Molluscum Contagiosum Virus: Biology and Immune Response.

Molluscum contagiosum virus is a poxvirus belonging to the Poxviridae family, which includes Orthopoxvirus, Parapoxvirus, Yantapoxvirus, Molluscipoxvirus, Smallpox virus, Cowpox virus and Monkeypox virus. MCV belongs to the genus Molluscipoxvirus and has a tropism for skin tissue. MCV infects keratinocytes and, after an incubation period of 2 weeks to 6 weeks, causes a breakdown of the skin barrier with the development of papules of variable size depending on the proper functioning of the immune response (both adaptive and acquired). MCV only infects humans and does not cause viraemia. MCV encodes for several inhibitory proteins responsible to circumvent the immune response through different signalling pathways. Individuals who can be infected with MCV are children, immunocompromised individuals such as organ transplant recipients and Human Immunodeficiency Virus (HIV)-infected individuals. Current treatments to manage MCV-induced lesions are different and include the use of immunomodulators, which, however, do not provide an effective response.

Exogenous factors in the pathogenesis of atopic dermatitis: Irritants and cutaneous infections.

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections.

Intralesional vitamin D immunotherapy for recalcitrant molluscum contagiosum.

Molluscum contagiosum (MC) is a benign viral infection, which may have florid manifestations in immunosuppressed patients. Moreover, the treatment is often unsatisfactory in these patients and it maybe recalcitrant. We hereby report the use of intralesional vitamin D immunotherapy in two immunosuppressed patients with persistent widespread MC lesions.

A case of intracranial molluscum contagiosum virus infection diagnosed by metagenomic sequencing of cerebrospinal fluid.

Molluscum contagiosum is a common, self-limiting infectious disease of the skin caused by molluscum contagiosum virus (MCV). The disease primarily affects children, sexually active adults, and immunocompromised individuals. Transmission of the virus occurs by direct skin contact. Therefore, the virus is usually detected in the skin and genitals of patients. However, the diagnosis of intracranial infection by the virus is difficult if the skin/mucosa lessons are atypical or absent, and the presence of the virus in the cerebrospinal fluid has not been reported. We report a very rare case of intracranial infection by molluscum contagiosum virus. A 25-year-old girl was admitted to our hospital due to severe headache but no fever or other symptoms. Upon examination, some small flesh-colored flattened papules on both arms were noticed. Blood tests showed slightly reduced levels of CD3 and CD4 T lymphocytes. Three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) and head magnetic resonance (MR) were both normal. Lumbar puncture was performed, and metagenomic sequencing was applied to the spinal fluid. The unique sequences of the molluscum contagiosum virus were identified in the fluid. The patient was then diagnosed with intracranial molluscum contagiosum virus infection. No special treatment was given. The headache gradually disappeared, and the patient was discharged. During our quarterly follow-up, the girl appeared normal, and her skin lesions disappeared. However, her CD3 and CD4 T lymphocyte counts were still slightly lower than the normal level. Our case shows that the application of metagenomic sequencing to cerebrospinal fluid is a sensitive and powerful means to detect pathogens causing intracranial infection. Keywords: Molluscum contagiosum; intracranial infection; metagenomics sequencing.

Molluscum contagiosum virus MC80 sabotages MHC-I antigen presentation by targeting tapasin for ER-associated degradation.

The human specific poxvirus molluscum contagiosum virus (MCV) produces skin lesions that can persist with minimal inflammation, suggesting that the virus has developed robust immune evasion strategies. However, investigations into the underlying mechanisms of MCV pathogenesis have been hindered by the lack of a model system to propagate the virus. Herein we demonstrate that MCV-encoded MC80 can disrupt MHC-I antigen presentation in human and mouse cells. MC80 shares moderate sequence-similarity with MHC-I and we find that it associates with components of the peptide-loading complex. Expression of MC80 results in ER-retention of host MHC-I and thereby reduced cell surface presentation. MC80 accomplishes this by engaging tapasin via its luminal domain, targeting it for ubiquitination and ER-associated degradation in a process dependent on the MC80 transmembrane region and cytoplasmic tail. Tapasin degradation is accompanied by a loss of TAP, which limits MHC-I access to cytosolic peptides. Our findings reveal a unique mechanism by which MCV undermines adaptive immune surveillance.

Mucocutaneous manifestations of human immunodeficiency virus (HIV) infection in children in relation to the degree of immunosuppression.

