Ex Vivo Infection of Human Skin Models with Herpes Simplex Virus 1: Accessibility of the Receptor Nectin-1 during Formation or Impairment of Epidermal Barriers Is Restricted by Tight Junctions.

Herpes simplex virus 1 (HSV-1) must overcome epidermal barriers to reach its receptors on keratinocytes and initiate infection in human skin. The cell-adhesion molecule nectin-1, which is expressed in human epidermis, acts as an efficient receptor for HSV-1 but is not within reach of the virus upon exposure of human skin under nonpathological conditions. Atopic dermatitis skin, however, can provide an entry portal for HSV-1 emphasizing the role of impaired barrier functions. Here, we explored how epidermal barriers impact HSV-1 invasion in human epidermis and influence the accessibility of nectin-1 for the virus. Using human epidermal equivalents, we observed a correlation of the number of infected cells with tight-junction formation, suggesting that mature tight junctions prior to formation of the stratum corneum prevent viral access to nectin-1. Consequently, impaired epidermal barriers driven by Th2-inflammatory cytokines interleukin 4 (IL-4) and IL-13 as well as the genetic predisposition of nonlesional atopic dermatitis keratinocytes correlated with enhanced infection supporting the impact of functional tight junctions for preventing infection in human epidermis. Comparable to E-cadherin, nectin-1 was distributed throughout the epidermal layers and localized just underneath the tight-junctions. While nectin-1 was evenly distributed on primary human keratinocytes in culture, the receptor was enriched at lateral surfaces of basal and suprabasal cells during differentiation. Nectin-1 showed no major redistribution in the thickened atopic dermatitis and IL-4/IL-13-treated human epidermis in which HSV-1 can invade. However, nectin-1 localization toward tight junction components changed, suggesting that defective tight-junction barriers make nectin-1 accessible for HSV-1 which enables facilitated viral penetration. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a widely distributed human pathogen which productively infects epithelia. The open question is which barriers of the highly protected epithelia must the virus overcome to reach its receptor nectin-1. Here, we used human epidermal equivalents to understand how physical barrier formation and nectin-1 distribution contribute to successful viral invasion. Inflammation-induced barrier defects led to facilitated viral penetration strengthening the role of functional tight-junctions in hindering viral access to nectin-1 that is localized just underneath tight junctions and distributed throughout all layers. We also found nectin-1 ubiquitously localized in the epidermis of atopic dermatitis and IL-4/IL-13-treated human skin implying that impaired tight-junctions in combination with a defective cornified layer allow the accessibility of nectin-1 to HSV-1. Our results support that successful invasion of HSV-1 in human skin relies on defective epidermal barriers, which not only include a dysfunctional cornified layer but also depend on impaired tight junctions.

Eccema coxsackium en pacientes con dermatitis atópica / Coxsackium eczema in patients with atopic dermatitis

El eccema coxsackium es una dermatosis infecciosa caracterizada por lesiones papulovesiculosas, eccematosas e incluso costrosas de predominio en extremidades, nalgas y región perioral. Suele aparecer en pacientes con afectación cutánea previa, como es el caso de la dermatitis atópica de los niños. El germen causante más frecuentemente aislado es el Coxsackie A6. Está considerado como una forma atípica de la enfermedad mano-pie-boca y es importante un correcto diagnóstico diferencial para evitar tratamientos innecesarios (AU)

Eczema coxsackium is an infectious dermatosis characterized by papulovesicular, ezzematous and even crusty lesions predominantly on the extremities, buttocks and perioral region. It usually appears in patients with previous skin involvement, as in the case of atopic dermatitis in children. The most frequently isolated causative germ is Coxsackie A6. It is considered an atypical form of Hand, Foot and Mouth Disease and a correct differential diagnosis is important to avoid unnecessary treatments. (AU)

Herpes simplex virus 1 proteins can induce skin inflammation in an atopic dermatitis-like mouse model.

Herpes simplex virus type 1 (HSV-1) can induce in certain individuals with atopic dermatitis (AD) severe cutaneous infections that can spread throughout the entire body, a condition named as AD complicated by eczema herpeticum (ADEH). It has been recently found that ADEH patients can produce specific IgE against HSV-1 proteins, which may contribute to lower protection against HSV-1. However, little is known about the capacity of these HSV-1 proteins to produce an inflammatory response at the skin level. In this study, using a mouse model of AD-like dermatitis, three HSV-1 proteins (glycoprotein D -gD-, glycoprotein B -gB- and VP22) were applied on tape-stripped back skin mice in three exposures periods. Ovalbumin (OVA) and 0.9% NaCl were used as positive and negative controls, respectively. Skin samples were obtained for analysis of specific cell components of skin infiltration. The results showed that the viral protein gD induced a statistically significant increase in the number of dermal infiltrating CD3+, CD4+ cells and mast cells compared with the negative control group. gD was also able to induce epidermal thickening and epidermal infiltration of T cells closely related to the one produced in mice sensitized with OVA. However, VP22 and gB contributed to a lesser extent to skin inflammation. These results showed that proteins from HSV-1, especially gD, can have per se an important T cell and mast cell-driven inflammatory potential at the skin level.

Viral metagenomic identification of a novel anellovirus in blood sample of a child with atopic dermatitis.

Here, using viral metagenomics, a novel anellovirus with strain name HuAV-zj-ad1 was detected in blood sample from a child with atopic dermatitis. The complete genome sequence of HuAV-zj-ad1 was determined and fully characterized. The circular genome of HuAV-zj-ad1 is 2841 nt in length and includes four polyprotein ORFs. Phylogenetic analysis and pairwise sequence comparisons based on the amino acid sequences of ORF1, ORF2, ORF3, ORF4 indicated that HuAV-zj-ad1 belonged to a novel species within the genus Betatorquevirus. Polymerase chain reaction screening results showed this anellovirus was not present 50 blood samples from normal children. Whether this novel species of anellovirus has association with a certain disease needs further study.

Microbiome and skin biology.

PURPOSE OF REVIEW: The skin is home to a diverse milieu of bacteria, fungi, viruses, bacteriophages, and archaeal communities. The application of culture-independent approaches has revolutionized the characterization of the skin microbiome and have revealed a previously underappreciated phylogenetic and functional granularity of skin-associated microbes in both health and disease states. RECENT FINDINGS: The physiology of a given skin-niche drives the site-specific differences in bacterial phyla composition of healthy skin. Changes in the skin microbiome have consistently been associated with atopic dermatitis. In particular, Staphylococcus aureus overgrowth with concomitant decline in Staphylococcus epidermidis is a general feature associated with atopic dermatitis and is not restricted to eczematous lesions. Changes in fungal species are now also being described. Changes in the composition and metabolic activity of the gut microbiota are associated with skin health. SUMMARY: We are now beginning to appreciate the intimate and intricate interactions between microbes and skin health. Multiple studies are currently focused on the manipulation of the skin or gut microbiome to explore their therapeutic potential in the prevention and treatment of skin inflammation.

[A man with severe skin rash]. / Een man met heftige huiduitslag.

A 31-year-old man visited the outpatient clinic Dermatology with an exacerbation of his atopic eczema. Since a few day vesicles and crusts had appeared and his eyelids were swollen. He was known to have eczema, for which he was treated with ciclosporin 200 mg 2 times a day (4 mg/kg per day) since four months. Under this treatment the eczema used to be under control. There were no neurological symptoms or vision problems. At physical examination we saw erythematous papules, vesicles, superficial erosions and crusts on all body regions, but especially on the trunk and in the main neck region. The patient was diagnosed with eczema herpeticum and he was treated with intravenous aciclovir 1000 mg 3 times a day (10 mg/kg 3 dd) and flucloxacillin 1000 mg 4 times a day for seven days.

