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Vivek Paulbuddhe,1 Sujit Addya,1 Bharat Gurnani,2 Dheerendra Singh,3 Koushik Tripathy,4 Rohan Chawla5 1Department of Vitreoretina, ASG Eye Hospital, Guwahati, 781006, Assam, India; 2Department of Cornea, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, 605007, Puducherry, India; 3Department of Retina, ASG Eye Hospital, Bhopal, 462016, Madhya Pradesh, India; 4Department of Vitreoretina, ASG Eye Hospital, Kolkata, 700058, West Bengal, India; 5Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, 110029, IndiaCorrespondence: Koushik TripathyDepartment of Vitreoretina, ASG Eye Hospital, 149, BT Road, Kolkata, 700058, West Bengal, IndiaTel +913325632222Email koushiktripathy@gmail.comAbstract: Sympathetic ophthalmia is a rare bilateral diffuse granulomatous panuveitis that usually results from surgical or penetrating trauma to one eye. The symptoms range from impaired near vision to pain, photophobia, and loss of visual acuity. Anterior segment manifestations include bilateral acute uveitis with mutton-fat keratic precipitates and posterior segment findings include vitritis, multifocal neurosensory retinal detachment, choroiditis, optic nerve edema, and Dalen–Fuchs nodules. The diagnosis is clinical. Ancillary investigations include fundus fluorescein angiography, indocyanine green angiography, optical coherence tomography (OCT), ultrasound B scan, and autofluorescence imaging. The management options include corticosteroids (topical and systemic) as the first line along with immunomodulatory therapy started at the presentation of the disease. Recent advances include imaging with OCT-angiography, enhanced depth imaging-OCT (EDI-OCT, choroidal vascular index/CVI), targeting IL-23/IL-17 pathway, and use of biologics for the management of this rare entity. Recent advances in early diagnosis and prompt treatment has led to improved final visual outcomes in both the sympathizing and exciting eye. This review is aimed at giving a comprehensive overview of sympathetic ophthalmia along with a special emphasis on current treatment strategies and recent advances.Keywords: ocular trauma, inciting eye, exciting eye, corticosteroids, open globe injury, infliximab, adalimumab

Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference >  + 2, < - 2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention., (© 2024. The Author(s).)

Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. The RC protocol exhibited a stronger treatment effect with significantly higher fold differences between the groups compared to the NRC protocol ( p  < 0.001, fold differences RC vs NRC). In microarrays, miR-34a-5p showed cystitis-induced downregulation in both protocols. Bioinformatics analysis identified multiple 3'UTRs complementary binding sites for miR-34a-5p on Grin2b, Notch1, Grip2, Scn2b, and Arc genes. The enhanced response in the RC protocol indicates a possible priming effect of early life cystitis on rechallenge in adulthood. These long-term molecular alterations may play a critical role in the development of chronic bladder pain conditions as seen in patients with Interstitial Cystitis/Bladder pain syndrome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Lupus nephritis (LN) is the assemblage of glomerular, tubulointerstitial and vascular changes. Despite the fact that glomerular changes are overemphasized in pathological classification and scoring system, but the existence of vascular damage negatively impact the clinical course., Aims and Objective: This study was conducted to determine the clinicopathological spectrum of renal vascular lesions in lupus nephritis., Materials and Methods: Renal microvascular lesions in biopsy proven lupus nephritis were classified into 5 major categories-thrombotic microangiopathy, true vasculitis; lupus vasculopathy, uncomplicated vascular immune deposits, and arterial. Clinical details, laboratory parameters and histopathological variables were compared among all groups. Summary of chronic changes was also assessed., Results: Biopsies from 56 patients revealed thrombotic microangiopathy (2), lupus vasculopathy (3), uncomplicated vascular immune deposit (6), PAN type vasculitis (1) and arterial sclerosis (13). No renal vascular lesions were found in 35.18% of patients. At the time of biopsy, arterial sclerosis or lupus vasculopathy patients were older Nephritis subtype. Activity indices were higher in lupus vasculopathy group whereas patients with arteriosclerosis showed highest chronicity index., Conclusions: Renal vascular lesions are common in systemic lupus erythematosus patients with nephritis and may be associated with aggressive clinical course.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About 18.4% of total Covid-19 cases were reported in children. Even though vertical transmission from mother to infant is likely to occur at a low rate, exposure to COVID-19 during fetal life may alter DNA methylation patterns with potential long-term effects., Objective: To determine if COVID-19 infection during pregnancy alters the DNA methylation patterns in umbilical cord blood cells from term infants and to identify potential pathways and genes affected by exposure to COVID-19 infection., Methods: Umbilical cord blood was collected from 8 infants exposed to COVID-19 during pregnancy and 8 control infants with no COVID-19 exposure. Genomic DNA was isolated from umbilical cord blood cells and genome-wide DNA methylation was performed using Illumina Methylation EPIC Array., Results: 119 differentially methylated loci were identified at the FDR level of 0.20 (64 hypermethylated loci and 55 hypomethylated loci) in umbilical cord blood cells of COVID-19 exposed neonates compared to the control group. Important canonical pathways identified by Ingenuity Pathway Analysis (IPA) were related to stress response (corticotropin releasing hormone signaling, glucocorticoid receptor signaling, and oxytocin in brain signaling pathway), and cardiovascular disease and development (nitric oxide signaling in the cardiovascular system, apelin cardiomyocyte signaling pathways, factors promoting cardiogenesis, and renin-angiotensin signaling). The genes affected by the differential methylations were associated with cardiac, renal, hepatic, neurological diseases, developmental and immunological disorders., Conclusions: COVID-19 induces differential DNA methylation in umbilical cord blood cells. The differentially methylated genes may contribute to hepatic, renal, cardiac, developmental and immunological disorders in offspring born to mothers with COVID-19 infection during pregnancy, and their developmental regulation., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background  Understanding the genetic basis for the molecular classification of sinonasal undifferentiated carcinoma (SNUC) based on SMARCB1 may improve our understating regarding the nature of the disease. The objective of the study was to compare the genetic profile of SMARCB1-retained (SR-SNUC) and SMARCB1-deficient SNUC (SD-SNUC). Methods  Formalin-fixed, paraffin-embedded tissue from treatment-naive patients with SNUC were selected. Three cases of SR-SNUC, four cases of SD-SNUC, and four samples of nontumor tissue (control samples) were selected. Ribonucleic acid (RNA) sequencing was performed. Results  SR-SNUC had a higher number of variants (1 variant for every 15,000 bases) compared with SD-SNUC (1 variant every 29,000 bases). The ratio of missense to silent mutation ratio was higher for SR-SNUC (0.8) as compared with SD-SNUC (0.7). Approximately 1,500 genes were differentially expressed between SR-SNUC and SD-SNUC. The genes that had a higher expression in SR-SNUC included TPD52L1, B3GNT3, GFY, TJP3, ELL3, CYP4F3, ALDH3B2, CKMT1B, VIPR1, SLC7A5, PPP2R2C, UPK3B, MUC1, ELF5, STY7, and H2AC14. The gene that had a higher expression in SD-SNUC was ZFHX4. Most of these genes were related to either protein translation or immune regulation. The most common ( n  = 3, 75%) mechanisms of loss of SMARCB1 gene in SD-SNUC was loss of heterozygosity. Conclusion  RNA sequencing is a viable and informative approach for genomic profiling of archival SNUC samples. Both SR-SNUC and SD-SNUC were noted to have distinct genetic profiles underlying the molecular classification of these diseases., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFβ activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFβ kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies., (© 2023. The Author(s).)

