Gene editing of pigs to control influenza A virus infections

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,...

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Bibliographic Details
Published in:bioRxiv 2024-01
Main Authors: Kwon, Taeyong, Artiaga, Bianca L, McDowell, Chester D, Whitworth, Kristin M, Wells, Kevin D, Prather, Randall S, Delhon, Gustavo, Cigan, Mark, White, Stephen N, Retallick, Jamie, Gaudreault, Natasha N, Morozov, Igor, Richt, Juergen A
Format: Article
Language:English
Subjects:
Antiviral agents
Avian flu
CRISPR
Hemagglutinins
Hogs
Infectivity
Influenza
Influenza A
Pandemics
Patent applications
Proteolysis
Replication
Respiratory tract
Serine proteinase
Trypsin
Viruses
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Summary: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) knockout (KO) pigs. Delayed IAV replication was demonstrated in primary respiratory cells of KO pigs . IAV infection 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 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.
ISSN:2692-8205
2692-8205
DOI:10.1101/2024.01.15.575771