What is the role of Staphylococcus aureus and herpes virus infections in the pathogenesis of atopic dermatitis?

Atopic dermatitis (AD) is a chronic, relapsing disease. Genetic, environmental and immunological factors are involved in its pathophysiology. Individuals with AD have an increased predisposition to colonization and/or infection of the skin by various pathogens, especially Staphylococcus aureus and herpes simplex virus. The composition of their skin microbiome is also different, and changes during flares. The disease severity can be related to the degree of colonization by S. aureus. In addition, the presence of this bacterial species can predispose the host to more severe and disseminated viral infections. This article reviews the role of S. aureus and herpes virus infections and the skin microbiome in the pathogenesis of AD and their importance in the treatment and prevention strategies of this dermatosis.

Case for diagnosis. Infective dermatitis associated with HTLV-1: differential diagnosis of atopic dermatitis.

Infective dermatitis associated with HTLV-1 (IDH) is the main cutaneous marker of HTLV-1 infection. This disease occurs primarily in children and should be differentiated from other eczemas, especially from atopic dermatitis. The largest series of IDH are from Jamaica and Brazil. There are an estimated 15 to 20 million infected people in the world, and Brazil is one of the endemic regions. Studies suggest that IDH in children may be a marker for the development of T-cell leukemia/lymphoma (ATL) or myelopathy associated with HTLV-1/tropical spastic paraparesis (HAM / TSP) in adulthood.

Case for diagnosis. Infective dermatitis associated with HTLV-1: differential diagnosis of atopic dermatitis

Abstract: Infective dermatitis associated with HTLV-1 (IDH) is the main cutaneous marker of HTLV-1 infection. This disease occurs primarily in children and should be differentiated from other eczemas, especially from atopic dermatitis. The largest series of IDH are from Jamaica and Brazil. There are an estimated 15 to 20 million infected people in the world, and Brazil is one of the endemic regions. Studies suggest that IDH in children may be a marker for the development of T-cell leukemia/lymphoma (ATL) or myelopathy associated with HTLV-1/tropical spastic paraparesis (HAM / TSP) in adulthood.

High Staphylococcus epidermidis Colonization and Impaired Permeability Barrier in Facial Seborrheic Dermatitis.

BACKGROUND: Seborrheic dermatitis (SD) is a common inflammatory skin condition. The etiology is unclear, although overgrowth of Malassezia on the skin has been suggested to cause SD. This study investigated whether colonization with Staphylococcus plays a role in facial SD, which was not well addressed previously. METHODS: The study was conducted from September 1, 2011 to February 20, 2012 in the First Hospital of China Medical University. In the first phase, the study evaluated the level of transepidermal water loss (TEWL) and the number of colony-forming units (CFU) of Staphylococcus in defined skin areas of SD patients who were human immunodeficiency virus (HIV) seropositive (HIV [+] SD [+] group, n = 13), classical SD (HIV [-] SD [+] group, n = 24) patients, HIV seropositive-non-SD (HIV [+] SD [-] group, n = 16) patients, and healthy volunteers (HIV [-] SD [-] group, n = 16). In the second phase, we enrolled another cohort of HIV (-) SD (+) patients who applied topical fusidic acid (n = 15), tacrolimus (n = 16), or moisturizer (n = 12). Changes in the Seborrheic Dermatitis Area Severity Index (SDASI), TEWL, and Staphylococcus density were evaluated 2 weeks later. Comparisons of each index were performed using analysis of variance (ANOVA) and least significant difference method. RESULTS: The level of TEWL was greater through lesional sites in the HIV (+) SD (+) group than that in HIV (+) SD (-) and HIV (-) SD (-) groups (95% confidence interval [CI]: 18.873-47.071, P < 0.001 and 95% CI: 28.755-55.936, P < 0.001, respectively). The number of CFU of Staphylococcus was greater in the HIV (+) SD (+) group than that in HIV (+) SD (-) and HIV (-) SD (-) groups (95% CI: 37.487-142.744, P = 0.001 and 95% CI: 54.936-156.400, P < 0.001, respectively). TEWL was significantly more improved in patients treated with tacrolimus and fusidic acid than that in those treated with moisturizers (95% CI: 7.560-38.987, P = 0.004 and 95% CI: 4.659-37.619, P = 0.011, respectively). Topical tacrolimus and fusidic acid were significantly associated with decreased SDASI as compared with moisturizer (95% CI: 0.03-0.432, P = 0.025 and 95% CI: 0.033-0.44, P = 0.024, respectively). CONCLUSIONS: High colonization with Staphylococcus epidermidis, along with impaired skin permeability barrier function, contributes to the occurrence of SD.