ERK1/2 (extracellular signal-regulated kinases 1 and 2) regulate the activity of various transcription factors that contribute to asthma pathogenesis. Although an attractive drug target, broadly inhibiting ERK1/2 is challenging because of unwanted cellular toxicities. We have identified small molecule inhibitors with a benzenesulfonate scaffold that selectively inhibit ERK1/2-mediated activation of AP-1 (activator protein-1). Herein, we describe the findings of targeting ERK1/2-mediated substrate-specific signaling with the small molecule inhibitor SF-3-030 in a murine model of house dust mite (HDM)-induced asthma. In 8- to 10-week-old BALB/c mice, allergic asthma was established by repeated intranasal HDM (25 μg/mouse) instillation for 3 weeks (5 days/week). A subgroup of mice was prophylactically dosed with 10 mg/kg SF-3-030/DMSO intranasally 30 minutes before the HDM challenge. Following the dosing schedule, mice were evaluated for alterations in airway mechanics, inflammation, and markers of airway remodeling. SF-3-030 treatment significantly attenuated HDM-induced elevation of distinct inflammatory cell types and cytokine concentrations in BAL and IgE concentrations in the lungs. Histopathological analysis of lung tissue sections revealed diminished HDM-induced pleocellular peribronchial inflammation, mucus cell metaplasia, collagen accumulation, thickening of airway smooth muscle mass, and expression of markers of cell proliferation (Ki-67 and cyclin D1) in mice treated with SF-3-030. Furthermore, SF-3-030 treatment attenuated HDM-induced airway hyperresponsiveness in mice. Finally, mechanistic studies using transcriptome and proteome analyses suggest inhibition of HDM-induced genes involved in inflammation, cell proliferation, and tissue remodeling by SF-3-030. These preclinical findings demonstrate that function-selective inhibition of ERK1/2 signaling mitigates multiple features of asthma in a murine model.

Henoch-Schönlein purpura (HSP) is a small vessel vasculitis with multiorgan involvement. Renal involvement is the key factor predicting morbidity. We have aimed to analyze the clinicopathological spectrum of HSP vasculitis and HSP nephritis to assess the risk factors associated with kidney involvement. This retrospective study was performed in the department of pathology with collaboration of department of dermatology and department of nephrology of a tertiary care center. All clinical details along with biopsy findings were retrieved. Starting materials of the study were cases of leukocytoclastic vasculitis with only perivascular IgA deposit of more than ++ in the absence of other immunoglobulin and trace complements. To investigate the possible factors that are influential on the development of biopsy-proven HSP nephritis, we divided the whole study population in two groups -group 1: with and group 2: without biopsy-proven nephritis. One-way analysis of variance was carried out during comparative analysis between two groups using IBM SPSS statistics software, version 19 and MedCalc software, version 12.3.0.0. HSP vasculitis comprised 11.6% (n = 19) of total cutaneous vasculitis in 2 years (164 cases) with a mean age of 13.52 ± 8.10 (range: 4-33 years). Three cases developed de novo kidney disease (15.79%). A correlation analysis revealed that predictors were seasonal variation (P = 0.018), severe gastrointestinal involvement (P = 0.03), and subcutaneous edema (P = 0.005). Various clinical and laboratory parameters were associated with renal consequences. Occult nephritis was the most common presentation with crescent as a constant histopathological feature., (Copyright © 2022 Copyright: © 2022 Saudi Journal of Kidney Diseases and Transplantation.)

There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3-chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bisserier, Brojakowska, Saffran, Rai, Lee, Coleman, Sebastian, Evans, Mills, Addya, Arakelyan, Garikipati, Hadri and Goukassian.)

Background: The COVID-19 pandemic continues worldwide with fluctuating case numbers in the United States. This pandemic has affected every segment of the population with more recent hospitalizations in the pediatric population. Vertical transmission of COVID-19 is uncommon, but reports show that there are thrombotic, vascular, and inflammatory changes in the placenta to which neonates are prenatally exposed. Individuals exposed in utero to influenza during the 1918 pandemic had increased risk for heart disease, kidney disease, diabetes, stomach disease and hypertension. Early exposure of COVID-19 during fetal life may lead to altered gene expression with potential long-term consequences., Objective: To determine if gene expression is altered in cord blood cells from term neonates who were exposed to COVID-19 during pregnancy and to identify potential gene pathways impacted by maternal COVID-19., Methods: Cord blood was collected from 16 term neonates (8 exposed to COVID-19 during pregnancy and 8 controls without exposure to COVID-19). Genome-wide gene expression screening was performed using Human Clariom S gene chips on total RNA extracted from cord blood cells., Results: We identified 510 differentially expressed genes (374 genes up-regulated, 136 genes down-regulated, fold change ≥1.5, p -value ≤ 0.05) in cord blood cells associated with exposure to COVID-19 during pregnancy. Ingenuity Pathway Analysis identified important canonical pathways associated with diseases such as cardiovascular disease, hematological disease, embryonic cancer and cellular development. Tox functions related to cardiotoxicity, hepatotoxicity and nephrotoxicity were also altered after exposure to COVID-19 during pregnancy., Conclusions: Exposure to COVID-19 during pregnancy induces differential gene expression in cord blood cells. The differentially expressed genes may potentially contribute to cardiac, hepatic, renal and immunological disorders in offspring exposed to COVID-19 during pregnancy. These findings lead to a further understanding of the effects of COVID-19 exposure at an early stage of life and its potential long-term consequences as well as therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gayen nee' Betal, Urday, Al-Kouatly, Solarin, Chan, Addya, Boelig and Aghai.)

