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Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6‐methyladenosine (m6A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome‐wide transcriptional m6A profiles of TM mono‐infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6A levels and upregulation of the m6A reader YTH N6‐methyladenosine RNA binding protein C2 (YTHDC2) in TM‐infected macrophages. Knockdown of YTHDC2 in TM‐infected cells showed an elevated expression of TLR2 through m6A‐dependence, along with upregulation of TNF‐α and IL1‐β. Overall, we characterized the m6A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases. [ABSTRACT FROM AUTHOR]

Herpetic‐related neuralgia (HN) caused by varicella‐zoster virus (VZV) infection is one of the most typical and common neuropathic pain in the clinic. However, the potential mechanisms and therapeutic approaches for the prevention and treatment of HN are still unclear. This study aims to provide a comprehensive understanding of the molecular mechanisms and potential therapeutic targets of HN. We used an HSV‐1 infection‐induced HN mouse model and screened the differentially expressed genes (DEGs) in the DRG and spinal cord using an RNAseq technique. Moreover, bioinformatics methods were used to figure out the signaling pathways and expression regulation patterns of the DEGs enriched. In addition, quantitative real‐time RT‐PCR and western blot were carried out to further confirm the expression of DEGs. HSV‐1 inoculation in mice resulted in mechanical allodynia, thermal hyperalgesia, and cold allodynia, following the infection of HSV‐1 in both DRG and spinal cord. Besides, HSV‐1 inoculation induced an up‐regulation of ATF3, CGRP, and GAL in DRG and activation of astrocytes and microglia in the spinal cord. Moreover, 639 genes were upregulated, 249 genes were downregulated in DRG, whereas 534 genes were upregulated and 12 genes were downregulated in the spinal cord of mice 7 days after HSV‐1 inoculation. GO and KEGG enrichment analysis suggested that immune responses and cytokine‐cytokine receptor interaction are involved in DRG and spinal cord neurons in mice after HSV‐1 infection. In addition, CCL5 and its receptor CCR5 were significantly upregulated in DRG and spinal cord upon HSV‐1 infection in mice. And blockade of CCR5 exhibited a significant analgesic effect and suppressed the upregulation of inflammatory cytokines in DRG and spinal cord induced by HSV‐1 infection in mice. HSV‐1 infection‐induced allodynia and hyperalgesia in mice through dysregulation of immune response and cytokine‐cytokine receptor interaction mechanism. Blockade of CCR5 alleviated allodynia and hyperalgesia probably through the suppression of inflammatory cytokines. Therefore, CCR5 could be a therapeutic target for the alleviation of HSV‐1 infection‐induced HN. [ABSTRACT FROM AUTHOR]

Dynamic alteration of the epitranscriptome exerts regulatory effects on the lifecycle of oncogenic viruses in vitro. However, little is known about these effects in vivo because of the general lack of suitable animal infection models of these viruses. Using a model of rapid‐onset Marek's disease lymphoma in chickens, we investigated changes in viral and host messenger RNA (mRNA) N6‐methyladenosine (m6A) modification during Marek's disease virus (MDV) infection in vivo. We found that the expression of major epitranscriptomic proteins varies among viral infection phases, reprogramming both the viral and the host epitranscriptomes. Specifically, the methyltransferase‐like 3 (METTL3)/14 complex was suppressed during the lytic and reactivation phases of the MDV lifecycle, whereas its expression was increased during the latent phase and in MDV‐induced tumors. METTL3/14 overexpression inhibits, whereas METTL3/14 knockdown enhances, MDV gene expression and replication. These findings reveal the dynamic features of the mRNA m6A modification program during viral replication in vivo, especially in relation to key pathways involved in tumorigenesis. [ABSTRACT FROM AUTHOR]

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N 6 -methyladenosine (m 6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m 6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m 6 A levels and upregulation of the m 6 A reader YTH N 6 -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m 6 A-dependence, along with upregulation of TNF-α and IL1-β. Overall, we characterized the m 6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m 6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases., (© 2024 Wiley Periodicals LLC.)

The human oncogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to Kaposi's sarcoma (KS), a tumor of endothelial cells characterized by angiogenesis and invasiveness. KSHV genome encodes 25 mature microRNAs (miRNAs), but their roles in KSHV-induced tumor dissemination and angiogenesis are not fully understood. In this study, we constructed the sensor reporters of KSHV miRNAs and used a luciferase reporter assay to demonstrate the function of the mimics of KSHV miRNAs. Then, we examined the expression of matrix metalloproteinases (MMPs) and pro-angiogenic cytokines that are related to cell migration and angiogenesis in the KSHV 25 miRNAs transfected endothelial cells. We found that all KSHV miRNAs increased the expression of the transcripts of MMP1, MMP13, VEGFA, and VEGFR2 in different degrees, as well as the secretion of VEGFA protein in the supernatant of endothelial cells. Our results reveal that KSHV miRNAs contribute to regulating MMPs and expression of pro-angiogenic factors, thus, suggesting that these miRNAs might play a crucial role in KSHV-induced cell motility and angiogenesis. [ABSTRACT FROM AUTHOR]