Productive Replication of Ebola Virus Is Regulated by the c-Abl1 Tyrosine Kinase

Ebola virus growth is regulated by a c-Abl tyrosine kinase, which modulates the viral protein VP40, and can be blocked by c-Abl antagonists. Disabling Ebola virus Ebola virus causes severe, often fatal, hemorrhagic fever in humans and is well known for its fulminant replication that ultimately overwhelms the capacity of the human immune system to contain it. Because it is easily transmitted from one human to another and causes high mortality, Ebola virus has been classified as a category A agent, the highest-priority biological threat classification. There are no effective prophylactic or therapeutic interventions available to treat infections with Ebola virus or another highly pathogenic filovirus, Marburg virus. Information about mechanisms of assembly and release of these viruses will be crucial for developing effective countermeasures. Viruses exploit a variety of components within the host cell to complete their life cycles. In a new study, García et al. show that the growth of Ebola virus is regulated by the c-Abl1 tyrosine kinase. They demonstrate that release of Ebola virus–like particles in a cell culture cotransfection system could be blocked by c-Abl1–specific small interfering RNAs (siRNAs) or by Abl-specific kinase inhibitors such as nilotinib. They show that this effect is mediated by tyrosine phosphorylation of the Ebola matrix protein VP40. The researchers identified at least one site of tyrosine phosphorylation (Y13) on VP40 and demonstrated that mutation of this residue reduced release of Ebola virus–like particles. The drug nilotinib or siRNAs directed against c-Abl1 also reduced productive replication of the Zaire strain of Ebola virus in cultured Vero cells by up to four orders of magnitude. Together, these data indicate that the c-Abl1 tyrosine kinase regulates budding or release of Ebola virus through a mechanism involving phosphorylation of VP40. The authors propose that this critical interaction between a viral and a host cell protein represents a target for antiviral therapy. These findings suggest that drugs such as nilotinib that inhibit c-Abl1 and are already in clinical use as anticancer therapeutics may be useful for reducing the severity of Ebola virus infection. Ebola virus causes a fulminant infection in humans resulting in diffuse bleeding, vascular instability, hypotensive shock, and often death. Because of its high mortality and ease of transmission from human to human, Ebola virus remains a biological threat for which effective preventive and therapeutic interventions are needed. An understanding of the mechanisms of Ebola virus pathogenesis is critical for developing antiviral therapeutics. Here, we report that productive replication of Ebola virus is modulated by the c-Abl1 tyrosine kinase. Release of Ebola virus–like particles (VLPs) in a cell culture cotransfection system was inhibited by c-Abl1–specific small interfering RNA (siRNA) or by Abl-specific kinase inhibitors and required tyrosine phosphorylation of the Ebola matrix protein VP40. Expression of c-Abl1 stimulated an increase in phosphorylation of tyrosine 13 (Y13) of VP40, and mutation of Y13 to alanine decreased the release of Ebola VLPs. Productive replication of the highly pathogenic Ebola virus Zaire strain was inhibited by c-Abl1–specific siRNAs or by the Abl-family inhibitor nilotinib by up to four orders of magnitude. These data indicate that c-Abl1 regulates budding or release of filoviruses through a mechanism involving phosphorylation of VP40. This step of the virus life cycle therefore may represent a target for antiviral therapy.