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Title: Alterations in the expression of CCSP and SPLUNC1 in the respiratory tract following viral infection of murine models
Author: Leeming, Gail
ISNI:       0000 0004 2712 3166
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2010
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Murid herpesvirus 4 (MHV-68) has been widely studied as a model of gammaherpesvirus infection. Infection of Apodemus sylvaticus, a natural host for MHV-68, revealed that a virally-encoded chemokine binding protein (M3) influences the composition of the perivascular and peribronchiolar inflammatory infiltration and the formation of BALT in the lung during lytic infection. In addition, host genes were identified which were expressed at higher levels in the presence of MHV-68 M3 at 14 days post infection (dpi), including Clara cell secretory protein (CCSP), Short palate lung and nasal epithelium clone 1 (SPLUNC1) and Anterior gradient 3 (AGR3). The aim of this work was to further investigate the expression of these genes and their corresponding proteins in relation to respiratory viral infection. CCSP and SPLUNC1 have previously been shown to have antiinflammatory properties in models of virus, bacteria and allergen induced inflammation. AGR3 is thought to be homologous to AGR2, which is associated with the transition of Clara cells to mucous cells in the lung. Following MHV-68 infection in A. sylvaticus, levels of both CCSP and SPLUNC1 were reduced in the bronchioles at 7 dpi and increased at 14 dpi, compared to mock-infected controls. In the absence of M3, the level of CCSP was reduced compared to wild type MHV-68 infected animals at both timepoints, whereas no significant difference in the expression of SPLUNC1 in the bronchioles was present. The regulation of both of these genes has previously been associated with interferon γ (IFNγ); infection of 129 wild type and IFNγR-/- mice revealed that CCSP expression was increased and SPLUNC1 expression decreased in the presence of IFNγ. However, this effect was smaller than that due to MHV-68 infection. Expression of AGR3 in the respiratory tract was increased in response to MHV-68 infection, whereas AGR2 was decreased. To investigate whether these effects were specific to MHV-68, infection with other respiratory viruses, with different cellular tropisms in the respiratory tract were examined in BALB/c mice. Infection with Human respiratory syncytial virus, Sendai virus and several strains of Influenzavirus A led to a decrease in both CCSP and SPLUNC1 expression during acute infection, when this was associated with a significant inflammatory response in the lung. The findings of this work showed that CCSP and SPLUNC1 are constitutively expressed in the non-ciliated cells of the respiratory epithelium and support the hypothesis that they have an antiinflammatory role in the lung. Expression of both proteins is reduced in the event of acute viral infection resulting in significant inflammation. In MHV-68 infection of A. sylvaticus, increased expression of CCSP and SPLUNC1 at later timepoints suggests that these proteins are implicated in the resolution of the inflammatory response.
Supervisor: Kipar, Anja ; Stewart, James Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: SF Animal culture