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Experimental and Molecular Pathology Dec 2023Molluscum contagiosum virus (MCV) is a poxvirus that causes benign, persistent skin lesions. MCV encodes a variety of immune evasion molecules to dampen host immune...
Molluscum contagiosum virus (MCV) is a poxvirus that causes benign, persistent skin lesions. MCV encodes a variety of immune evasion molecules to dampen host immune responses. Two of these proteins are the MC159 and MC160 proteins. Both MC159 and MC160 contain two tandem death effector domains and share homology to the cellular FLIPs, FADD, and procaspase-8. MC159 and MC160 dampen several innate immune responses such as NF-κB activation and mitochondrial antiviral signaling (MAVS)-mediated induction of type 1 interferon (IFN). The type 1 IFN response is also activated by the cytosolic DNA sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Both cGAS and STING play a vital role in sensing a poxvirus infection. In this study, we demonstrate that there are nuanced differences between both MC160 and MC159 in terms of how the viral proteins modulate the cGAS/STING and MAVS pathways. Specifically, MC160 expression, but not MC159 expression, dampens cGAS/STING-mediated induction of IFN in HEK 293 T cells. Further, MC160 expression prevented the K63-ubiquitination of both STING and TBK1, a kinase downstream of cGAS/STING. Ectopic expression of the MC160 protein, but not the MC159 protein, resulted in a measurable decrease in the TBK1 protein levels as detected via immunoblotting. Finally, using a panel of MC160 truncation mutants, we report that the MC160 protein requires both DEDs to inhibit cGAS/STING-induced activation of IFN-β. Our model indicates MC160 likely alters the TBK1 signaling complex to decrease IFN-β activation at the molecular intersection of the cGAS/STING and MAVS signaling pathways.
Topics: Humans; Molluscum contagiosum virus; HEK293 Cells; Viral Proteins; Nucleotidyltransferases; Immunity, Innate; Interferon-beta; Interferons
PubMed: 37890651
DOI: 10.1016/j.yexmp.2023.104876 -
Virus Research Oct 2017Poxviruses have previously been detected in macropods with cutaneous papillomatous lesions, however to date, no comprehensive analysis of a poxvirus from kangaroos has...
Poxviruses have previously been detected in macropods with cutaneous papillomatous lesions, however to date, no comprehensive analysis of a poxvirus from kangaroos has been performed. Here we report the genome sequences of a western grey kangaroo poxvirus (WKPV) and an eastern grey kangaroo poxvirus (EKPV), named for the host species from which they were isolated, western grey (Macropus fuliginosus) and eastern grey (Macropus giganteus) kangaroos. Poxvirus DNA from WKPV and EKPV was isolated and entire coding genome regions determined through Roche GS Junior and Illumina Miseq sequencing, respectively. Viral genomes were assembled using MIRA and SPAdes, and annotations performed using tools available from the Viral Bioinformatics Resource Centre. Histopathology and transmission electron microscopy analysis was also performed on WKPV and its associated lesions. The WKPV and EKPV genomes show 96% identity (nucleotide) to each other and phylogenetic analysis places them on a distinct branch between the established Molluscipoxvirus and Avipoxvirus genera. WKPV and EKPV are 170 kbp and 167 kbp long, containing 165 and 162 putative genes, respectively. Together, their genomes encode up to 47 novel unique hypothetical proteins, and possess virulence proteins including a major histocompatibility complex class II inhibitor, a semaphorin-like protein, a serpin, a 3-β-hydroxysteroid dehydrogenase/δ 5→4 isomerase, and a CD200-like protein. These viruses also encode a large putative protein (WKPV-WA-039 and EKPV-SC-038) with a C-terminal domain that is structurally similar to the C-terminal domain of a cullin, suggestive of a role in the control of host ubiquitination. The relationship of these viruses to members of the Molluscipoxvirus and Avipoxvirus genera is discussed in terms of sequence similarity, gene content and nucleotide composition. A novel genus within subfamily Chordopoxvirinae is proposed to accommodate these two poxvirus species from kangaroos; we suggest the name, Thylacopoxvirus (thylaco-: [Gr.] thylakos meaning sac or pouch).
Topics: Animals; Genome, Viral; Histocytochemistry; Macropodidae; Microscopy, Electron; Molecular Sequence Annotation; Phylogeny; Poxviridae; Poxviridae Infections; Sequence Analysis, DNA
PubMed: 28958947
DOI: 10.1016/j.virusres.2017.09.016 -
JAMA Ophthalmology Sep 2015
Topics: Administration, Oral; Child; Chronic Disease; Cimetidine; Conjunctivitis, Viral; Eye Infections, Viral; Histamine H2 Antagonists; Humans; Male; Molluscum Contagiosum; Molluscum contagiosum virus; Skin Diseases, Viral; Warts
PubMed: 26180942
DOI: 10.1001/jamaophthalmol.2015.1284 -
Viruses Nov 2022That cidofovir, an acyclic nucleoside phosphonate (ANP), was inhibitory to the replication of poxviruses was first demonstrated by De Clercq et al.. That its active...