Correlation of symptomatic enterovirus infection and later risk of allergic diseases via a population-based cohort study.

Infants who are exposed to the rhinovirus or respiratory syncytial virus are at a higher risk of subsequently developing wheezing or asthma. This study aims to determine whether preschoolers with a history of symptomatic enterovirus infection are at an increased risk of developing allergic diseases or not.We used data from the Taiwan National Health Insurance Research Database from 1999 to 2006 for this nationwide population-based cohort study. The subsequent risks for allergic diseases, which included asthma (International Classification of Diseases [ICD]-9: 493.X), allergic rhinitis (AR; ICD-9 CM code 477.X), and atopic dermatitis (AD; ICD-9-CM code 691.X), were compared between herpangina (ICD-9: 074.0) and hand, foot, and mouth disease (HFMD; ICD-9: 074.3) throughout the follow-up period using the Cox proportional hazards model.In this database, 12,016 neonates were born between January 1999 and December 1999. Among them, we further evaluated 8337 subjects; 3267 children infected with either herpangina or HFMD served as the study cohort, and the other 5070 children made up the comparison cohort. Children in the herpangina group had a higher risk of developing AR and AD, with adjusted hazard ratios of 1.15 (1.02-1.30, 95% CI) and 1.38 (1.17-1.63. 95% CI), respectively, while children suffered from HFMD had decreased risks of asthma, with an adjusted hazard ratio of 0.76 (0.63-0.93, 95% CI).Children who previously suffered from herpangina experienced an increased risk of subsequently developing AD and AR. Meanwhile, children who had suffered from HFMD experienced a decrease in the subsequent occurrence of asthma compared to the general population.

Extremely high HIV-1 viral load in a patient with undiagnosed clinical indicator disease for HIV infection.

We report a case of a new diagnosis of HIV with an extremely high viral load presenting with HIV encephalopathy, in a 54-year-old woman who had been treated with 2 years of extended high-dose immunosuppressant therapy for a recalcitrant pruritic rash before diagnosis.

Filaggrin deficiency promotes the dissemination of cutaneously inoculated vaccinia virus.

BACKGROUND: Eczema vaccinatum is a life-threatening complication of smallpox vaccination in patients with atopic dermatitis (AD) characterized by dissemination of vaccinia virus (VV) in the skin and internal organs. Mutations in the filaggrin (FLG) gene, the most common genetic risk factor for AD, confer a greater risk for eczema herpeticum in patients with AD, suggesting that it impairs the response to cutaneous viral infections. OBJECTIVE: We sought to determine the effects of FLG deficiency on the response of mice to cutaneous VV inoculation. METHODS: VV was inoculated by means of scarification of unsensitized skin or skin topically sensitized with ovalbumin in FLG-deficient flaky tail (ft/ft) mice or wild-type (WT) control mice. The sizes of primary and satellite skin lesions were measured, and hematoxylin and eosin staining was performed. VV genome copy numbers and cytokine mRNA levels were measured by using quantitative PCR. RESULTS: VV inoculation in unsensitized skin of ft/ft mice, independent of the matted hair mutation, resulted in larger primary lesions, more abundant satellite lesions, heavier viral loads in internal organs, greater epidermal thickness, dermal cellular infiltration, and higher local Il17a, Il4, Il13, and Ifng mRNA levels than in WT control mice. VV inoculation at sites of topical ovalbumin application amplified all of these features in ft/ft mice but had no detectable effect in WT control mice. The number of satellite lesions and the viral loads in internal organs after cutaneous VV inoculation were significantly reduced in both unsensitized and topically sensitized ft/ftxIl17a(-/-) mice. CONCLUSION: FLG deficiency predisposes to eczema vaccinatum. This is mediated primarily through production of IL-17A.