BACKGROUND: Human immunodeficiency virus (HIV) infection in children is becoming a common occurrence. Worldwide, limited studies have been done on the mucocutaneous manifestations in HIV-positive children. The aim of our study was to analyze the spectrum of mucocutaneous manifestations of pediatric HIV infection and correlate to degree of immunosuppression. MATERIAL AND METHODS: One hundred and sixty-five children under 18 years with HIV, who presented to the departments of dermatology and pediatrics, were examined for mucocutaneous manifestations. Patients were classified into four groups of immunodeficiency such as normal, mild, advanced, and severe, based on NACO guidelines of immunosuppression. The most recent CD4 count (within 6 months of study period) was considered. RESULTS: One hundred and sixty-five patients were examined, and skin manifestations were seen in 100 (61%) of them.The highest incidence of mucocutaneous manifestations was in 6-10 age group. Papular pruritic eruptions (PPE) (16%) was the most common condition, with highest prevalence in severe CD4 category (38%). Molluscum contagiosum (MC) (10%) was the most common infectious condition, with highest prevalence in advanced CD4 category (14%). Severe cutaneous adverse reactions (SCAR) caused by nevirapine were seen in three children. The percentage of skin manifestations was highest in the advanced (107%) and severe (100%) CD4 category. There was no significant difference in manifestations between those who were on antiretroviral therapy (ART) and those not. CONCLUSION: The percentage of skin manifestations increased with degree of CD4 depletion. PPE was found to be the hallmark of severe immunosuppression. However, opportunistic infections did not correlate with severity of immunodeficiency.

New Insights into the Evolutionary and Genomic Landscape of Molluscum Contagiosum Virus (MCV) based on Nine MCV1 and Six MCV2 Complete Genome Sequences.

Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and the causative agent of molluscum contagiosum (MC), a common skin disease. Although it is an important and frequent human pathogen, its genetic landscape and evolutionary history remain largely unknown. In this study, ten novel complete MCV genome sequences of the two most common MCV genotypes were determined (five MCV1 and five MCV2 sequences) and analyzed together with all MCV complete genomes previously deposited in freely accessible sequence repositories (four MCV1 and a single MCV2). In comparison to MCV1, a higher degree of nucleotide sequence conservation was observed among MCV2 genomes. Large-scale recombination events were identified in two newly assembled MCV1 genomes and one MCV2 genome. One recombination event was located in a newly identified recombinant region of the viral genome, and all previously described recombinant regions were re-identified in at least one novel MCV genome. MCV genes comprising the identified recombinant segments have been previously associated with viral interference with host T-cell and NK-cell immune responses. In conclusion, the two most common MCV genotypes emerged along divergent evolutionary pathways from a common ancestor, and the differences in the heterogeneity of MCV1 and MCV2 populations may be attributed to the strictness of the constraints imposed by the host immune response.

Molluscum contagiosum in immunocompromised patients: AIDS presenting as molluscum contagiosum in a patient with psoriasis on biologic therapy.

Molluscum contagiosum (MC) is a common, self-limited cutaneous infection in immunocompetent individuals. However, in immunocompromised individuals the infection often has an atypical presentation and can be difficult to eradicate, making both the diagnosis and treatment challenging. Due to advancements in the management of patients with human immunodeficiency virus (HIV) and cancer, there is a growing population of immunosuppressed individuals, signaling the need for dermatologists to recognize and manage related skin diseases. We present a case of an atypical MC eruption in a patient on biologic therapy for psoriasis and an unrecognized underlying HIV infection, followed by a current review of the presentation and treatment of MC in various immunosuppressed states. With a growing population of immunosuppressed patients, it is important to recognize MC as a potential indicator of underlying immunosuppression. Testing for HIV should be offered to any patient starting immunosuppressive therapy such as biologic agents.

Interventions for Nongenital Molluscum Contagiosum in Persons Without Immune Deficiency.

Clinical Question: How effective and safe are treatments for nongenital molluscum contagiosum in persons without immune deficiency? Bottom Line: Compared with placebo, imiquimod, 5%, cream was not more effective in clearing molluscum contagiosum and caused more local adverse effects, including application site reactions, in children aged 2 to 12 years; because high-quality evidence for other interventions is lacking, allowing for natural resolution of the infection remains a reasonable approach.

Filaggrin mutations and Molluscum contagiosum skin infection in patients with atopic dermatitis.

BACKGROUND: Although mutations in the filaggrin (FLG) gene have been reported to predispose patients with atopic dermatitis (AD) skin infection susceptibility, to date, the data reported in the literature are still controversial. OBJECTIVE: To evaluate the role of FLG polymorphisms expression and risk of developing a concomitant Molluscum contagiosum sustained skin infection in the pediatric population with AD. METHODS: A total of 100 children with AD and 97 healthy children were enrolled. AD was diagnosed and assessed according to the validated European Task Force on Atopic Dermatitis. DNA samples of patients were analyzed for allelic variants in the promoter and coding exon of FLG. Genotyping was performed with polymerase chain reaction amplification and direct sequencing. RESULTS: Sixteen FLG variants have been detected in 29% of patients with AD: 2 synonymous (rs79808464 and rs116222149), 12 missense (rs11584340, rs113136594, rs145828067, rs374910442, rs747005144, rs145627745, rs144209313, rs74129443, rs192455877, rs150957860, rs138055273, rs147472105), 1 stop gained (rs183942200), and 1 frameshift (rs 558269137). In contrast, only 13% of the control group reported FLG mutations (22 heterozygous variants). In addition, the age at disease onset correlated significantly with FLG variants (P < .001). In addition, the AD with FLG gene variants (rs145627745, rs79808464, rs150957860, rs145828067, rs747005144, rs374910442, rs138055273, rs183942200, rs11584340, and rs113136594) reported moderate to severe Scoring Atopic Dermatitis scores. Finally, the AD group and the AD plus M contagiosum skin infection group had a significant association with FLG mutations when compared with the control group (P < .01). CONCLUSION: FLG mutations are associated with early onset of AD, more severe clinical course of disease, and a significantly increased risk of M contagiosum sustained skin infection.

