Cutaneous Viral Infections Research Articles

195 N/TERTs replicate primary keratinocytes in barrier formation and viral infectivity

Atopic dermatitis (AD) is a skin disease characterized by an impaired epidermal barrier and increased susceptibility to cutaneous viral infections. We have previously observed that barrier disruption (caused by our tight junction disrupting peptide [TJDP®]), enhances vaccinia virus (VV) infection of primary human foreskin keratinocytes (PHFK). To evaluate the importance of AD-relevant tight junction proteins in epidermal viral infections, we sought to identify an epidermal cell line that we could genetically manipulate. We tested N/TERT cells (immortalized PHFK) to determine whether they faithfully recapitulated primary cells in both our barrier and VV infection models. We found that N/TERTs developed a robust barrier, as measured by transepithelial electrical resistance (TEER), with peak values of 300–400 ohms/cm2 observed 4-5 days after treatment with high Ca+2 (1.8mM) containing media. After exposure to our TJDP®, N/TERTs exhibited a substantial reduction in barrier compared to media controls (e.g. TEER reduction: 46% ± 13 and 68% ± 11 at Days 2 and 3, respectively; n=3). We previously observed that PHFK are more susceptible to VV when treated with TJDP® during differentiation. With N/TERTs, we observed an increase in VV susceptibility as measured by % change in plaque number (179% ± 64 at Day 2; n=3) and % of the monolayer infected (27% ± 24 vs 42% ± 20 at Day 2 for media compared to TJDP® treated samples, n=3). These observations suggest that N/TERTs behave similarly to PHFK in both our infection and barrier experiments. Future studies will focus on determining how reduction in AD-relevant TJ barrier proteins (Claudin 1, 4, 23, occludin, and zonula occludens 1) using the CRISPR/Cas9 system impacts the susceptibility of N/TERTs to viral infections (VV and herpes simplex virus).

Molluscum Contagiosum: Review and Update on Clinical Presentation, Diagnosis, Risk, Prevention, and Treatment

Molluscum contagiosum (MC) is a self-limited cutaneous viral infection that most commonly affects children and immunocompromised populations. This review provides an update on the clinical manifestations, risk, diagnosis, treatment, and prevention of this frequently encountered infection. A recent Cochrane review concluded that there is insufficient evidence to establish the superiority of any specific treatment modality or to confirm that active intervention is superior to benign neglect (van der Wouden JC et al., Cochrane Database Syst Rev 5:CD004767, 2017). Interim pilot study data suggests that cantharidin outperforms placebo (Guzman AK et al., Int J Dermatol 57:1001–1006, 2018). Imiquimod is no longer recommended for treatment of MC (van der Wouden JC et al., Cochrane Database Syst Rev 5:CD004767, 2017; Papadopoulos EJ, https://www.fda.gov/files/drugs/published/N20-723S020-Imiquimod-Clinical-BPCA.pdf, 2006; Katz KA et al., Pediatr Dermatol 35:282–283, 2018). Optimal management strategies for MC remain unclear due to the multitude of proposed therapies, lack of high-quality evidence, and uncertain benefit of intervention for uncomplicated disease. Aside from watchful waiting, destructive therapies such as cantharidin and curettage are among the best studied methods and remain the treatment of choice for most patients.

Viruses in Skin Cancer (VIRUSCAN): Study Design and Baseline Characteristics of a Prospective Clinic-Based Cohort Study.

