Gene editing of pigs to control influenza A virus infections.

Autor:	Kwon T; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA., Artiaga BL; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA., McDowell CD; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA., Whitworth KM; Division of Animal Science & National Swine Resource and Research Center, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, Columbia, MO 65211, USA., Wells KD; Division of Animal Science & National Swine Resource and Research Center, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, Columbia, MO 65211, USA., Prather RS; Division of Animal Science & National Swine Resource and Research Center, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, Columbia, MO 65211, USA., Delhon G; School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA., Cigan M; Genus plc, DeForest, WI, USA., White SN; Genus plc, DeForest, WI, USA., Retallick J; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA., Gaudreault NN; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA., Morozov I; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA., Richt JA; Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 16. Date of Electronic Publication: 2024 Jan 16.
DOI:	10.1101/2024.01.15.575771
Abstrakt:	Proteolytic activation of the hemagglutinin (HA) glycoprotein by host cellular proteases is pivotal for influenza A virus (IAV) infectivity. Highly pathogenic avian influenza viruses possess the multibasic cleavage site of the HA which is cleaved by ubiquitous proteases, such as furin; in contrast, the monobasic HA motif is recognized and activated by trypsin-like proteases, such as the transmembrane serine protease 2 (TMPRSS2). Here, we aimed to determine the effects of TMPRSS2 on the replication of pandemic H1N1 and H3N2 subtype IAVs in the natural host, the pig. The use of the CRISPR/Cas 9 system led to the establishment of homozygous gene edited (GE) TMPRSS2 knockout (KO) pigs. Delayed IAV replication was demonstrated in primary respiratory cells of KO pigs in vitro . IAV infection in vivo resulted in significant reduction of virus shedding in the upper respiratory tract, and lower virus titers and pathological lesions in the lower respiratory tract of TMPRSS2 KO pigs as compared to WT pigs. Our findings could support the commercial use of GE pigs to minimize (i) the economic losses caused by IAV infection in pigs, and (ii) the emergence of novel IAVs with pandemic potential through genetic reassortment in the "mixing vessel", the pig. Competing Interests: Competing interests The J.A.R. laboratory received support from Tonix Pharmaceuticals, Genus plc, Xing Technologies, and Zoetis, outside of the reported work. J.A.R. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by Kansas State University. M.C and S.N.W were employees of Genus plc. Other authors declare no competing interests.
Databáze:	MEDLINE
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