Antagonistic fungal enterotoxins intersect at multiple levels with host innate immune defences.
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ABSTRACT:
SUBMITTER: Zhang X
PROVIDER: S-EPMC8263066 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Amphibian skin is a mucosal surface in direct and continuous contact with a microbially diverse and laden aquatic and/or terrestrial environment. As such, frog skin is an important innate immune organ and first line of defence against pathogens in the environment. Critical to the innate immune functions of frog skin are the maintenance of physical, chemical, cellular, and microbiological barriers and the complex network of interactions that occur across all the barriers. Despite the global decline in amphibian populations, largely as a result of emerging infectious diseases, we understand little regarding the cellular and molecular mechanisms that underlie the innate immune function of amphibian skin and defence against pathogens. In this review, we discuss the structure, cell composition and cellular junctions that contribute to the skin physical barrier, the antimicrobial peptide arsenal that, in part, comprises the chemical barrier, the pattern recognition receptors involved in recognizing pathogens and initiating innate immune responses in the skin, and the contribution of commensal microbes on the skin to pathogen defence. We briefly discuss the influence of environmental abiotic factors (natural and anthropogenic) and pathogens on the immunocompetency of frog skin defences. Although some aspects of frog innate immunity, such as antimicrobial peptides are well-studied; other components and how they contribute to the skin innate immune barrier, are lacking. Elucidating the complex network of interactions occurring at the interface of the frog's external and internal environments will yield insight into the crucial role amphibian skin plays in host defence and the environmental factors leading to compromised barrier integrity, disease, and host mortality.
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Project description:Preterm neonates are highly vulnerable to infection.To investigate the developmental contribution of prematurity, chorioamnionitis and antenatal corticosteroids (ANS) on the maturation of neonatal microbial pathogen recognition responses.Using standardized protocols, we assayed multiple inflammatory cytokine responses (IL-1?, IL-6, TNF-? and IL-12/23p40) to three prototypic Toll-like receptor (TLR) agonists, i.e. TLR4 (lipopolysaccharide), TLR5 (flagellin) and TLR7/8 (R848), and to the non-TLR retinoic acid-inducible gene I (RIG-I)-like receptor agonist, in cord blood mononuclear cells from neonates born before 33 weeks of gestation and at term.TLR responses develop asynchronously in preterm neonates, whereby responses to TLR7/8 were more mature and were followed by the development of TLR4 responses, which were also heterogeneous. Responses to TLR5 were weakest and most immature. Maturity in TLR responses was not influenced by sex. Overall, we detected no significant contribution of ANS and chorioamnionitis to the developmental attenuation of either TLR or RIG-I responses.The maturation of anti-microbial responses in neonates born early in gestation follows an asynchronous developmental hierarchy independently of an exposure to chorioamnionitis and ANS. Our data provide an immunological basis for the predominance of specific microbial infections in this age group.
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Project description:Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
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Project description:BackgroundThe development, maintenance, and use of immune defences are costly. Therefore, animals face trade-offs in terms of resource allocation within their immune system and between their immune system and other physiological processes. To maximize fitness, evolution may favour investment in one immunological defence or subsystem over another in a way that matches a species broader life history strategy. Here, we used phylogenetically-informed comparative analyses to test for relationships between two immunological components. Natural antibodies and complement were used as proxies for the innate branch; structural complexity of the major histocompatibility complex (MHC) region was used for the acquired branch.ResultsWe found a negative association between the levels of natural antibodies (i.e., haemagglutination titre) and the total MHC gene copy number across the avian phylogeny, both at the species and family level. The family-level analysis indicated that this association was apparent for both MHC-I and MHC-II, when copy numbers within these two MHC regions were analysed separately. The association remained significant after controlling for basic life history components and for ecological traits commonly linked to pathogen exposure.ConclusionOur results provide the first phylogenetically robust evidence for an evolutionary trade-off within the avian immune system, with a more developed acquired immune system (i.e., more complex MHC architecture) in more derived bird lineages (e.g., passerines) being accompanied by an apparent downregulation of the innate immune system.
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Project description:Various fungi and bacteria can colonize in the brain and produce physical alterations seen in Alzheimer's disease (AD). Environmental and genetic factors affect the occurrence of fungal colonization, and how fungi can grow, enter the brain, and interact with the innate immune system. The essence of AD development is the defeat of the innate immune system, whether through vulnerable patient health status or treatment that suppresses inflammation by suppressing the innate immune system. External and mechanical factors that lead to inflammation are a door for pathogenic opportunity. Current research associates the presence of fungi in the etiology of AD and is shown in cerebral tissue at autopsy. From the time of the discovery of AD, much speculation exists for an infective cause. Identifying any AD disease organism is obscured by processes that can take place over years. Amyloid protein deposits are generally considered to be evidence of an intrinsic response to stress or imbalance, but instead amyloid may be evidence of the innate immune response which exists to destroy fungal colonization through structural interference and cytotoxicity. Fungi can remain ensconced for a long time in niches or inside cells, and it is the harboring of fungi that leads to repeated reinfection and slow wider colonization that eventually leads to a grave outcome. Although many fungi and bacteria are associated with AD affected tissues, discussion here focuses on Candida albicans as the archetype of human fungal pathology because of its wide proliferation as a commensal fungus, extensive published research, numerous fungal morphologies, and majority proliferation in AD tissues.
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2018-12-07 | GSE104785 | GEO
Project description:RNA viruses infecting vertebrates differ fundamentally in their ability to establish persistent infections with markedly different patterns of transmission, disease mechanisms and evolutionary relationships with their hosts. Although interactions with host innate and adaptive responses are complex and persistence mechanisms likely multi-factorial, we previously observed associations between bioinformatically predicted RNA secondary formation in genomes of positive-stranded RNA viruses with their in vivo fitness and persistence. To analyse this interactions functionally, we transfected fibroblasts with non-replicating, non-translated RNA transcripts from RNA viral genomes with differing degrees of genome-scale ordered RNA structure (GORS). Single-stranded RNA transcripts induced interferon-β mediated though RIG-I and PKR activation, the latter associated with rapid induction of antiviral stress granules. A striking inverse correlation was observed between induction of both cellular responses with transcript RNA structure formation that was independent of both nucleotide composition and sequence length. The consistent inability of cells to recognize RNA transcripts possessing GORS extended to downstream differences from unstructured transcripts in expression of TNF-α, other interferon-stimulated genes and induction of apoptosis. This functional association provides novel insights into interactions between virus and host early after infection and provides evidence for a novel mechanism for evading intrinsic and innate immune responses.
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Project description:Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
2019-03-12 | GSE128173 | GEO
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