Accumulating evidence suggests that cutaneous viral infections are risk factors for the development of keratinocyte carcinomas. The Viruses in Skin Cancer (VIRUSCAN) Study, a prospective cohort study, was established in 2014 to investigate the risk of keratinocyte carcinoma associated with cutaneous human papillomavirus and polyomavirus infection and the possible interaction with ultraviolet radiation exposure (UVR). VIRUSCAN incorporates repeated measures of viral infection using multiple markers of infection and quantitative measures of UVR using a spectrophotometer. Participants were recruited between July 14, 2014 and August 31, 2017 at the University of South Florida Dermatology Clinic in Tampa, FL. After excluding 124 individuals with prevalent keratinocyte carcinomas at baseline, 1,179 participants (53.2% women, 46.8% men, all ages 60 years and older) were followed for up to 4 years with routine skin exams occurring every 6 to 12 months. Here, we present the VIRUSCAN Study design, methods, and baseline characteristics, including demographics, sun exposure behavior, quantitative UVR exposure measurements, and cutaneous viral prevalence, for the full study cohort. The VIRUSCAN Study will provide critical temporal evidence needed to assess the causality of the role cutaneous viral infections play in the development of keratinocyte carcinomas, as well as the potential interaction between cutaneous viral infections and UVR exposure. Study findings will be valuable in future development of novel keratinocyte carcinoma prevention strategies.

A Study to Evaluate the Role of Intradermal and Intralesional Measles, Mumps, Rubella (MMR) Vaccine in Treatment of Common Warts.

Background:Warts are common cutaneous viral infection with a wide range of therapeutic modalities. Various agents have been tried for immunotherapy in warts.Objectives:Determine the role of intralesional and intradermal measles, mumps, rubella (MMR) vaccine in the treatment of common warts; to compare the efficacy of intralesional versus intradermal MMR vaccine.Methods and Materials:Patients diagnosed with verruca vulgaris were divided into two groups. In study group A, the individuals were injected with an intralesional MMR vaccine of 0.3 mL in the representative wart (largest) once in 3 weeks till there is complete clearance or maximum of four injections whichever is earlier, while in study group B, the individuals were injected with an intradermal MMR vaccine of 0.3 mL over the unilateral deltoid muscle area at similar intervals.Results:There were 33 patients in each group. In group A, 10 (30.3%) patients showed complete, 9 (27.3%) marked, 6 (18.2%) moderate, 3 (9.1%) mild, and 5 (15.2%) no response. In group B, seven (21.2%) patients showed complete, one (3.0%) marked, one (3.0%) moderate, four (12.1%) mild, and 20 (60.6%) no response. There were minimal side effects in the form of pain, erythema, itching at the injection site in a few patients, only one patient had syncope.Conclusion:We conclude that the MMR vaccine is an effective and safe modality of treatment for verruca vulgaris without any serious adverse effects. Also, the intralesional route showed better results in comparison to the intradermal route when we consider the treatment of a representative wart.

Metabolomics Distinguishes DOCK8 Deficiency from Atopic Dermatitis: Towards a Biomarker Discovery.

Bi-allelic mutations in the dedicator of cytokinesis 8 (DOCK8) are responsible for a rare autosomal recessive primary combined immunodeficiency syndrome, characterized by atopic dermatitis, elevated serum Immunoglobulin E (IgE) levels, recurrent severe cutaneous viral infections, autoimmunity, and predisposition to malignancy. The molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. Severe atopic dermatitis (AD) and DOCK8 deficiency share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. Increased serum IgE levels are characteristic of, but not specific to allergic diseases. Herein, we aimed to study the metabolomic profiles of DOCK8-deficient and AD patients for potential disease-specific biomarkers using chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Serum samples were collected from DOCK8-deficient (n = 10) and AD (n = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls (n = 33). Seven metabolites were positively identified, distinguishing DOCK8-deficient from AD patients. Aspartic acid and 3-hydroxyanthranillic acid (3HAA, a tryptophan degradation pathway intermediate) were up-regulated in DOCK8 deficiency, whereas hypotaurine, leucyl-phenylalanine, glycyl-phenylalanine, and guanosine were down-regulated. Hypotaurine, 3-hydroxyanthranillic acid, and glycyl-phenylalanine were identified as potential biomarkers specific to DOCK8 deficiency. Aspartate availability has been recently implicated as a limiting metabolite for tumour growth and 3HAA; furthermore, other tryptophan metabolism pathway-related molecules have been considered as potential novel targets for cancer therapy. Taken together, perturbations in tryptophan degradation and increased availability of aspartate suggest a link of DOCK8 deficiency to oncogenesis. Additionally, perturbations in taurine and dipeptides metabolism suggest altered antixidation and cell signaling states in DOCK8 deficiency. Further studies examining the mechanisms underlying these observations are necessary.