Human Antigen R (HuR/ELAVL1) is known to regulate stability of mRNAs involved in pancreatic ductal adenocarcinoma (PDAC) cell survival. Although several HuR targets are established, it is likely that many remain currently unknown. Here, we identified BARD1 mRNA as a novel target of HuR. Silencing HuR caused a >70% decrease in homologous recombination repair (HRR) efficiency as measured by the double-strand break repair (pDR-GFP reporter) assay. HuR-bound mRNAs extracted from RNP-immunoprecipitation and probed on a microarray, revealed a subset of HRR genes as putative HuR targets, including the BRCA1-Associated-Ring-Domain-1 (BARD1) (p < 0.005). BARD1 genetic alterations are infrequent in PDAC, and its context-dependent upregulation is poorly understood. Genetic silencing (siRNA and CRISPR knock-out) and pharmacological targeting of HuR inhibited both full length (FL) BARD1 and its functional isoforms (α, δ, Φ). Silencing BARD1 sensitized cells to olaparib and oxaliplatin; caused G2-M cell cycle arrest; and increased DNA-damage while decreasing HRR efficiency in cells. Exogenous overexpression of BARD1 in HuR-deficient cells partially rescued the HRR dysfunction, independent of an HuR pro-oncogenic function. Collectively, our findings demonstrate for the first time that BARD1 is a bona fide HuR target, which serves as an important regulatory point of the transient DNA-repair response in PDAC cells.

Vesiculobullous disorders could be either immunobullous or non-immunobullous. The spectrum was analyzed using histopathology, direct immunofluorescence (DIF), and salt-split technique. Among the 104 patients analyzed, 77 (74%) were immunobullous and 25 (24%) were having non-immunobullous diseases. Bullous pemphigoid (20.2%) is the commonest among immunobullous lesions, and epidermolysis bullosa (11.5%) was the most frequent non-immunobullous lesion. Involvement of the hair and nail and a positive family history were common relationships for non-immunobullous disorders. Immunobullous lesions showed DIF positivity whereas non-immunobullous lesions were DIF negative. Perilesional DIF was more sensitive and specific than lesional DIF. The commonest antibody was immunoglobulin G (IgG) (78.9%) followed by complement 3c (C3c) (38.1%), immunoglobulin A (IgA) (25%), and immunoglobulin M (IgM) (6.6%). No lesion should be considered non-immunobullous unless both lesional and perilesional DIF results were negative.

