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To analyze the associations of the gut and circulating microbiota with circulating vitamin D3 (VD3), type I interferon (IFNI), systemic inflammation, and clinical profiles in chronic spontaneous urticaria (CSU) patients. Methods: A total of 36 CSU patients with VD3 insufficiency (VDI; serum 25(OH)VD3 < 30 ng/mL) and 36 sex-, age-, and body mass index–matched CSU patients with non-VDI were enrolled. Fecal and serum bacteria were identified through 16S rRNA sequencing, and serum 25(OH)VD3 and inflammation biomarkers were assessed using ELISA kits. IFNI response was determined by measuring the stimulatory activity of serum on IFNI-stimulated response element in HEK293 cells in vitro with luciferase assays. Results: Higher urticarial activity score over 7 days (UAS7), higher frequency of levocetirizine resistance, and more severe proinflammation but weaker IFNI response were observed in VDI than non-VDI patients (all P< 0.05). IFNI response was strongly positively associated with serum 25(OH)VD3 level in both groups (P< 0.001). Compared to non-VDI patients, abundance of the fecal genera Prevotella 9, Escherichia–Shigella, and Klebsiella was significantly increased, while Bacteroides, Faecalibacterium, and Agathobacter were remarkably reduced in VDI patients (all P< 0.05). Burkholderia–Caballeronia–Paraburkholderia (40.95%), Acinetobacter (3.05%), and Aquabacterium (2.37%) were the top three bacteria in sera from VDI patients. Both serum 25(OH)VD3 level and IFNI response were positively associated with fecal Bacteroides in the two groups (P< 0.05). In non-VDI patients, there were moderately positive associations between IFNI response and fecal Lachnoclostridium, unclassified_f__Lachnospiraceae, and Phascolarctobacterium and between serum 25(OH)VD3 level and fecal Lachnoclostridium (all P< 0.01). Circulating microbiota in VDI patients was closely related only to proinflammation and UAS7 (both P< 0.05). Conclusion: Changes in gut but not circulating microbiota composition are associated with serum 25(OH)VD3 insufficiency and impaired IFNI homeostasis, which points to greater disease severity (UAS7) and systemic proinflammation in CSU patients. [ABSTRACT FROM AUTHOR]

Background The increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71). This study aimed to verify the occurrence of bacterial translocation (BT) and further explore the contributory role of BT to severity of EV-A71-mediated HFMD cases. Methods Serum specimens from 65 mild and 65 severe EV-A71-associated HFMD cases and 65 healthy children were collected. EV-A71 VP1 in serum, inflammatory mediators including C-reactive protein, IL-1[beta], IL-6, interferon-[gamma] and tumor necrosis factor-[alpha], BT related biomarkers including Claudin-3, intestinal fatty acid binding protein, lipopolysaccharide (LPS), soluble CD14 (sCD14) and endotoxin core antibody were measured by ELISA. Bacterial DNA (BactDNA) fragments were quantified by quantified PCR (qPCR). Rhabdomyosarcoma (RD) or SH-SY5Y cells, infected with LPS-pre-incubated EV-A71 or transfected with plasmid containing viral 2A.sup.pro or mRNA containing viral internal ribosomal entry site (IRES), were post-treated with or without LPS in vitro. EV-A71 RNA and viral or cellular proteins were determined by qPCR and western blot, respectively. Results Compared to mild HFMD patients, remarkably higher inflammatory mediators as well as BT-related biomarkers except BactDNA were observed in severe HFMD cases (all P < 0.05). In severe HFMD group, circulating concentrations of LPS and sCD14 showed statistical correlations with inflammation indices (all P < 0.05), serum levels of EV-A71 VP1 were found to be positively correlated with serum LPS (r = 0.341, P = 0.005) and serum sCD14 (r = 0.458, P < 0.001). In vitro, EV-A71 attachment and internalization were only slightly promoted by LPS pre-incubation; however, EV-A71 proliferation and viral 2A.sup.pro-mediated IRES activity were significantly accelerated by LPS post-treatment. Conclusions Our results collectively indicate that gut-derived translocating LPS contributes to the severity of EV-A71-induced HFMD by driving inflammatory response and viral proliferation via viral 2A.sup.pro-mediated IRES. Keywords: Hand, foot, and mouth disease, Enterovirus A71, 2A protease (2A.sup.pro), Lipopolysaccharide, Inflammation, Internal ribosomal entry site (IRES), Author(s): Yuya Wang[sup.1], Kena Dan[sup.2], Xiaoling Xue[sup.3], Xiongbo Yang[sup.4], Xujiao Feng[sup.5], Qingqing Yang[sup.5], Jing Yang[sup.4] and Bangtao Chen[sup.4] Background Enterovirus A71 (EV-A71) is well known to be the major etiological [...]

