No abstract

The 2013–2016 West Africa Ebola virus (EBOV) epidemic caused by the EBOV-Makona isolate is the largest and longest recorded to date. It incurred over 28,000 infections and ∼11,000 deaths. Early in this epidemic, several mutations in viral glycoprotein (A82V), nucleoprotein (R111C), and polymerase L (D759G) emerged and stabilized. In vitro studies of these new EBOV-Makona isolates showed enhanced fitness and viral replication capacity. However, in vivo studies in mice and rhesus macaques did not provide any evidence of enhanced viral fitness or shedding. Infection with late isolates carrying or early isolates lacking (early) these mutations resulted in uniformly lethal disease in nonhuman primates (NHPs), albeit with slightly delayed kinetics with late isolates. The recent report of a possible reemergence of EBOV from a persistent infection in a survivor of the epidemic highlights the urgency for understanding the impact of genetic variation on EBOV pathogenesis. However, potential molecular differences in host responses remain unknown. To address this gap in knowledge, we conducted the first comparative analysis of the host responses to lethal infection with EBOV-Mayinga and EBOV-Makona isolates using bivariate, longitudinal, regression, and discrimination transcriptomic analyses. Our analysis shows a conserved core of differentially expressed genes (DEGs) involved in antiviral defense, immune cell activation, and inflammatory processes in response to EBOV-Makona and EBOV-Mayinga infections. Additionally, EBOV-Makona and EBOV-Mayinga infections could be discriminated based on the expression pattern of a small subset of genes. Transcriptional responses to EBOV-Makona isolates that emerged later during the epidemic, specifically those from Mali and Liberia, lacked signatures of profound lymphopenia and excessive inflammation seen following infection with EBOV-Mayinga and early EBOV-Makona isolate C07. Overall, these findings provide novel insight into the mechanisms underlying the lower case fatality rate (CFR) observed with EBOV-Makona compared to EBOV-Mayinga.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease‐2019 (COVID‐19), a respiratory disease that varies in severity from mild to severe/fatal. Several risk factors for severe disease have been identified, notably age, male sex, and pre‐existing conditions such as diabetes, obesity, and hypertension. Several advancements in clinical care have been achieved over the past year, including the use of corticosteroids (e.g., corticosteroids) and other immune‐modulatory treatments that have now become standard of care for patients with acute severe COVID‐19. While the understanding of the mechanisms that underlie increased disease severity with age has improved over the past few months, it remains incomplete. Furthermore, the molecular impact of corticosteroid treatment on host response to acute SARS‐CoV‐2 infection has not been investigated. In this study, a cross‐sectional and longitudinal analysis of Ab, soluble immune mediators, and transcriptional responses in young (65 ≤ years) and aged (≥ 65 years) diabetic males with obesity hospitalized with acute severe COVID‐19 was conducted. Additionally, the transcriptional profiles in samples obtained before and after corticosteroids became standard of care were compared. The analysis indicates that severe COVID‐19 is characterized by robust Ab responses, heightened systemic inflammation, increased expression of genes related to inflammatory and pro‐apoptotic processes, and reduced expression of those important for adaptive immunity regardless of age. In contrast, COVID‐19 patients receiving steroids did not show high levels of systemic immune mediators and lacked transcriptional indicators of heightened inflammatory and apoptotic responses. Overall, these data suggest that inflammation and cell death are key drivers of severe COVID‐19 pathogenesis in the absence of corticosteroid therapy.

Distinct transcriptional responses to fatal Ebola virus infection in cynomolgus and rhesus macaques suggest species-specific immune responses, Emerging Microbes & Infections,

Background Chemoradiation therapy (CRT) is the standard of care for squamous cell carcinoma of the anus (SCCA), the most common type of anal cancer. However, approximately one fourth of patients still relapse after CRT. Methods We used RNA-sequencing technology to characterize coding and non-coding transcripts in tumor tissues from CRT-treated SCCA patients and compare them between 9 non-recurrent and 3 recurrent cases. RNA was extracted from FFPE tissues. Library preparations for RNA-sequencing were created using SMARTer Stranded Total RNA-Seq Kit. All libraries were pooled and sequenced on a NovaSeq 6000. Function and pathway enrichment analysis was performed with Metascape and enrichment of gene ontology (GO) was performed with Gene Set Enrichment Analysis (GSEA). Results There were 449 differentially expressed genes (DEGs) observed (390 mRNA, 12 miRNA, 17 lincRNA and 18 snRNA) between the two groups. We identified a core of upregulated genes ( IL4, CD40LG , ICAM2 , HLA-I (HLA-A, HLA-C) and HLA-II (HLA-DQA1, HLA-DRB5) in the non-recurrent SCCA tissue enriching to the gene ontology term ‘allograft rejection’, which suggests a CD4+ T cell driven immune response. Conversely, in the recurrent tissues, keratin ( KRT1, 10, 12, 20 ) and hedgehog signaling pathway ( PTCH2 ) genes involved in ‘Epidermis Development,’, were significantly upregulated. We identified miR-4316, that inhibit tumor proliferation and migration by repressing vascular endothelial growth factors, as being upregulated in non-recurrent SCCA. On the contrary, lncRNA-SOX21-AS1 , implicated in the progression of many other cancers, was also found to be more common in our recurrent compared to non-recurrent SCCA. Conclusions Our study identified key host factors which may drive the recurrence of SCCA and warrants further studies to understand the mechanism and evaluate their potential use in personalized treatment. Key Message Our study used RNA sequencing (RNA-seq) to identify pivotal factors in coding and non-coding transcripts which differentiate between patients at risk for recurrent anal cancer after treatment. There were 449 differentially expressed genes (390 mRNA, 12 miRNA, 17 lincRNA and 18 snRNA) between 9 non-recurrent and 3 recurrent squamous cell carcinoma of anus (SCCA) tissues. The enrichment of genes related to allograft rejection was observed in the non-recurrent SCCA tissues, while the enrichment of genes related to epidermis development was positively linked with recurrent SCCA tissues.