Mouse hepatitis virus (MHV; m-β-CoV) serves as a useful model for studying the cellular factors involved in neuroinflammation. To understand the role of matrix metalloproteinases (MMPs) in neuroinflammation, brain tissues from m-β-CoV-infected mice were harvested at different days post-infection (d.p.i) and investigated for Mmp expression by RT-qPCR. Mmp-2, -3, -8, -12 showed significant mRNA upregulation peaking with viral replication between 5 and 6 d.p.i. Elevated levels of MMP regulator TIMP-1 are suggestive of a TIMP-1 mediated host antiviral response. Biological network assessment suggested a direct involvement of MMP-3, -8, -14 in facilitating peripheral leukocyte infiltrations. Flow cytometry confirmed the increased presence of NK cells, CD4 + and CD8 + T cells, neutrophils, and MHCII expressing cells in the m-β-CoV infected mice brain. Our study revealed that m-β-CoV upregulated Park7, RelA, Nrf2, and Hmox1 transcripts involved in ROS production and antioxidant pathways, describing the possible nexus between oxidative pathways, MMPs, and TIMP in m-β-CoV-induced neuroinflammation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Systemic sclerosis (SSc) is characterised by severe fibroproliferative vasculopathy, fibrosis in skin and multiple internal organs, and humoral, cellular and innate immunity abnormalities. Vascular alterations are the earliest and most severe SSc manifestations, however, the mechanisms responsible have remained elusive. To investigate the molecular abnormalities involved in SSc-vasculopathy we examined global gene expression differences between highly purified lung microvascular endothelial cells (MVECs) from patients with SSc-interstitial lung disease (SSc-ILD) and normal lung MVECs., Methods: MVECs were isolated from fresh transplanted lungs from patients with SSc-ILD. Sequential CD31 and CD102 immunopurification was performed to obtain highly purified CD31+/CD102+ lung MVECs. Global gene expression analysis was successfully performed in CD31+/CD102+ MVEC from two SSc-ILD patients and from two normal lungs. RT-PCR, Western blots, and indirect immunofluorescence validated the gene expression results., Results: Numerous interferon-regulated genes (IRGs) including IFI44, IFI44L, IFI6, IFIH1, IFIT1, ISG-15, BST-2/Tetherin, and RSAD2/Viperin, genes encoding innate immunity antiviral responses (OAS1, OAS2, OAS3, OASL) and antiviral MX1 and MX2 proteins, and mesenchymal cell-specific genes were significantly overexpressed in CD31+/CD102+ SSc-ILD lung MVECs., Conclusions: Highly purified CD31+/CD102+ MVECs from lungs from SSc patients with end stage SSc-ILD displayed remarkable overexpression of numerous IRGs and of genes encoding antiviral innate immune response and antiviral proteins. These observations suggest that interferon-induced and antiviral response proteins may participate in the pathogenesis of SSc vasculopathy and SSc-ILD. The CD31+/CD102+ lung MVECs from SSc-ILD also showed elevated expression of mesenchymal cell-specific genes confirming the presence of endothelial to mesenchymal transition in SSc-ILD.

Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells. Alpha smooth muscle actin (α-SMA) expressing myofibroblasts and α-SMA negative cells were isolated employing laser capture microdissection from dermal cell cultures from four patients with diffuse SSc of recent onset. Total mRNA was extracted from both cell populations, amplified and analyzed employing microarrays. Results for specific genes were validated by Western blots and by immunohistochemistry. Transcriptome analysis revealed 97 differentially expressed transcripts in SSc myofibroblasts compared with non-myofibroblasts. Annotation clustering of the SSc myofibroblast-specific transcripts failed to show a TGF-β signature. The most represented transcripts corresponded to several different genes from the Neuroblastoma Breakpoint Family (NBPF) of genes. NBPF genes are highly expanded in humans but are not present in murine or rat genomes. In vitro studies employing cultured SSc dermal fibroblasts and immunohistochemistry of affected SSc skin confirmed increased NBPF expression in SSc. These results indicate that SSc myofibroblasts represent a unique cell lineage expressing a specific transcriptome that includes very high levels of transcripts corresponding to numerous NBPF genes. Elevated expression of NBPF genes in SSc myofibroblasts suggests that NBPF gene products may play a role in SSc pathogenesis and may represent a novel therapeutic target., (© 2021. The Author(s).)

Interferon regulatory factor 8 (IRF8), a myeloid lineage transcription factor, emerges as an essential regulator for microglial activation. However, the precise role of IRF8 during Japanese encephalitis virus (JEV) infection in the brain remains elusive. Here, we report that JEV infection enhances IRF8 expression in the infected mouse brain. Comparative transcriptional profiling of whole-brain RNA analysis and validation by quantitative reverse transcription-PCR (qRT-PCR) reveals an impaired interferon gamma (IFN-γ) and related gene expression in Irf8 knockout ( Irf8 -/- )-infected mice. Further, Ifnγ knockout ( Ifnγ -/- ) mice exhibit a reduced level of Irf8. Both Ifnγ -/- and Irf8 -/- mice exhibit significantly reduced levels of activated (CD11b + CD45 hi , CD11b + CD45 lo , Cd68, and CD86) and infiltrating immune cells (Ly6C + , CD4, and CD8) in the infected brain compared to those of wild-type (WT) mice. However, a higher level of granulocyte cell (Ly6G + ) infiltration is evident in Irf8 -/- mice as well as the increased concentration of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP1) levels in the brain. Interestingly, neither the Irf8 -/- nor the Ifnγ -/- conferred protection against lethal JEV challenge to mice and exhibit augmentation in JEV replication in the brain. The gain of function of Irf8 by overexpressing functional IRF8 in an IRF8-deficient cell line attenuates viral replication and enhances IFN-γ production. Overall, we summarize that in the murine model of JEV encephalitis, IRF8 modulation affects JEV replication. We also show that lack of Irf8 affects immune cell abundance in circulation and the infected brain, leading to a reduction in IFN-γ level and increased viral load in the brain. IMPORTANCE Microglial cells, the resident macrophages in the brain, play a vital role in Japanese encephalitis virus (JEV) pathogenesis. The deregulated activity of microglia can be lethal for the brain. Therefore, it is crucial to understand the regulators that drive microglia phenotype changes and induce inflammation in the brain. Interferon regulatory factor 8 (IRF8) is a myeloid lineage transcription factor involved in microglial activation. However, the impact of IRF8 modulation on JEV replication remains elusive. Moreover, the pathways regulated by IRF8 to initiate and amplify pathological neuroinflammation are not well understood. Here, we demonstrated the effect of IRF8 modulation on JEV replication, microglial activation, and immune cells infiltration in the brain.

