The role of receptor-induced conformational changes in the capsid of feline calicivirus during virus infectious entry
Feline calicivirus (FCV) is an important pathogen of cats with an overall prevalence in the feline population of ~30%. Clinical disease caused by FCV is common and is predominantly associated with clinical signs of upper respiratory tract disease accompanied by oral and lingual ulceration. Less commonly, some isolates of FCV can cause a virulent systemic disease with high morbidity and mortality (up to 60%).
The cellular receptor for FCV is feline junctional adhesion molecule A (fJAM-A). We have shown that incubation of FCV isolates with purified soluble fJAM-A causes conformational changes in the viral capsid that increase its hydrophobicity and for some virus isolates (those associated with virulent systemic disease) cause them to lose infectivity. Our long-term goal is to understand how the interactions between FCV and its receptor control infectious virus entry, viral tropism and virulence.
We hypothesize that fJAM-A-induced conformational changes are required for infectious entry of FCV. This hypothesis is supported by our finding that incubation of some FCV isolates with the soluble ectodomain of fJAM-A neutralizes infectivity and by studies with other non-enveloped viruses that have demonstrated the importance of conformational change in the viral capsid for association with the host cell membrane and for virus uncoating. The work in this study uses an FCV isolate, FCV-5, which causes virulent systemic disease in cats and mutants of FCV-5 that differ from parental virus by being resistant to neutralization by soluble receptor.
We expect that the results of this study will provide insight into the mechanisms underlying membrane penetration and uncoating of FCV. Moreover, we further expect that this information will in part explain the increased virulence of some isolates of FCV. This information is important not only for veterinary medicine, but also for basic virology as FCV is the only member of the Caliciviridae for which a functional receptor has been identified.
This study has two specific aims:
1) Determine the capacity of purified soluble fJAM-A to mediate genome release and membrane association of WT and mutant FCV capsids. We hypothesize that fJAM-A-induced conformational changes in the FCV capsid are required for release of the genome from the capsid and/or association of the capsid with membranes.
2) Determine if capsid mutations that dramatically reduce the capacity of FCV-5 to be neutralized by soluble fJAM-A, alter the kinetics of infectious entry. We hypothesize that changes in the FCV capsid that alter its resistance to neutralization by the fJAM-A ectodomain also alter the kinetics of cellular entry.