Epidemiologic Features of the Monkeypox Outbreak and the Public Health Response - United States, May 17-October 6, 2022.

On May 17, 2022, the Massachusetts Department of Health announced the first suspected case of monkeypox associated with the global outbreak in a U.S. resident. On May 23, 2022, CDC launched an emergency response (1,2). CDC's emergency response focused on surveillance, laboratory testing, medical countermeasures, and education. Medical countermeasures included rollout of a national JYNNEOS vaccination strategy, Food and Drug Administration (FDA) issuance of an emergency use authorization to allow for intradermal administration of JYNNEOS, and use of tecovirimat for patients with, or at risk for, severe monkeypox. During May 17-October 6, 2022, a total of 26,384 probable and confirmed* U.S. monkeypox cases were reported to CDC. Daily case counts peaked during mid-to-late August. Among 25,001 of 25,569 (98%) cases in adults with information on gender identity,† 23,683 (95%) occurred in cisgender men. Among 13,997 cisgender men with information on recent sexual or close intimate contact,§ 10,440 (75%) reported male-to-male sexual contact (MMSC) ≤21 days preceding symptom onset. Among 21,211 (80%) cases in persons with information on race and ethnicity,¶ 6,879 (32%), 6,628 (31%), and 6,330 (30%) occurred in non-Hispanic Black or African American (Black), Hispanic or Latino (Hispanic), and non-Hispanic White (White) persons, respectively. Among 5,017 (20%) cases in adults with information on HIV infection status, 2,876 (57%) had HIV infection. Prevention efforts, including vaccination, should be prioritized among persons at highest risk within groups most affected by the monkeypox outbreak, including gay, bisexual, and other men who have sex with men (MSM); transgender, nonbinary, and gender-diverse persons; racial and ethnic minority groups; and persons who are immunocompromised, including persons with advanced HIV infection or newly diagnosed HIV infection.

Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells.

OBJECTIVE: We examined genome-wide DNA methylation changes in CD8+ T cells from patients with lupus and controls and investigated the functional relevance of some of these changes in lupus. METHODS: Genome-wide DNA methylation of lupus and age, sex and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR. Inhibiting STAT1 and CIITA was performed using fludarabine and CIITA siRNA, respectively. RESULTS: Lupus CD8+ T cells had 188 hypomethylated CpG sites compared with healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. CIITA knockdown and STAT1 inhibition experiments revealed that HLA-DRB1 expression in lupus CD8+ T cells is dependent on CIITA and STAT1 signalling. Coincubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69 and cytokine production, in patients with lupus but not in healthy controls. This can be blocked by neutralising antibodies targeting HLA-DR. CONCLUSIONS: Lupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in patients with lupus. A possible pathogenic role for CD8+ T cells in lupus that is dependent on a high type-I interferon environment and epigenetic priming warrants further characterisation.

Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma.

Binding of the bromodomain and extraterminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. We sought to determine the antifibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan-BET inhibitor, JQ1; BRD2 inhibitor, BIC1; or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed antifibrotic effects in an animal model of SSc and in patient-derived diffuse cutaneous SSc (dcSSc) fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium (Ca2+) signaling. The antifibrotic effect of BRD4 inhibition was mediated at least in part by downregulation of Ca2+/calmodulin-dependent protein kinase II α and reduction of intracellular Ca2+ concentrations. On the basis of these results, we propose targeting Ca2+ pathways or BRD4 as potentially novel therapeutic approaches for progressive tissue fibrosis.

Inhibition of EZH2 Ameliorates Lupus-Like Disease in MRL/lpr Mice.

OBJECTIVE: We previously identified a role for EZH2, a transcriptional regulator in inducing proinflammatory epigenetic changes in lupus CD4+ T cells. This study was undertaken to investigate whether inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice. METHODS: EZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and messenger RNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by intraperitoneal 3'-deazaneplanocin (DZNep) administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-double-stranded DNA (anti-dsDNA) antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed. RESULTS: EZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibition of EZH2 by DZNep was confirmed by significant reduction of EZH2 and H3K27me3 in splenocytes. Inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy. Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep-treated mice. Concentrations of circulating cytokines and chemokines, including tumor necrosis factor, interferon-γ, CCL2, RANTES/CCL5, interleukin-10 (IL-10), keratinocyte-derived chemokine/CXCL1, IL-12, IL-12p40, and CCL4/macrophage inflammatory protein 1ß, were decreased in DZNep-treated mice. CONCLUSION: EZH2 is up-regulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option for lupus patients.