Competing Interests: None

Background: Preterm infants with bronchopulmonary dysplasia (BPD) have lifelong increased risk of respiratory morbidities associated with environmental pathogen exposure and underlying mechanisms are poorly understood. The resident immune cells of the lung play vital roles in host defense. However, the effect of perinatal events associated with BPD on pulmonary-specific immune cells is not well understood., Methods: We used a double-hit model of BPD induced by prenatal chorioamnionitis followed by postnatal hyperoxia, and performed a global transcriptome analysis of all resident pulmonary immune cells., Results: We show significant up-regulation of genes involved in chemokine-mediated signaling and immune cell chemotaxis, and down-regulation of genes involved in multiple T lymphocyte functions. Multiple genes involved in T cell receptor signaling are downregulated and Cd8a gene expression remains downregulated at 2 months of age in spite of recovery in normoxia for 6 weeks. Furthermore, the proportion of CD8a+CD3+ pulmonary immune cells is decreased., Conclusions: Our study has highlighted that perinatal lung inflammation in a double-hit model of BPD results in short- and long-term dysregulation of genes associated with the pulmonary T cell receptor signaling pathway, which may contribute to increased environmental pathogen-associated respiratory morbidities seen in children and adults with BPD., Impact: In a translationally relevant double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia, we identified pulmonary immune cell-specific transcriptomic changes and showed that T cell receptor signaling genes are downregulated in short term and long term. This is the first comprehensive report delineating transcriptomic changes in resident immune cells of the lung in a translationally relevant double-hit model of BPD. Our study identifies novel resident pulmonary immune cell-specific targets for potential therapeutic modulation to improve short- and long-term respiratory health of preterm infants with BPD., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced COVID-19 has emerged as a defining global health crisis in current times. Data from the World Health Organization shows demographic variations in COVID-19 severity and lethality. Diet may play a significant role in providing beneficial host cell factors contributing to immunity against deadly SARS-CoV-2 pathogenesis. Spices are essential components of the diet that possess anti-inflammatory, antioxidant, and antiviral properties. Hyperinflammation, an aberrant systemic inflammation associated with pneumonia, acute respiratory failure, and multiorgan dysfunction, is a major clinical outcome in COVID-19. Knowing the beneficial properties of spices, we hypothesize that spice-derived bioactive components can modulate host immune responses to provide protective immunity in COVID-19. This study emphasizes that biologically active components of spices might alleviate the sustained pro-inflammatory condition by inhibiting the activity of tumor necrosis factor-alpha (TNF-α), interleukins (IL6, IL8), and chemokine (CCL2) known to be elevated in COVID-19. Spices may potentially prevent the tissue damage induced by oxidative stress and pro-inflammatory mediators during SARS-CoV-2 infection. The current study also highlights the effects of spices on the antioxidant pathways mediated by Nrf2 (nuclear factor erythroid 2-related factor 2) and Hmox1 (heme oxygenase 1) to restore oxidative homeostasis and protect from aberrant tissue damage. Taken together, the anti-inflammatory and antioxidant activities of bioactive components of spices may hold a promise to target the cellular pathways for developing antivirals against SARS-CoV-2 and pan β-coronaviruses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sengupta, Bhattacharyya, Kasle, Karmakar, Sahu, Ganguly, Addya and Das Sarma.)