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Corynebacterium bovis is the causative agent of Corynebacterium-associated hyperkeratosis in immunocompromised mice. The resulting skin pathology can be profound and can be associated with severe wasting, making the animals unsuitable for research. Although the administration of antibiotics is effective in resolving clinical symptoms, antibiotics do not eradicate the offending bacterium. Furthermore, antibiotic use may be contraindicated as it can affect tumor growth and is associated with Clostridioides difficile enterotoxemia in highly immunocompromised murine strains. Lysins, which are lytic enzymes obtained from bacteriophages, are novel antimicrobial agents for treating bacterial diseases. The advantage of lysins are its target specificity, with minimal off-target complications that could affect the host or the biology of the engrafted tumor. The aim of this study was to identify lysins active against C. bovis. Chemical activation of latent prophages by using mitomycin C in 3 C. bovis isolates did not cause bacteriophage induction as determined through plaque assays and transmission electron microscopy. As an alternative approach, 8 lysins associated with other bacterial species, including those from the closely related species C. falsenii, were tested for their lytic action against C. bovis but were unsuccessful. These findings were congruent with the previously reported genomic analysis of 21 C. bovis isolates, which failed to reveal bacteriophage sequences by using the PHAST and PHASTER web server tools. From these results, we suggest C. bovis is among those rare bacterial species devoid of lysogenic bacteriophages, thus making the identification of C. bovis-specific lysins more challenging. However, C. bovis may be a useful model organism for studying the effects of antiphage systems.

Obesity is accompanied by dysfunction of many organs, but effects on the skin have received little attention. We studied differences in epithelial thickness by histology and gene expression by Affymetrix gene arrays and PCR in the skin of 10 obese (BMI 35-50) and 10 normal weight (BMI 18.5-26.9) postmenopausal women paired by age and ethnicity. Epidermal thickness did not differ with obesity but the expression of genes encoding proteins associated with skin blood supply and wound healing were altered. In the obese, many gene expression pathways were broadly downregulated and subdermal fat showed pronounced inflammation. There were no changes in skin microbiota or metabolites. African American subjects differed from European Americans with a trend to increased epidermal thickening. In obese African Americans, compared to obese European Americans, we observed altered gene expression that may explain known differences in water content and stress response. African Americans showed markedly lower expression of the gene encoding the cystic fibrosis transmembrane regulator characteristic of the disease cystic fibrosis. The results from this preliminary study may explain the functional changes found in the skin of obese subjects and African Americans.

Dear Editor, Nielsen et al.1 recently highlighted the need for additional studies detailing pain in hidradenitis suppurativa (HS) before giving specific treatment recommendations. Few studies have evaluated HS‐specific pain using patients’ own words, and this study was designed to address this gap. A descriptive understanding of different elements of the pain experience will aid dermatologists, pain management specialists and health psychologists in the comprehensive, interdisciplinary assessment and treatment of HS.

Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes in mouse inguinal white adipose tissues (iWATs). Both cold exposure and iAdFASNKO upregulate the sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, and require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for beige adipocyte appearance, as it is blocked by adipocyte Gs alpha deficiency. Surprisingly, however, in contrast to cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated adipocyte browning in iAdFASNKO mice. Single-cell transcriptomic analysis of iWAT stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type in iAdFASNKO mice, and their depletion abrogated iWAT beiging. Altogether, these findings reveal that divergent cellular pathways are sufficient to cause adipocyte browning. Importantly, adipocyte signaling to enhance alternatively activated macrophages in iAdFASNKO mice is associated with enhanced adipose thermogenesis independent of the sympathetic neuron involvement this process requires in the cold.

Freshwater polyps of the genusHydrado not age. However, temperature stress induces aging and a shift from reproduction by asexual budding to sexual gamete production in a cold-sensitive (CS) strain ofH. oligactis.We sequenced the transcriptome of a male CS strain before and after this life history shift and compared changes in gene expression relative to those seen in a cold-resistant (CR) strain that does not undergo a life history shift in response to altered temperature. We found that the switch from non-aging asexual reproduction to aging and sexual reproduction involves upregulation of genes not only involved in gametogenesis but also genes involved in cellular senescence, apoptosis, and DNA repair accompanied by a downregulation of genes involved in stem cell maintenance. These results suggest that aging is a byproduct of sexual reproduction-associated cellular reprogramming and underscore the power of theseH. oligactisstrains to identify intrinsic mechanisms of aging.

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes:IFNAR1,IFNAR2,IFNGR2, andIL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF)STAT1mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-alpha R1, IFN-alpha R2, and IFN-gamma R2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-alpha- and IFN-gamma-stimulated monocytes from DS patients but lower than those in patients with GOFSTAT1mutations. Following stimulation with IFN-alpha or -gamma, but not with IL-6 or IL-21, pSTAT1 and IFN-gamma activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients withSTAT1GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-alpha- and IFN-gamma-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOFSTAT1mutations. Unlike patients with GOFSTAT1mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8(+)T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

Background Transcription factor retinoic acid-related orphan receptor 2 (RORC2/ROR gamma T) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. Aim To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. Methods This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. Results In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. Conclusion Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)(1-4). However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories. A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.

Active co-delivery of tumor antigens (Ag) and alpha-galactosylceramide (alpha-GalCer), a potent agonist for invariant Natural Killer T (iNKT) cells, to cross-priming CD8 alpha(+) dendritic cells (DCs) was previously shown to promote strong anti-tumor responses in mice. Here, we designed a nanoparticle-based vaccine able to target human CD141(+) (BDCA3(+)) DCs - the equivalent of murine CD8 alpha(+) DCs - and deliver both tumor Ag (Melan A) and alpha-GalCer. This nanovaccine was inoculated into humanized mice that mimic the human immune system (HIS) and possess functionaliNKT cells and CD8(+) T cells, called HIS-CD8/NKT mice. We found that multiple immunizations of HIS-CD8/NKT mice with the nanovaccine resulted in the activation and/or expansion of human CD141(+) DCs andiNKT cells and ultimately elicited a potent Melan-A-specific CD8(+) T cell response, as determined by tetramer staining and ELISpot assay. Single-cell proteomics further detailed the highly polyfunctional CD8(+) T cells induced by the nanovaccine and revealed their predictive potential for vaccine potency. This finding demonstrates for the first time the unique ability of humaniNKT cells to license cross-priming DCsin vivoand adds a new dimension to the current strategy of cancer vaccine development.