Disseminated coxsackievirus A6 affecting children with atopic dermatitis.

Coxsackievirus A6 (CV-A6) is an emerging pathogen that has in recent years been associated with atypical hand, foot and mouth disease. This manifests as a generalized papular or vesicular eruption, which may be associated with fever and systemic disturbance. We report a series of six children presenting to a single centre in the UK with disseminated CV-A6 infection on a background of atopic dermatitis (AD). Our patients exhibited a widespread papular or vesicular eruption in association with exacerbation of AD. Several of our cases mimicked eczema herpeticum, but the extent was more generalized, and individual lesions were discrete rather than clustered and were less circumscribed in character. This series highlights that CV-A6 infection may be encountered in the UK, and should be considered in the differential diagnosis of an acute exacerbation of AD, particularly in children.

HPV16 E7 expression in skin induces TSLP secretion, type 2 ILC infiltration and atopic dermatitis-like lesions.

Atopic dermatitis is a common pruritic and inflammatory skin disorder with unknown etiology. Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin. In this study, we report an atopic dermatitis-like pathophysiology results in a murine model following the expression of the high-risk human papillomavirus (HPV) 16 oncoprotein E7 in keratinocytes under the keratin 14 promoter. We show that HPV16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis. Locally, HPV16 E7-expressing skin secreted high levels of thymic stromal lymphopoietin (TSLP) and contained increased numbers of innate lymphoid cells (ILCs). High levels of circulating immunoglobulin E were associated with increased susceptibility to skin allergy in a model of cutaneous challenge, and to airway bronchiolar inflammation, enhanced airway goblet cell metaplasia and mucus production in a model of atopic march. Surprisingly, skin pathology occurred independently of T cells and mast cells. Thus, our findings suggest that the expression of a single HPV oncogene in the skin can drive the onset of atopic dermatitis-like pathology through the induction of TSLP and type 2 ILC infiltration.

Molluscum contagiosum clears atopic dermatitis: a case report.

A 14-year-old patient with severe widespread atopic dermatitis (AD) and concurrent molluscum contagiosum virus (MCV) presented with MCV papules that were surrounded by dermatitis-free zones. It appeared that components inhibited the expression of AD, with inhibitory effects that persisted throughout 6 years of follow-up, even in the presence of a Staphylococcus aureus infection, which was proven by skin culture.

IL-10 suppresses IL-17-mediated dermal inflammation and reduces the systemic burden of Vaccinia virus in a mouse model of eczema vaccinatum.

Individuals with atopic dermatitis (AD) are susceptible to a severe, potentially fatal, systemic infection and inflammatory response following exposure to Vaccinia virus (VV). IL-10 acts both as an inducer of Th2 responses and as a regulator of T cell activation. It has been shown to limit skin inflammation elicited by contact sensitizers. AD exacerbations have been associated with decreased IL-10 function. We used IL-10(-/-) mice to test the role of the cytokine in VV immunity. They exhibited larger primary lesions and increased cutaneous neutrophil infiltration compared to wild-type (WT) counterparts. This was associated with enhanced production of IL-17A, IL-17F and CXCL2. Paradoxically, despite intact adaptive immune responses, tissue viral burdens were increased in IL-10(-/-) mice. These findings suggest that IL-10 is important in limiting skin inflammation induced by VV and that abnormal IL-17-driven neutrophil recruitment at the primary infection site in the skin results in increased systemic viral dissemination.