Phospholipid Scramblase 1 (PLSCR1) Regulates Interferon-Lambda Receptor 1 (IFN-lambdaR1) and IFN-lambda Signaling in Influenza A Virus (IAV) Infection DOI Creative Commons
Alina X. Yang,

Lisa Ramos-Rodriguez,

Parand Sorkhdini

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions such as interfering with viral nuclear import, regulating toll-like receptor (TLR) 9 and potentiating the expression of other ISGs. However, exact mechanisms anti-flu activity PLSCR1 in relation to its compartment enzymatic activity, molecular cellular involved have not been completely explored. Moreover, only limited animal models studied delineate role at tissue level influenza infections. We hypothesize protects hosts against IAV infection by type 3 interferon (IFN-λ) signaling pathways. Our results showed Plscr1 was highly induced

Language: Английский

Phospholipid Scramblase 1 (PLSCR1) Regulates Interferon-Lambda Receptor 1 (IFN-λR1) and IFN-λ Signaling in Influenza A Virus (IAV) Infection DOI Open Access
Alina X. Yang,

Lisa Ramos-Rodriguez,

Parand Sorkhdini

et al.

Published: March 11, 2025

Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions such as interfering with viral nuclear import, regulating toll-like receptor (TLR) 9 and potentiating the expression of other ISGs. However, exact mechanisms anti-flu activity PLSCR1 in relation to its compartment enzymatic activity, molecular cellular involved have not been completely explored. Moreover, only limited animal models studied delineate role at tissue level influenza infections. We hypothesize protects hosts against IAV infection by type 3 interferon (IFN-λ) signaling pathways. Our results showed Plscr1 was highly induced vivo epithelial cells treated IFN-λ. found knockout (KO) mice exhibited exacerbated body weight loss, decreased survival rates, heightened replication, increased lung damage. Interestingly, transcriptomic analyses demonstrated required for (Ifn-λr1) expression, impaired Ifn-λr1 downstream ISGs may be responsible delayed clearance KO mice. In addition, interacted within following infection, suggesting modulate IFN-λ via protein-protein interactions. Finally, single-cell RNA sequencing data indicated significantly upregulated ciliated airway infection. Consistently, floxStop Foxj1-Cre + cell-specific overexpression reduced susceptibility, less inflammation enhanced research will elucidate virus-host interactions pave way development novel drugs target human elements like PLSCR1, thereby mitigating emergence drug-resistant strains.

Language: Английский

Citations

0
Phospholipid Scramblase 1 (PLSCR1) Regulates Interferon-Lambda Receptor 1 (IFN-λR1) and IFN-λ Signaling in Influenza A Virus (IAV) Infection DOI Open Access
Alina X. Yang,

Lisa Ramos-Rodriguez,

Parand Sorkhdini

et al.

Published: March 11, 2025

Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions such as interfering with viral nuclear import, regulating toll-like receptor (TLR) 9 and potentiating the expression of other ISGs. However, exact mechanisms anti-flu activity PLSCR1 in relation to its compartment enzymatic activity, molecular cellular involved have not been completely explored. Moreover, only limited animal models studied delineate role at tissue level influenza infections. We hypothesize protects hosts against IAV infection by type 3 interferon (IFN-λ) signaling pathways. Our results showed Plscr1 was highly induced vivo epithelial cells treated IFN-λ. found knockout (KO) mice exhibited exacerbated body weight loss, decreased survival rates, heightened replication, increased lung damage. Interestingly, transcriptomic analyses demonstrated required for (Ifn-λr1) expression, impaired Ifn-λr1 downstream ISGs may be responsible delayed clearance KO mice. In addition, interacted within following infection, suggesting modulate IFN-λ via protein-protein interactions. Finally, single-cell RNA sequencing data indicated significantly upregulated ciliated airway infection. Consistently, floxStop Foxj1-Cre + cell-specific overexpression reduced susceptibility, less inflammation enhanced research will elucidate virus-host interactions pave way development novel drugs target human elements like PLSCR1, thereby mitigating emergence drug-resistant strains.

Language: Английский

Citations

0
Cross one single body 49 tissues single-cell transcriptome reveals detailed macrophage heterogeneity during pig pregnancy DOI Creative Commons
Xiaoyun Chen, Chih‐Huang Lai, Liping Cai

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 2, 2025

Pregnancy involves complex physiological adaptations across maternal organs and the immune system to support fetal development. Macrophages play a dual role during pregnancy: defending against pathogens supporting tissue adaptation. However, comprehensive in-depth studies of cross-tissue transcriptional heterogeneity macrophages healthy pregnancy at single-cell level remain elusive. We performed RNA sequencing (scRNA-seq) profile from pregnant pig 49 tissues. Immunofluorescence was verify specific expression transcription factors. In this study, we generated macrophage atlas containing 114,881 tissues/organs within one single pig, identified 33 subtypes, revealed extensive tissue-specific diversity. observed significant subtypes five different anatomical sites adipose tissue. Notably, Mφ MARCO+ subtype, primarily derived mesenteric tissue, showed higher activity in pattern recognition receptor signaling pathways compared other tissues, including fat depots. Cross-tissue analysis distinct patterns factors, cytokines, cell surface receptors, factor PLSCR1, specifically expressed lung verified by immunofluorescence. Cross-species unveiled conservation among pigs, humans, mice. constructed multiple-tissue transcriptome revealing their molecular differences commonalities tissues species. Our study provides valuable resource for understanding diversity pigs.

