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Title: Assessment of the potential of a narrow spectrum kinase inhibitor in the treatment of influenza infection
Author: Ashcroft, Jonathan William
ISNI:       0000 0004 6059 1180
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Severe outcome following influenza infection has been linked to the over induction of the host innate immune response resulting in a 'cytokine storm'. In certain patient populations, a therapeutic approach to help control the innate immune response may be of benefit. However concerns have been expressed that suppression of the host immune response might also lead to an increase in virus replication and directly enhance viral induced pathology. Using cultures of primary well-differentiated human airway epithelium (HAEs), the ability of a small molecule, narrow spectrum kinase inhibitor, developed by RespiVert (RV1088) to inhibit the extent of influenza virus induced expression of an array of human cytokines including IL6, IL8, IP10, and RANTES was investigated. The virus-induced response following infection with influenza virus was found to be diminished at the mRNA and protein level in the presence of the drug. Importantly, drug treatment did not adversely increase viral replication. In contrast, treatment with a steroid did not suppress the cytokine/chemokine response and resulted in increased viral titres. RV1088 inhibited the viral induction of transcription from the interferon promoter acting at or below the level of MAVS, preventing nuclear translocation of both IRF-3 and NFkB. Used alone, RV1088 inhibited cytokine production by all currently circulating subtypes and lineages of influenza A and B virus. Used in combination with currently licenced antivirals, the virus titre released from HAE cells was suppressed even further than for either drug alone, suggesting a synergistic antiviral effect. Finally, a novel murine model of influenza infection using nebulized virus to infect the mouse airways was developed. Drug also administered through the nebulised route suppressed the interferon response in the mouse lung and did not result in increased viral lung titre or weight loss. Administered intranasally with or without Relenza to mice infected with pH1N1 2009 virus, RV1088 suppressed interferon levels in mouse lung and reduced weight loss and mortality. This, or similar molecules, may represent a new generation of compounds suitable for the treatment of respiratory virus infections.
Supervisor: Barclay, Wendy Sponsor: RespiVert (Firm)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral