that compare experimental vector-borne disease systems incorporating elements of natural pathogen-vector-host interactions with model systems using unnatural associations have highlighted quantitative, and even qualitative, differences in the results. Here, Sarah Randolph and Pat Nuttall argue that the use of mathematical models to explore epidemiological processes and patterns depends on accurate parameter values obtained from natural systems.

Journal Article↗

PubMed1993

Arabidopsis as a model host for studying plant-pathogen interactions.

Because the molecular biology and genetics of Arabidopsis thaliana are so well defined, it is potentially a superb subject for research on plant-pathogen interactions. Viruses, bacteria and fungi that infect Arabidopsis and are representative pathogens of economically important plants have recently been described. The search now is for a pathogenic fungus with tractable genetics to combine with a direct analysis of plant resistance genes.

Arabidopsis↗