Language: Английский

Citations

0
Phospholipid scramblase 1: a frontline defense against viral infections DOI Creative Commons
Alina X. Yang, Carmelissa Norbrun, Parand Sorkhdini

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: April 3, 2025

Phospholipid scramblase 1 (PLSCR1) is the most studied member of phospholipid protein family. Its main function to catalyze calcium (Ca 2+ )-dependent, ATP-independent, bidirectional and non-specific translocation phospholipids between inner outer leaflets plasma membrane. Additionally, PLSCR1 identified as an interferon-stimulated gene (ISG) with antiviral activities, its expression can be highly induced by all types interferons in various viral infections. Indeed, numerous studies have reported direct activities through interrupting replication processes a variety viruses, including entry severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nuclear localization influenza A virus (IAV), transactivation human immunodeficiency (HIV), Epstein-Barr (EBV), T-cell leukemia type-1 (HTLV1), cytomegalovirus (HCMV) hepatitis B (HBV). In addition these also regulates endogenous immune components defend against viruses both nonimmune cells. Such include potentiation ISG transcription, activation JAK/STAT pathway, upregulation type 3 interferon receptor (IFN-λR1) recruitment Toll-like 9 (TLR9). This review aims summarize current understanding PLSCR1’s multiple roles frontline defense

Language: Английский

Citations

0
Antecedent Flu-Like Illness and Onset of Idiopathic Dilated Cardiomyopathy: The DCM Precision Medicine Study DOI
Hanyu Ni, Jinwen Cao, Daniel D. Kinnamon

et al.

Circulation Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

BACKGROUND: Previous studies have speculated that a viral infection may act as trigger in the development of idiopathic dilated cardiomyopathy (DCM) among individuals genetically at risk. This study aims to describe frequency patients with DCM who reported experiencing symptoms flu-like illness before their diagnosis and examine if this experience modified association between genetics DCM. METHODS: We analyzed data from family-based cross-sectional Study conducted 2016 2021. Self-reported proximal were obtained patient interviews. Exome sequencing identified rare variants (pathogenic, likely pathogenic, or variant uncertain significance) genes. In case-only design, logistic mixed models used effect these on Firth regression was each 13 400 141 common autosomal (minor allele ≥1%) RESULTS: Of 1164 DCM, 30.2% diagnosis. The percentage antecedent by classification 30.0% for pathogenic/likely 29.6% significance only, no pathogenic/variant significance. Antecedent not found modify carrying any risk (interaction relative risk, 0.9 [95% CI, 0.7–1.3]). However, significant modification rs2102158 (3q24) ( P =2.74×10 − 8 ) genome-wide study. CONCLUSIONS: Approximately one-third experienced did find evidence risk; however, our analysis suggested REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

Language: Английский

Citations

0
Syntaxin-6 restricts SARS-CoV-2 infection by facilitating virus trafficking to autophagosomes DOI Creative Commons
Hao Sun, Qi Yang, Yecheng Zhang

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

ABSTRACT Despite the diminishing global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus continues to circulate and undergo mutations, posing ongoing challenges for public health. A comprehensive understanding entry mechanisms is crucial managing new epidemic strains. However, cellular processes post-endocytosis remain largely unexplored. This study employs proximity labeling examine proteins near ACE2 post-viral infection identified syntaxin-6 (STX6) as a factor that inhibits SARS-CoV-2 by impeding endocytic release virus. enhances early endosome recruitment STX6. STX6 appears hinder maturation viral particles-laden endosomes into late endosomes, from which could escape. Instead, it promotes trafficking toward autophagy-lysosomal degradation pathway. exhibits broad-spectrum effect against various variants several other viruses enter via endocytosis. We report first time function restrictive in infection. IMPORTANCE Virus step life cycle, exploitation endo-lysosome pathway has been well documented. Meanwhile, intrinsic defense present within cells interferes with entry. host restriction facilitating Notably, antiviral activity diverse employing endocytosis

Language: Английский

Citations

0
Virological characteristics of a SARS-CoV-2-related bat coronavirus, BANAL-20-236 DOI Creative Commons
Shigeru Fujita, Arnon Plianchaisuk, Sayaka Deguchi

et al.