Assessment of macrophage migration inhibitory factor in patients with verruca vulgaris.

BackgroundCommon warts are caused by human papillomaviruses (HPVs), they are among the most common cutaneous viral infections. Macrophage migration inhibitory factor (MIF) is an essential contributor in many inflammatory and immune skin diseases. Yet, its role in the pathology of common warts is unclear.ObjectiveTo assess MIF levels in lesional and perilesional skin in patients with common warts in comparison to apparently healthy control group with matching age and sex.Subjects and methodsA case-control study performed on 60 patients with common warts (group A) and 30 age and sex matching healthy controls (group B). Two biopsies were taken from each patient in group A; one from the lesion (lesional) and the other one from the skin around the wart (perilesional), while biopsies of controls were taken from matched sites to patients. Measurement of MIF in all groups was done by quantitative ELISA kits.ResultsSignificant high MIF levels were detected in lesional and perilesional skin biopsies compared to controls (P<0.001). Yet, the difference in MIF levels between lesional and perilesional skin biopsy was non-significant. No significant relations were found between lesional and perilesional MIF levels and clinical characteristics of the studied patients while both lesional and perilesional MIF levels were significantly correlated (rh=0.269, P=0.021).ConclusionThe significantly elevated MIF levels in lesional and perilesional skin biopsies compared to controls point to its role in wart progression from HPV infected cells.

Treg lymphocytes and cutaneous viral infections

Approximately three million non‐melanoma skin cancers (NMSCs) are diagnosed worldwide each year, although this number is likely an underestimate given that these cancers are not always recorded in cancer registries. Studies have suggested that skin (cutaneous) infections with human papillomaviruses (HPV) and polyomaviruses (HPyV) may play a role in the development of some NMSC types. Suppression of the immune system is also a risk factor for NMSC. This study, from the U.S.A, aimed to understand the relationship between T‐regulatory (Treg) cells, cells which suppress immune response, and cutaneous viral infections. Blood, skin swabs and eyebrow hairs were collected from 352 patients who underwent skin cancer screening and did not have cancer detected. The researchers examined whether the skin swabs (SSW) and eyebrow hairs (EBH) contained genetic material (DNA) corresponding to 98 cutaneous HPV types (including beta HPV and gamma HPV) and 5 HPyV types. The blood samples were analyzed to determine proportions of different types of Treg cell populations in circulation (in the blood). The researchers found no association between total percent of circulating Treg cells and beta HPV or HPyV infection. However, two types of Treg cells were found at lower levels in those that had gamma HPV infection in their EBH and/or SSW. Those two types were CLA+ Treg cells (known to travel to the skin) and effector CD27‐CD45RA‐FOXP3+CD4+ Treg cells (known to become active when exposed to a foreign viral infection). The study results suggest that gamma HPV infection may stimulate Treg cells to move from circulation into the skin tissues.

Are regulatory T cells associated with cutaneous viral infections?

Are regulatory T cells associated with cutaneous viral infections?

Cross-sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation.

Cutaneous viral infections and immune suppression are risk factors for some forms of nonmelanoma skin cancer; however, their interrelationship is poorly understood. To examine cross-sectional associations between cutaneous viral infections and circulating forkhead-box P3 (FOXP3)-expressing T-regulatory (Treg) cells, suppressive cells that dampen effective antitumour immunity. Blood, eyebrow hair (EBH) and skin swab (SSW) samples were collected from 352 patients 60 years and older undergoing skin screening, without prevalent skin cancer, while participating in an ongoing prospective cohort study of cutaneous viral infections and skin cancer. DNA corresponding to 98 cutaneous human papillomavirus (HPV) types and five human polyomaviruses (HPyV) was assessed in EBH and SSW. Distinct classes of circulating Treg-cell subpopulations were defined by flow cytometry including cutaneous lymphocyte antigen (CLA) and CCR4high Treg cells, both previously associated with cutaneous diseases. Age- and sex-adjusted associations between circulating T-cell populations and infection were estimated using logistic regression. Total Treg-cell proportion in peripheral blood was not associated with β HPV or HPyV infection. However, the proportion of circulating CLA+ Treg cells was inversely associated with γ HPV EBH infection [odds ratio (OR) 0·54, 95% confidence interval (CI) 0·35-0·84]. Interestingly, circulating Treg cells expressing markers indicative of antigen activation (CD27- CD45RA- FOXP3+ CD4+ ) were also inversely associated with γ HPV infection in SSW (OR 0·55, 95% CI 0·30-0·99) and EBH (OR 0·56, 95% CI 0·36-0·86). Inverse associations between circulating Treg cells and γ HPV infection suggest that localized viral infection may promote immunosuppressive cell migration into skin.