That cidofovir, an acyclic nucleoside phosphonate (ANP), was inhibitory to the replication of poxviruses was first demonstrated by De Clercq et al.. That its active metabolite, the diphosphate, was found to be inhibitory to the molluscum contagiosum () DNA polymerase was demonstrated by Watanabe and Tamaki. Twelve different independent observations have then indicated that cidofovir administered intravenously, topically or intralesionally is efficacious in the treatment of mostly in immunosuppressed patients.
Topics: Humans; Cidofovir; Molluscum contagiosum virus; Cytosine; Organophosphonates; Molluscum Contagiosum
PubMed: 36366582
DOI: 10.3390/v14112484 -
Journal of Cutaneous Pathology Jan 2016Molluscum contagiosum (MC) is the commonest human poxvirus infection. Follicular induction has rarely been observed in the epidermis surrounding lesions of MC. A...
BACKGROUND
Molluscum contagiosum (MC) is the commonest human poxvirus infection. Follicular induction has rarely been observed in the epidermis surrounding lesions of MC. A virus-induced localized proliferation of germinative/stem cells of the folliculosebaceous-apocrine unit has been suggested as the underlying cause, however few reports of this peculiar phenomenon exist in the literature and the mechanisms involved in this proliferation require further study.
METHODS
We prospectively collected MC cases showing multifocal areas of primitive follicular induction involving the adjacent undersurface epidermis. Immunohistochemical expression of BerEP4, PHLDA1 and cytokeratin 20 (CK20) was evaluated in the basaloid germs surrounding the lesions. For PHLDA1, we used epidermal melanocytes as a positive internal control. For BerEP4, we employed a basal cell carcinoma (BCC) and for CK20, colon as positive external controls. An incubation without the primary antibody functioned as an external negative control.
RESULTS
All the cases studied showed an intense positive staining of the basaloid buds with BerEP4 and weaker stain for PHLDA1. CK20 showed the presence of scattered Merkel cells within the induced epidermal basaloid proliferations favoring their reactive origin.
DISCUSSION
The pathogenetic mechanisms behind the development of these microscopic features and the link between follicular induction and poxvirus infection are explored. Awareness of this unusual phenomenon by dermatopathologists will be helpful in avoiding a misdiagnosis of a superficial BCC in such cases.
CONCLUSIONS
BerEP4 and PHLDA1 were consistently expressed in the areas of primitive follicular induction surrounding lesions of MC. CK 20 stained the Merkel cells present in the basaloid buds. All these findings support the reactive origin of this phenomenon, which we believe is most probably viral-induced.
Topics: Biomarkers, Tumor; Carcinoma, Basal Cell; Case-Control Studies; Hair Follicle; Humans; Immunohistochemistry; Keratin-20; Merkel Cells; Molluscipoxvirus; Molluscum Contagiosum; Poxviridae Infections; Prospective Studies; Skin Neoplasms; Transcription Factors
PubMed: 26265178
DOI: 10.1111/cup.12584 -
Journal of the American Academy of... Feb 2024
Topics: Humans; Molluscum Contagiosum; Molluscum contagiosum virus
PubMed: 37871806
DOI: 10.1016/j.jaad.2023.10.033 -
The Pan African Medical Journal 2019Molluscums contagiosum (MC) are benign skin lesions caused by Molluscipoxvirus, primarily affecting children and young adults. They manly involve the skin and rarely the...
Molluscums contagiosum (MC) are benign skin lesions caused by Molluscipoxvirus, primarily affecting children and young adults. They manly involve the skin and rarely the mucous membranes. Clinical diagnosis is easy, confirmed by histological examination of the lesion. However there is no consensus regarding therapy. Eyelid molluscum contagiosum is rare, posing a problem of differential diagnosis especially when it is isolated as well as a therapeutic problem given the proximity of the eyeball. We report the case of a 7-year old girl with isolated eyelid lesion. The patient underwent lesion excision. Anatomopathological examination showed molluscum contagiosum. This study aims to describe the clinical, therapeutic and evolutionary features of this rare localization of molluscum contagiosum.
Topics: Child; Diagnosis, Differential; Eyelid Diseases; Female; Humans; Molluscum Contagiosum
PubMed: 31312291
DOI: 10.11604/pamj.2019.32.177.18418 -
MBio Nov 2023Four molluscum contagiosum virus (MOCV) genotypes (MOCV1-4) and four subtype variants (MOCV1p, MOCV1va, MOCV1vb, and MOCV1vc) were partially characterized using...
Comprehensive analysis of 66 complete molluscum contagiosum virus (MOCV) genomes: characterization and functional annotation of 47 novel complete MOCV genomes, including the first genome of MOCV genotype 3, and a proposal for harmonized MOCV genotyping indexing.