EBioMedicine, Journal Year: 2024, Volume and Issue: 104, P. 105181 - 105181

Published: June 1, 2024

BackgroundAlthough several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences virological characteristics between SARS-CoV-2 SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat found to lack furin cleavage site (FCS) spike (S) protein. The comparison its with FCS-deleted (SC2ΔFCS) has not been conducted yet.MethodsWe prepared human induced pluripotent stem cell (iPSC)-derived airway lung epithelial cells colon organoids as organ-relevant models. B236, SARS-CoV-2, artificially generated SC2ΔFCS used for viral experiments. To investigate pathogenicity B236 vivo, we intranasal infection experiments hamsters.FindingsIn iPSC-derived cells, growth significantly lower than that SC2ΔFCS. A fusion assay showed S proteins less fusogenic experiment hamsters pathogenic even Interestingly, organoids, greater SARS-CoV-2.InterpretationCompared demonstrated exhibited tropism toward intestinal rather respiratory cells. Our results are consistent previous report showing is enterotropic macaques. Altogether, our strengthens assumption replicate primarily tissues tissues.FundingThis study supported part by AMED ASPIRE (JP23jf0126002, Keita Matsuno, Kazuo Takayama, Kei Sato); SCARDA Japan Initiative World-leading Vaccine Research Development Centers "UTOPIA" (JP223fa627001, Sato), Program on R&D new generation vaccine including modality application (JP223fa727002, Hokkaido University Institute (HU-IVReD) (JP223fa627005h0001, Takasuke Fukuhara, Matsuno); Emerging Re-emerging Infectious Diseases (JP21fk0108574, Hesham Nasser; JP21fk0108493, Fukuhara; JP22fk0108617 JP22fk0108146, Sato; JP21fk0108494 G2P-Japan Consortium, Shinya Tanaka, Terumasa Ikeda, JP21fk0108425, Takayama JP21fk0108432, Fukuhara JP22fk0108534, JP22fk0108511, Yuki Yamamoto, JP22fk0108506, HIV/AIDS (JP22fk0410055, Ikeda; JP22fk0410039, Infrastructure (JP22wm0125008 CREST (JP21gm1610005, Takayama; JP22gm1610008, JST PRESTO (JPMJPR22R1, Jumpei Ito); (JPMJCR20H4, JSPS KAKENHI Fund Promotion Joint International (International Leading Research) (JP23K20041, SPRING (JPMJSP2108 Shigeru Fujita); Grant-in-Aid Scientific C (22K07103, Ikeda); B (21H02736, Fukuhara); Early-Career Scientists (22K16375, 20K15767, Core-to-Core (A. Advanced Networks) (JPJSCCA20190008, Fellow DC2 (22J11578, Keiya Uriu); DC1 (23KJ0710, Yusuke Kosugi); Excellent Young Researchers (LEADER) (to Innovative Smart Education (WISE) 1801 Ministry Education, Culture, Sports, Science Technology (MEXT) Naganori Nao); Health, Labour Welfare (MHLW) under grant 23HA2010 Nao Cooperative (Joint Usage/Research Center program) Life Medical Sciences, Kyoto Project Science, Tokyo Ikeda Biochemical Foundation Takeda Mochida Memorial Pharmaceutical Naito Hokuto Bioscience Tomokazu Tamura); Hirose Mitsubishi Sato).

Language: Английский

Citations

3
Restriction factors regulating human herpesvirus infections DOI
Manutea Serrero, Søren R. Paludan

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(9), P. 662 - 677

Published: Aug. 27, 2024

Language: Английский

Citations

2
An ultra-early, transient interferon-associated innate immune response associates with protection from SARS-CoV-2 infection despite exposure DOI Creative Commons
Joe Fenn, Kieran J Madon, Emily Conibear

et al.

EBioMedicine, Journal Year: 2024, Volume and Issue: 111, P. 105475 - 105475

Published: Dec. 11, 2024

Language: Английский

Citations

2
Pre-existing interferon gamma conditions the lung to mediate early control of SARS-CoV-2 DOI Open Access
Kerry L. Hilligan, Sivaranjani Namasivayam, Chad S. Clancy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 17, 2023

Abstract Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs typically associated with early control of viral replication promotion inflammatory immune responses; however, less is known about the role IFNγ in immunity, particularly context SARS-CoV-2. We have previously observed that lung infection attenuated bacteria Mycobacterium bovis BCG achieved though intravenous ( iv ) administration provides strong protection against SARS-CoV-2 (SCV2) disease two mouse models. Assessment pulmonary cytokine milieu revealed induces a robust response low levels IFNβ. Here we examined ongoing responses due to pre-established bacterial on SCV2 outcomes murine report required induced reduction loads this outcome dependent receptor expression by non-hematopoietic cells. Further analysis promotes upregulation interferon-stimulated genes (ISGs) reported activity pneumocytes bronchial epithelial cells an IFNγ-dependent manner, suggesting possible mechanism protection. Finally, confirmed importance these effects demonstrating recombinant itself challenge when administered intranasally. Together, our data show within protective infection, concurrent or recent infections drive may limit pathogenesis supporting prophylactic uses COVID-19 management.

Language: Английский

Citations

4