Cell Death Inhibition by African Swine Fever Virus
Programmed cell death or apoptosis is an important physiological process to remove damaged or unwanted cells during tissue homeostasis, adaptive immunity and embryonic cell differentiation. In addition, apoptosis has also been recognized as a major defense mechanism to combat viral infections. Deregulation of apoptosis can lead to cancer, autoimmune disease and viral infections. The Bcl-2 family of proteins is the major group of regulatory proteins of apoptosis via the intrinsic pathway, with the interplay between the different pro and anti-apoptotic Bcl-2 family members ultimately deciding whether or not a cell will live or die. Viruses have evolved molecular mimics of cellular pro-survival Bcl-2 proteins, which they use to subvert the apoptotic pathway and prevent premature host cell death. This ultimately creates a sufficiently large time window for the virus to replicate, and for viral progeny to escape the host cell and infect new cells. A179L is a virulence protein expressed by African Swine Fever Virus (ASFV) that has been shown to modulate host cell apoptosis, however the molecular and structural basis for its anti-apoptotic activity remains to be clarified. Due to the unavailability of treatment and vaccines, the livestock industries in ASFV affected countries bear tremendous amounts of economic losses during outbreaks. Consequently an improved understanding of ASFV would be of significant benefit to the agricultural industry. This research aims to understand the molecular and structural mechanisms employed by ASFV to circumvent the natural apoptotic defenses of the host for its own benefit. For this purpose we characterize A179L biochemically and biophysically using X-ray crystallography and site directed mutagenesis to decipher the molecular basis of action of this important virulence factor.