Oral ranitidine: A promising novel therapeutic option in molluscum contagiosum in children

Background: Molluscum contagiosum(MC) is one of the most common cutaneous viral infection observed in children. Though, it is benign and self-limiting, treatment is often sought for cosmetic reasons. Existing invasive therapeutic modalities are generally not well tolerated in children because of pain and risk of scarring. Immunomodulatory potential of cimetidine is well established. We thus extrapolated the same to ranitidine and conducted this study. Aim: To assess the efficacy of oral ranitidine in treatment of molluscum contagiosum in immunocompetent children. Methods: A multicentre longitudinal study was conducted in the dermatology departments of tertiary care hospitals in Ahmedabad and Wardha, India over a period of 4 months. 24 children with MC were included. Oral ranitidine was started in dose of 5 mg/kg/day in two divided doses for 8 weeks. Follow up was done very 15 days and changes in number and size of lesions were noted. Results: Mean age of patients was 5.08 years. 19 patients completed the study. 15 patients had improvement in the lesions at the end of 8 weeks while 4 patients did not show any improvement. Complete clearance was seen in 14 patients(73.6%) and 1 patient had decrease in size of the lesions without change in the number. Mean duration of complete clearance of lesion was 6.5 weeks. Conclusion: Oral ranitidine may be considered as a safe and effective alternative therapeutic option in widespread MC in immunocompetent children where invasive painful procedures are less desirable.

Cutaneous Viral Infections Across 2 Anatomic Sites Among a Cohort of Patients Undergoing Skin Cancer Screening.

Findings from previous studies of cutaneous human papillomavirus (cuHPV) infection and keratinocyte carcinomas have varied due to several factors, including use of different sample types for cuHPV DNA detection. Elucidating the relationship between cuHPV infection in eyebrow hairs (EBHs) and skin swabs (SSWs) is critical for advancing the design of future studies. DNA corresponding to 46 β-HPV and 52 γ-HPV types was measured in EBHs and SSWs obtained from 370 individuals undergoing routine skin cancer screening examinations. Prevalence of β-HPV/γ-HPV was 92%/84% and 73%/43% in SSWs and EBHs, respectively, with 71%/39% of patients testing positive for β-HPV/γ-HPV in both sample types. Number of cuHPV types detected and degree of infection were correlated across SSWs and EBHs. When the EBH was positive for a given β-HPV/γ-HPV type, the SSW was positive for that same type 81%/72% of the time. Testing SSWs captures more cuHPV infection than EBHs, with EBH infections usually representing a subset of SSW infections. The importance of optimizing sensitivity of cuHPV infection detection using SSWs vs specificity using EBHs (or a combination of the 2) will be ascertained in an ongoing cohort study investigating cuHPV associations with subsequent keratinocyte carcinomas.

Major Comorbidities of Atopic Dermatitis: Beyond Allergic Disorders.