Enteroviral 2A proteinase (2Apro), a well‐established and important viral functional protein, plays a key role in shutting down cellular cap‐dependent translation, mainly via its proteolytic activity, and creating optimal conditions for Enterovirus survival. Accumulated data show that viruses take advantage of various signaling cascades for their life cycle; studies performed by us and others have demonstrated that the extracellular signal‐regulated kinase (ERK) pathway is essential for enterovirus A71 (EV‐A71) and other viruses replication. We recently showed that ERK1/2 is required for the proteolytic activity of viral 2Apro; however, the mechanism underlying the regulation of 2Apro remains unknown. Here, we demonstrated that the 125th residue Ser125 of EV‐A71 2Apro or Thr125 of coxsackievirus B3 2Apro, which is highly conserved in the Enterovirus, was phosphorylated by ERK1/2. Importantly, 2Apro with phosphor‐Ser/Thr125 had much stronger proteolytic activity toward eukaryotic initiation factor 4GI and rendered the virus more efficient for multiplication and pathogenesis in hSCARB2 knock‐in mice than that in nonphospho‐Ser/Thr125A (S/T125A) mutants. Notably, phosphorylation‐mimic mutations caused deleterious changes in 2Apro catalytic function (S/T125D/E) and in viral propagation (S125D). Crystal structure simulation analysis showed that Ser125 phosphorylation in EV‐A71 2Apro enabled catalytic Cys to adopt an optimal conformation in the catalytic triad His‐Asp‐Cys, which enhances 2Apro proteolysis. Therefore, we are the first to report Ser/Thr125 phosphorylation of 2Apro increases enteroviral adaptation to the host to ensure enteroviral multiplication, causing pathogenicity. Additionally, weakened viruses containing a S/T125A mutation could be a general strategy to develop attenuated Enterovirus vaccines. [ABSTRACT FROM AUTHOR]

Background: Allergic contact dermatitis to cosmetics (ACDC) complicates the diagnosis and treatment of rosacea, and is increasingly observed in daily practice. Aims: The present study aimed to identify the contact allergens responsible for ACDC in Chinese female rosacea patients with or without suspected ACDC (SACDC). Methods: From a total of 1267 women with rosacea, 122 with SACDC, 145 without SACDC, and 100 age‐matched healthy controls without rosacea or SACDC were examined on a voluntary basis. Skin patch tests with C‐1000 cosmetic series (Chemotechnique Diagnostics, Malmo, Sweden) were conducted, including 20 selected allergens. Results: Positive allergic reaction was found in 85.2% and 33.8% of SACDC and non‐SACDC (P <.001), respectively, and 27.0% of healthy volunteers. Most reactions occurred at day 3, and the majority of all the examinees including normal controls reacted to more than 1 allergen. In SACDC patients, leading allergens were methylchloroisothiazolinone/methylisothiazolinone (28.7%), linalool hydroperoxide (27.1%), fragrance mix I (21.3%), methylisothiazolinone (17.2%), limonene hydroperoxides (16.4%), formaldehyde (14.8%), myroxylon pereirae (13.9%), and propolis (10.7%); the overall allergic reaction rate positively correlated with new onset of facial pruritus (P <.001). The occurrence of irritant contact reactions correlated with positive allergic reactions in rosacea patients with or without SACDC (P =.032 or P <.001, respectively). Conclusions: Preservatives and fragrances are primary culprits for ACDC in Chinese female rosacea patients. Patch testing should be considered in the suspected patients. [ABSTRACT FROM AUTHOR]