Abstract
Rabies virus (RABV) causes a fatal neurological disease in both humans and animals. Understanding the mechanism of RABV infection is vital for prevention and therapy of virulent rabies infection. Our previous proteomics analysis based on isobaric tags for relative and absolute quantitation to identify factors revealed that RABV infection enhanced AP-2-associated protein kinase 1 (AAK1) in N2a cells. In this study, to further confirm the role of AAK1, we showed that RABV infection increased the transcription and expression of AAK1 in N2a cells. AAK1 knockdown significantly decreased RABV infection in both N2a and BHK-21 cells. AAK1 knockout inhibited RABV infection in N2a cells. Furthermore, inhibition of AAK1 kinase activity using sunitinib decreased RABV infection. However, AAK1 overexpression did not change RABV infection in vitro. Therapeutic administration of sunitinib did not significantly improve the survival rate of mice following lethal RABV challenge. In addition, AAK1 knockdown decreased infection in N2a cells by vesicular stomatitis virus, which is another rhabdovirus. These results indicate that rhabdovirus infection is dependent on AAK1 and inhibition of AAK1 is a potential strategy for the prevention and therapy of rabies.
Highlights
Rabies, which is caused by rabies virus (RABV), is an ancient zoonosis of the central nervous system (CNS) that causes more than 55,000 human deaths each year [1]
Our previous study showed that rabies viruses (HEP-Flury strain and rHEP-dG strain) proliferation increased associated protein kinase 1 (AAK1) expression in N2a cells by isobaric tags for relative and absolute quantitation (iTRAQ) protein profile analysis [27]
N2a cells were infected with Rabies virus (RABV) rHEP-GFP, which carries a green fluorescent protein gene between the N and P genes [29], to investigate the expression of AAK1
Summary
Rabies, which is caused by rabies virus (RABV), is an ancient zoonosis of the central nervous system (CNS) that causes more than 55,000 human deaths each year [1]. There is no treatment for RABV infection once symptoms of the disease have become evident. Rabies can be averted by effective and timely post exposure treatment, consisting of rabies vaccination and serotherapy [2]. Rabies immune globulin used for PEP is expensive, so many people in developing countries cannot afford it. PEP has occasionally failed to prevent rabies-related deaths because of nonstandard and delayed treatment. Alternative approaches to the treatment of rabies are urgently required. RABV is a negative-stranded RNA virus in the genus Lyssavirus of the family
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