The consequences of atopic dermatitis reach beyond the skin and past childhood. Patients with atopic dermatitis are at risk of developing allergic comorbidities, but less is known about the associations between atopic dermatitis and non-allergic conditions. Understanding these non-allergic comorbidities has the potential to improve patient outcomes and to help mitigate the cost and burdens associated with these conditions. Atopic dermatitis is associated with cutaneous bacterial infections, more severe forms/courses of cutaneous viral infections, and extra-cutaneous infections. Atopic dermatitis is also associated with several mental health comorbidities particularly attention-deficit hyperactivity disorder, anxiety, and depression. Data are largely inconsistent for specific cancers, but atopic dermatitis appears to protect against malignancy overall; severe long-term atopic dermatitis is associated with adult lymphomas. Atopic dermatitis may also be associated with obesity, cardiovascular disease, and autoimmune disease, particularly alopecia areata and gastrointestinal immune-mediated disorders. Although the causative mechanisms underlying these associations are poorly understood, treating physicians should be aware of associations in seeking to alleviate the burden for patients with atopic dermatitis.

Genital molluscum contagiosum in females - therapeutic efficacy and comparative evaluation of topical 10% and 20% potassium hydroxide.

Introduction:Molluscum contagiosum (MC) is a cutaneous viral infection caused by a poxvirus, manifested by discrete, papular, pearly lesions with central umbilication. Genital lesions are mainly transmitted sexually. Till date, several forms of medical and surgical therapies have been used with variable success. In the present study, an attempt was made to review all the female patients of genital MC attending the sexually transmitted infection (STI) clinic of the Department of Dermatology, Venereology, and Leprosy of Guru Nanak Dev Hospital, Amritsar.Aims and Objectives:In the present study, therapeutic efficacy and comparative evaluation of topical 10% and 20% of potassium hydroxide (KOH) were undertaken.Materials and Methods:A total of 30 female patients of age group 18–50 years with clinically diagnosed MC and more than ten lesions were enrolled in this study. The lesions in each patient were divided into two equal Groups A and B. Topical 10% KOH was applied over lesions of Group A and 20% over lesions of Group B with the help of 26G needle. First, two applications were done by the doctor, and subsequent applications were done twice a week at bedtime at home by the patient herself until crusting. These cases were followed up at 4th day, 1st, 2nd, 3rd, 4th, 6th, 8th, 10th, and 12th week. Results were analyzed objectively and photographically at each follow-up and at the end of the study statistically.Results:Mean duration of treatment ± standard deviation in normal patients, HIV-positive patients, patients with associated STIs, patients with associated non-STIs, and pregnant patients in Group A and Group B was 6.83 ± 2.692, 9.33 ± 1.633, 6.83 ± 2.887, 8.20 ± 3.347, and 8.75 ± 2.121 weeks and 5.2 ± 2.156, 7.33 ± 1.633, 5.25 ± 2.050, 6.20 ± 2.864, and 6.50 ± 1.414 weeks, respectively.Conclusion:Topical 20% KOH is better than 10% KOH in genital MC in females.

Lymphatic Vessels Balance Viral Dissemination and Immune Activation following Cutaneous Viral Infection

Lymphatic vessels lie at the interface between peripheral sites of pathogen entry, adaptive immunity, and the systemic host. Though the paradigm is that their open structure allows for passive flow of infectious particles from peripheral tissues to lymphoid organs, virus applied to skin by scarification does not spread to draining lymph nodes. Using cutaneous infection by scarification, we analyzed the effect of viral infection on lymphatic transport and evaluated its role at the host-pathogen interface. We found that, in the absence of lymphatic vessels, canonical lymph-node-dependent immune induction was impaired, resulting in exacerbated pathology and compensatory, systemic priming. Furthermore, lymphatic vessels decouple fluid and cellular transport in an interferon-dependent manner, leading to viral sequestration while maintaining dendritic cell transport for immune induction. In conclusion, we found that lymphatic vessels balance immune activation and viral dissemination and act as an "innate-like" component of tissue host viral defense.

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.

Recurrent and Sustained Viral Infections in Primary Immunodeficiencies.

Viral infections are commonplace and often innocuous. Nevertheless, within the population of patients with primary immunodeficiencies (PIDDs), viral infections can be the feature that drives a diagnostic evaluation or can be the most significant morbidity for the patient. This review is focused on the viral complications of PIDDs. It will focus on respiratory viruses, the most common type of viral infection in the general population. Children and adults with an increased frequency or severity of respiratory viral infections are often referred for an immunologic evaluation. The classic teaching is to investigate humoral function in people with recurrent sinopulmonary infections, but this is often interpreted to mean recurrent bacterial infections. Recurrent or very severe viral infections may also be a harbinger of a primary immunodeficiency as well. This review will also cover persistent cutaneous viral infections, systemic infections, central nervous system infections, and gastrointestinal infections. In each case, the specific viral infections may drive a diagnostic evaluation that is specific for that type of virus. This review also discusses the management of these infections, which can become problematic in patients with PIDDs.

IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.

The IL-1 superfamily of cytokines and receptors has been studied extensively. However, the specific roles of IL-1 elements in host immunity to cutaneous viral infection remain elusive. In this study, we applied vaccinia virus (VACV) by scarification to IL-1R1 knockout mice (IL-1R1-/-) and found that these mice developed markedly larger lesions with higher viral genome copies in skin than did wild-type mice. The phenotype of infected IL-1R1-/- mice was similar to eczema vaccinatum, a severe side effect of VACV vaccination that may develop in humans with atopic dermatitis. Interestingly, the impaired cutaneous response of IL-1R1-/- mice did not reflect a systemic immune deficiency, because immunized IL-1R1-/- mice survived subsequent lethal VACV intranasal challenge, or defects of T cell activation or T cell homing to the site of inoculation. Histologic evaluation revealed that VACV infection and replication after scarification were limited to the epidermal layer of wild-type mice, whereas lack of IL-1R1 permitted extension of VACV infection into dermal layers of the skin. We explored the etiology of this discrepancy and determined that IL-1R1-/- mice contained significantly more macrophages and monocyte-derived dendritic cells in the dermis after VACV scarification. These cells were vulnerable to VACV infection and may augment the transmission of virus to adjacent skin, thus leading to larger skin lesions and satellite lesions in IL-1R1-/- mice. These results suggest new therapeutic strategies for treatment of eczema vaccinatum and inform assessment of risks in patients receiving IL-1 blocking Abs for treatment of chronic inflammatory disorders.

Common warts revisited: a clinical study

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Common warts are cutaneous viral infections caused by various strains of human papilloma virus (HPV). Their variants include filiform, periungual and pigmented warts. At present more than 200 different HPV genotypes have been detected and a periodic clinical analysis will reveal whether any new morphological variations have occurred.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Hundred and ten patients with common warts were taken up for this study.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; The clinical characteristics of 637 common warts in 110 patients were studied over a span of 1 and a half years. The age group ranged from 18 years to 72 years. Seventy six were males and 34 were females. Majority belonged to the age group of 18-30 years. The most common occupational group involved were students followed by housewives. The initial site of onset in 44.5% of patients was on the fingers. Eleven patients had atopic diathesis. Similar complaints in friends and family were seen in 30%. The most common sites of involvement for classical common warts were on the fingers and for filiform warts were on the head. 30% had association with other warts out of which 28.1% had palmoplantar warts.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Common warts usually present as a cosmetic concern in most patients. Our study concluded that young male students are susceptible to acquiring them. Characteristics of warts in atopics did not differ significantly from non atopics. Regions most prone to contact and susceptible to trauma are the most common sites of inoculation i.e. fingers, scalp and face. &lt;/p&gt;

Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.

Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM) cells in lymph nodes. In vitro, CD8+ TRM cells, but not CD8+ TCM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+ TRM cells. The persistence of CD8+ TRM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8+ TRM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+ TRM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8+ TRM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8+ TRM cells, and suggest that CD8+ TRM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.

Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency: DOCK8 and DOCK2.

DOCK8 deficiency is an autosomal recessive combined immunodeficiency disease associated with elevated IgE, atopy, recurrent sinopulmonary and cutaneous viral infections, and malignancy. The DOCK8 protein is critical for cytoskeletal organization, and deficiency impairs dendritic cell transmigration, T-cell survival, and NK cell cytotoxicity. Early hematopoietic stem cell transplantation is gaining prominence as a definitive treatment given the potential for severe complications and mortality in this disease. Recently, DOCK2 deficiency has been identified in several patients with early-onset invasive bacterial and viral infections.