Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry.

Autor:	Stearns K; Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Department of Physiology & Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Lampe G; Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Hanan R; Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Marcink T; Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Niewiesk S; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA., Sternberg SH; Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Greninger AL; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Porotto M; Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Caserta, Italy., Moscona A; Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Department of Physiology & Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.; Department of Microbiology & Immunology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2024 Nov 13; Vol. 15 (11), pp. e0232724. Date of Electronic Publication: 2024 Oct 09.
DOI:	10.1128/mbio.02327-24
Abstrakt:	Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo , reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread. Importance: Enveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection. Competing Interests: K.S., M.P., and A.M. are listed as inventors on a provisional patent related to the work in this article.
Databáze:	MEDLINE
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