Biology subjects

Panfil, A. R.

Publications and source records attributed to Panfil, A. R..

2 recordsLinked to original sources

bioRxiv2026

Efficient replication of influenza D virus in the human airway underscores zoonotic potential

Influenza D virus (IDV), primarily found in livestock species, has demonstrated cross-species transmission potential, yet its threat to humans remains poorly understood. Here, we curated a panel of IDV isolates collected during field surveillance from 2011 to 2020 from swine and cattle to assess their ability to infect human airway cells as a proxy for zoonotic threat assessment. Using lung epithelial cell lines, primary well-differentiated airway epithelial cultures, and precision-cut lung slices, we demonstrated that IDV efficiently propagates in cells and tissues from the human respiratory tract, reaching titers comparable to human influenza A virus (IAV). Infection kinetics in primary porcine airway cultures and respiratory tissues mirrored those from human, suggesting similar infectivity across species. To define host responses to IDV infection, we evaluated innate immune sensing and downstream interferon signaling in human respiratory cells. IDV infection resulted in markedly reduced activation of interferon regulatory factor (IRF) signaling and diminished induction of interferon lambda 1 and interferon-stimulated genes compared to IAV, indicating inefficient activation of innate immune sensing pathways. However, IDV replication was potently restricted in interferon-pretreated cells, demonstrating sensitivity to interferon-mediated antiviral effector mechanisms once an antiviral state was established. Together, these findings show that IDV can efficiently infect the human airway while limiting innate immune sensing, a feature that may facilitate zoonotic spillover. Our study highlights the need for enhanced surveillance of IDV at the animal-human interface and provides a foundation for further investigation into its biology and potential for causing human infection and disease. SIGNIFICANCE STATEMENTInfluenza D virus (IDV) is a poorly understood virus type in the Orthomyxoviridae family. Although initially considered incapable of infecting humans, high seropositivity rates among cattle and swine workers suggest that zoonotic infections may already be occurring. However, the extent of human compatibility--and the potential for spillover--remains poorly understood. Our study demonstrates that IDV replicates efficiently in multiple human respiratory models while largely evading innate immune defenses, raising concern that only minimal evolutionary changes may be required for sustained human transmission. These findings underscore the need for further investigation into IDV biology and zoonotic risk. Such studies are critical for identifying viruses with the potential to adapt to humans before they become public health threats.

microbiology↗

bioRxiv2024

YTHDF1 and YTHDC1 m6A reader proteins regulate HTLV-1 tax and hbz activity

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurodegenerative disease. Regulation of viral gene expression plays a key role in viral persistence and pathogenesis. However, the molecular mechanisms underlying this fine-tuned regulation remain poorly understood. Little is known regarding RNA chemical modifications of HTLV-1 RNA and how these affect viral biology and disease development. Posttranscriptional chemical modification of RNA is common in eukaryotes, with N6-methyladenosine (m6A) being the most prevalent. In this study, we investigated the role of m6A RNA modifications on HTLV-1 gene expression. Using MeRIP-Seq, we mapped sites of m6A modification to the 3 end of the viral genome. We found HTLV-1 RNA, as well as viral oncogene transcripts tax and hbz, contained m6A modifications. m6A-depletion in HTLV-1-transformed cells decreased sense-derived viral genes (Tax, Gag, Env) and increased antisense-derived Hbz expression. Tax and hbz transcripts were bound by reader proteins YTHDF1 and YTHDC1 in a panel of HTLV-1 T-cell lines. Using expression vectors and shRNA-mediated knockdown, we found YTHDF1 had opposing effects on viral gene expression - decreasing sense-derived viral genes and increasing antisense-derived Hbz. Upon further study, the YTHDF1 effects on tax abundance were dependent on tax m6A deposition. The nuclear m6A reader protein YTHDC1 affected the abundance of both sense- and antisense-derived viral transcripts and specifically enhanced the nuclear export of tax transcript. Collectively, our results demonstrate global m6A levels and m6A reader proteins YTHDF1 and YTHDC1 regulate HTLV-1 gene expression. ImportanceHuman T-cell leukemia virus type 1 (HTLV-1) persistence and pathogenesis are controlled through tight regulation of viral gene expression. The fate of RNA can be controlled by epigenetic modifications which impact gene expression without altering the DNA sequence. Our study details the impact of N6-methyladenosine (m6A) RNA chemical modifications on HTLV-1 gene expression. We found reductions in global m6A levels affected viral gene expression, decreasing Tax and other sense-derived viral genes, while increasing the antisense-derived Hbz. Our results suggest the oncogenic viral transcripts, tax and hbz, are m6A-modified in cells. We found these viral RNA modifications are interpreted by reader proteins YTHDF1 and YTHDC1, which dictate the fate of the viral RNA. Understanding HTLV-1 RNA chemical modifications offers potential insights into novel therapeutic strategies for HTLV-1-associated diseases.

molecular biology↗