The molluscum contagiosum virus death effector domain containing protein MC160 RxDL motifs are not required for its known viral immune evasion functions.

The molluscum contagiosum virus (MCV) uses a variety of immune evasion strategies to antagonize host immune responses. Two MCV proteins, MC159 and MC160, contain tandem death effector domains (DEDs). They are reported to inhibit innate immune signaling events such as NF-κB and IRF3 activation, and apoptosis. The RxDL motif of MC159 is required for inhibition of both apoptosis and NF-κB activation. However, the role of the conserved RxDL motif in the MC160 DEDs remained unknown. To answer this question, we performed alanine mutations to neutralize the arginine and aspartate residues present in the MC160 RxDL in both DED1 and DED2. These mutations were further modeled against the structure of the MC159 protein. Surprisingly, the RxDL motif was not required for MC160's ability to inhibit MAVS-induced IFNß activation. Further, unlike previous results with the MC159 protein, mutations within the RxDL motif of MC160 had no effect on the ability of MC160 to dampen TNF-α-induced NF-κB activation. Molecular modeling predictions revealed no overall changes to the structure in the MC160 protein when the amino acids of both RxDL motifs were mutated to alanine (DED1 = R67A D69A; DED2 = R160A D162A). Taken together, our results demonstrate that the RxDL motifs present in the MC160 DEDs are not required for known functions of the viral protein.

Molluscum contagiosum of the eyelid: case report in a man receiving methotrexate and literature review of molluscum contagiosum in patients who are immunosuppressed secondary to methotrexate or HIV infection.

BACKGROUND: Molluscum contagiosum is a benign viral infection of the skin. Lesions typically present as dome-shaped, flesh-colored, umbilicated papules that range in size from 1 to 5 millimeters in diameter. They are usually asymptomatic, but can become tender or pruritic. Children and immunocompromised adults, including individuals being treated with immunosuppressive drugs, are most susceptible to infection. Single or multiple lesions most commonly appear on the extremities, face, genitals, and trunk. However, albeit rarely, molluscum contagiosum may also develop at other sites, including the eyelids. PURPOSE: We describe the clinical and pathologic findings of a man who developed molluscum contagiosum of the eyelid while receiving methotrexate. We also review the characteristics of other patients with molluscum contagiosum acquired either during treatment with methotrexate or associated with human immunodeficiency virus (HIV) infection and summarize the unusual sites of presentation for the viral lesions in these individuals. MATERIALS AND METHODS: The features of a man receiving methotrexate who developed molluscum contagiosum of the eyelid are presented. Using PubMed, the following terms were searched and relevant citations assessed: adalimumab, contagiosum, Enbrel, etanercept, Humira, infliximab, methotrexate, molluscum, Remicade, TNF alpha, and tumor necrosis factor alpha. In addition, the literature on methotrexate treatment and molluscum contagiosum is reviewed. RESULTS:  Several small papules were observed on the eyelid of a 24-year-old man who had been receiving methotrexate and adalimumab (Humira) for the treatment of Crohn disease. The lesions were removed by shave biopsy. Microscopic examination revealed epidermal hyperplasia composed of keratinocytes filled with large eosinophilic intracytoplasmic inclusions. Based on correlation of the clinical presentation and histopathologic findings, a diagnosis of molluscum contagiosum was established. The patient applied mupirocin 2% ointment to the biopsy sites, which subsequently healed without complication or recurrence. CONCLUSION: Molluscum contagiosum is a benign viral papular eruption that frequently affects children and immunocompromised adults. Patients treated with immunosuppressive agents, such as methotrexate, have a heightened risk of developing molluscum contagiosum lesions. It remains to be determined whether adjunct therapy with a tumor necrosis factor alpha inhibitor increasesthe risk of this viral infection. Diagnosis can usually be established by clinical presentation, although a biopsy is sometimesrequired to exclude other conditions. Molluscum contagiosum is generally self-limiting and often resolves spontaneously within18 months. However, topical (cantharidin) or locally destructive (curettage, cryotherapy, and/or laser) therapy may be indic tedfor patients who are concerned about persistent lesions and for children who are particularly susceptible to autoinoculation.

Extensive molluscum contagiosum virus infection in a young adult receiving fingolimod.

Fingolimod-related viral infections have been described on several occasions since its introduction in 2010. We hereby add a report on an otherwise immunocompetent, 18-year old Caucasian man with relapsing-remitting multiple sclerosis who developed a protracted and extensive molluscum contagiosum (MC) virus infection shortly after being started on fingolimod. Wide-spread cutaneous MC infections in adult patients are considered indicative of underlying immunosuppression. Neurologists prescribing fingolimod ought to be aware of a possibly increased risk of MC, but also need to know about its relative benignity, lack of extra-cutaneous complications, and adequate treatment options.