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Title: Unique and overlapping actions of Type I and III IFNs in influenza A virus infection and implications for therapy
Author: Davidson, Sophia Kate
ISNI:       0000 0004 7966 0027
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2016
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Influenza A virus (IAV) poses a significant public health burden. Severe disease is characterised by infected lung airway epithelial cells (AECs), inflammation and tissue damage. However, disease severity differs between individuals and this cannot be entirely explained by inter-individual differences in pre-existing immunity or comorbidities. Host-specific, genetically determined factors must contribute to susceptibility. Type I interferon (IFNαβ) is known to have antiviral function in vitro, but its role in restricting IAV infection in vivo is controversial. We demonstrate that responsiveness to IFNαβ signalling is a host-specific determinant with protective or pathogenic potential which determines the severity of IAV-induced disease. IAV infected 129, CBA/J and DBA mouse strains showed dramatically increased mortality and lung damage, yet higher levels of pulmonary IFNαβ, compared to C57BL/6 or BALB/C mice. Ablation of IFNαβR signalling in 129 mice markedly reduced mortality, levels of proinflammatory cytokines, inflammatory cell recruitment and AEC apoptosis. Susceptibility to IAV-induced disease is influenced by the number of functional alleles for the IFNαβR subunit, IFNAR1, within the genome. IFNAR1+/-(129) mice were less susceptible than wild type 129s yet more so than IFNαβR-/-(129) mice. Conversely, triplication of a section of murine chromosome 16 that includes IFNAR1 in C57BL/6 mice enhanced IFNα response to IAV infection and downstream immunopathology. Finally, IFNα therapy of infected B6. A2G-Mxl mice reduced IAV titers, yet increased secretion of proinflammatory cytokines, innate cell recruitment and AEC apoptosis in the lung, due to the potent immunostimulatory capability to IFNα. In contrast, treatment with IFNλ, whose receptor is largely restricted to AECs, promoted IAV control without exacerbating IAV-induced inflammation. Thus, by manipulating the IFNαβ signal in various ways, we demonstrate that excessive IFNαβ in IAV infection can increase AEC death and enhance proinflammatory responses that ultimately increase disease severity. Our findings have important implications for prediction and treatment of severe influenza.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral