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Yang, Jiayun (2021) Comparison of host innate immune response of human and porcine airway epithelial cells and anti-influenza exploitation. PhD thesis, University of Nottingham.

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Abstract

Influenza A virus (IAV) infection is a major global disease that continues to threaten wildlife, livestock production and human health. In humans, IAV infection can be severe leading to the complication of host hyperacute inflammatory response, also known as ‘cytokine storm’, with ensuing high mortality rate. Pigs infected with IAVs, however, often display no or only mild symptoms. Viral RNA is principally recognised by pattern-recognition receptors retinoic inducible gene-1 (RIG-I) and Toll-like receptor 7/8 (TLR 7/8), each of which signals to activate two key transcription factors, nuclear factor kappa B (NF-ĸB) and interferon regulatory factor 3 (IRF3), for the induction of pro-inflammatory cytokines and type I interferons (IFNs), respectively. To examine possible host-species differences in NF-ĸB function, we compared the antiviral role of NF-κB between pig and human primary and immortalised respiratory epithelial cells infected with IAV. Activation of NF-κB in pig cells significantly inhibited IAV replication and induced strong type I IFN associated gene response. In human cells, however, activation of NF-κB had limited effects on IFN associated response and IAV replication. Microarray RNA profiling comparison indicated that basal transcriptional activity of NF-κB associated genes in primary normal human bronchial (NHBE) cells was more active than corresponding genes in primary pig tracheal epithelial cells (PTECs). In particular, TNFRSF1A, a key upstream gene of NF-κB signalling, was found to be highly expressed in NHBE cells. Knockdown of TNFRSF1A in NHBE cells blocked IAV replication, but in PTECs had no effect on virus output. Overexpression of TNFRSF1A in PTECs increased IAV progeny production, but in NHBE cells had limited effect on virus output.

Aspirin, also known as acetylsalicylic acid (ASA), has been extensively used as an antiviral drug against influenza virus infection during the 1918 H1N1 virus pandemic. The antiviral mechanism of ASA is believed to be through the inhibition of NF-κB activity in sereral human cell lines. We, however, found that ASA in PTECs increased NF-κB activity to block the transcription of IAV; whereas ASA in NHBE cells reduced virus-induced apoptosis to block IAV replication at a post-translational level. Thus, ASA inhibits IAV replication by different mechanisms in PTECs and NHBE cells. Taken together, host species basal activity of NF-κB associated genes appears to be a key determinant of antiviral response to infection, such that the relatively low basal activity of NF-κB associated genes (as seen in pig cells) confers a strong antiviral response to NF-κB activation, whereas high basal NF-κB associated gene activity (as seen in human cells) is much less responsive to activated NF-κB.

The management of IAV infection with antivirals is limited by efficacy and development of virus resistance. In this study, ledene, a naturally occurring sesquiterpene from the Australian tea tree, was found to block IAV replication efficiently. Ledene inhibited IAV replication without affecting viral mRNA and protein expression, indicating that the inhibition occurs post-translationally. The selective index (SI), an in vitro indicator of efficacy and safety, of ledene was 791, which is higher than that of oseltamivir (SI=10), suggesting that ledene could potentially be more effective than oseltamivir as an antiviral.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Chang, Kin-Chow Kydd, Julia Mellits, Kenneth
Keywords:	Influenza A virus, Innate immunity, Anti-influenza therapy
Subjects:	S Agriculture > SF Animal culture
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	66730
Depositing User:	Yang, Jiayun
Date Deposited:	31 Dec 2021 04:41
Last Modified:	31 Dec 2021 04:41
URI:	https://eprints.nottingham.ac.uk/id/eprint/66730

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