Jobe, Fatoumatta (2021) Bovine respiratory syncytial virus modulation of NF-κB p65 mediated innate immune responses. PhD thesis, University of Warwick.

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Abstract

Respiratory syncytial viruses of humans (hRSV) and animals (bovine, bRSV) are the leading cause of lower respiratory tract infections – bronchiolitis and pneumonia – in their respective hosts. They pose serious health risks to young calves, children under 5, the elderly and immunocompromised. RSV is an enveloped, single-stranded negative-sense RNA virus taxonomically classified within the Orthopneumovirus genus in the Pneumoviridae family. The only available treatment option for hRSV is monoclonal antibody based immunoprophylaxis. There is no approved vaccine for hRSV, while bRSV vaccines are of varying effectiveness.

RSV can suppress the host immune response and prevents the generation of long-term immunity. RSV encodes two accessory proteins (NS1 and NS2) which are well established to block interferon signalling. Previous studies have also shown that the viral SH protein plays a role in pathogenesis by inhibiting the NF-κB pathway, an important regulator of the host innate immune response. However, the exact mechanisms employed are less well characterised. We aimed to understand the role of the RSV SH protein and found that expression reduced NF-κB signalling at the level of both IκBα degradation and subunit p65 nuclear translocation, when wild type virusinfected cells were compared to cells infected with viruses lacking SH expression. However, the differences were minimal, especially when NF-κB transactivation was assessed in cells ectopically expressing SH in the absence of all other viral proteins.

Interestingly however, during these experiments we identified separate RSV-mediated antagonism of the NF-κB pathway, with a mechanism entirely distinct from the NS1, NS2 and SH proteins. In both hRSV and bRSV infected cells we demonstrated that the p65 subunit of NF-κB is sequestered to perinuclear viral inclusion bodies (IBs). These were formed in the cytoplasm of RSV infected cells and were separately confirmed as the sites of viral RNA replication and synonymous with viral inclusion bodies. We also found that captured p65 is unable to translocate to the nucleus following TNF-α stimulation, highlighting the antagonistic nature of this event.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QP Physiology Q Science > QR Microbiology > QR355 Virology S Agriculture > SF Animal culture
Library of Congress Subject Headings (LCSH):	Respiratory syncytial virus, Natural immunity, Cattle -- Infections, NF-kappa B (DNA-binding protein)
Official Date:	April 2021
Dates:	Date Event April 2021 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	School of Life Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Bailey, Dalan
Format of File:	pdf
Extent:	xiv, 184, 1-21 leaves : illustrations
Language:	eng

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