Four molluscum contagiosum virus (MOCV) genotypes (MOCV1-4) and four subtype variants (MOCV1p, MOCV1va, MOCV1vb, and MOCV1vc) were partially characterized using restriction enzyme profiling in the early 1980s/1990s. However, complete genome sequences of only MOCV1 and MOCV2 are available. The evolutionary pathways of MOCV genotypes and subtype variants with unavailable sequences remain unclear, and also whether all MOCV genotypes/subtype variants can be reliably detected and appropriately categorized using available PCR-based protocols. We fully characterized and functionally annotated 47 complete MOCV genomes, including two putative non-MOCV1/2 isolates, expanding the number of fully characterized MOCV genomes to 66. To ascertain the placement of any putative novel MOCV sequence into the restriction profiling typing scheme, we developed an original framework for extracting complete MOCV genome sequence-based restriction profiles and matching them with reference restriction profiles. We confirmed that two putative non-MOCV1/2 isolates represent the first complete genomes of MOCV3. Comprehensive phylogenomic, recombination, and restriction enzyme recognition site analysis of all 66 currently available MOCV genomes showed that they can be agglomerated into six phylogenetic subgroups (PG1-6), corresponding to the subtype variants from the pioneering studies. PG5 was a novel subtype variant of MOCV2, but no PGs corresponded to the subtype variants MOCV1vb or MOCV4. We showed that the phylogenetic subgroups may have diverged from the prototype MOCV genotype lineages following large-scale recombination events and hinted at partial sequence content of MOCV4 and direction of recombinant transfer in the events that spawned PG5 and the yet undetected subtype variant MOCV1vb.IMPORTANCEFour molluscum contagiosum virus (MOCV) genotypes (MOCV1-4) and four subtype variants were partially characterized using restriction enzyme profiling in the 1980s/1990s, but complete genome sequences of only MOCV1 and MOCV2 are available. The evolutionary pathways whereby genotypes/subtype variants with unavailable sequences emerged and whether all MOCVs can be detected using current diagnostic approaches remain unclear. We fully characterized 47 novel complete MOCV genomes, including the first complete MOCV3 genome, expanding the number of fully characterized genomes to 66. For reliably classifying the novel non-MOCV1/2 genomes, we developed and validated a framework for matching sequence-derived restriction maps with those defining MOCV subtypes in pioneering studies. Six phylogenetic subgroups (PG1-6) were identified, PG5 representing a novel MOCV2 subtype. The phylogenetic subgroups diverged from the prototype lineages following large-scale recombination events and hinted at partial sequence content of MOCV4 and direction of recombinant transfer in the events spawning PG5 and yet undetected MOCV1vb variant.
PubMed: 37947415
DOI: 10.1128/mbio.02224-23 -
JAMA Dermatology Aug 2022
Topics: Humans; Molluscum Contagiosum; Molluscum contagiosum virus
PubMed: 35830172
DOI: 10.1001/jamadermatol.2022.2719 -
Journal of Virology Mar 2023Molluscum contagiosum virus (MCV) is a human-adapted poxvirus that causes a common and persistent yet mild infection characterized by distinct, contagious, papular skin...
Molluscum contagiosum virus (MCV) is a human-adapted poxvirus that causes a common and persistent yet mild infection characterized by distinct, contagious, papular skin lesions. These lesions are notable for having little or no inflammation associated with them and can persist for long periods without an effective clearance response from the host. Like all poxviruses, MCV encodes potent immunosuppressive proteins that perturb innate immune pathways involved in virus sensing, the interferon response, and inflammation, which collectively orchestrate antiviral immunity and clearance, with several of these pathways converging at common signaling nodes. One such node is the regulator of canonical nuclear factor kappa B (NF-κB) activation, NF-κB essential modulator (NEMO). Here, we report that the MCV protein MC008 specifically inhibits NF-κB through its interaction with NEMO, disrupting its early ubiquitin-mediated activation and subsequent downstream signaling. MC008 is the third NEMO-targeting inhibitor to be described in MCV to date, with each inhibiting NEMO activation in distinct ways, highlighting strong selective pressure to evolve multiple ways of disabling this key signaling protein. Inflammation lies at the heart of most human diseases. Understanding the pathways that drive this response is the key to new anti-inflammatory therapies. Viruses evolve to target inflammation; thus, understanding how they do this reveals how inflammation is controlled and, potentially, how to disable it when it drives disease. Molluscum contagiosum virus (MCV) has specifically evolved to infect humans and displays an unprecedented ability to suppress inflammation in our tissue. We have identified a novel inhibitor of human innate signaling from MCV, MC008, which targets NEMO, a core regulator of proinflammatory signaling. Furthermore, MC008 appears to inhibit early ubiquitination, thus interrupting later events in NEMO activation, thereby validating current models of IκB kinase (IKK) complex regulation.
Topics: Humans; NF-kappa B; Molluscum contagiosum virus; Viral Proteins; Signal Transduction; Ubiquitination; I-kappa B Kinase
PubMed: 36916940
DOI: 10.1128/jvi.00108-23