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The infamous avian influenza virus, strain H5N1, forms tiny tubules within which it secretes the double-stranded RNA it forms during the infection process. These tubules hide the dsRNA from the immune system of the host's infected cells, according to researchers at Baylor College of Medicine. The research could lead to new drug leads against a putative avian flu epidemic. Baylor biochemist Venkataram Prasad and former post-doctoral student Zachary Bornholdt (now at the Scripps Research Institute in La Jolla, California), explain that several studies have highlighted how a non-structural protein NS1 seems to be associated with increased pathogenicity and virulence of the H5N1 and related strains. "NS1, which consists of two domains-a double-stranded RNA (dsRNA) binding domain and the effector domain, separated through a linker-is an antagonist of antiviral type-I interferon response in the host," they explain. Understanding its mode of action has until now remained elusive. In a previous report, Prasad and Bornholdt described the structure of an area of the protein called the effector domain. The team has now developed a way to crystallise NS1 to make it amenable to X-ray crystallography. The result is that they have determined the structure of two domains of the full-length NS1, which combines to form these tiny tubules from the lethal A/Vietnam/1203/2004 strain that was linked to almost two-thirds of the 36 deaths in an outbreak in China, Thailand, and Vietnam. They found a tubular oligomeric NS1 with a 20Å-wide channel is formed. The team augmented their XRD results with cryo-electron microscopy. This tubule, Prasad says, provides a plausible site within which varying lengths of double-stranded RNA might be secreted. The formation of tubules as the two domains of NS1 in H5N1 wrap together was a previously unsuspected characteristic of virulence that essentially hides the viral RNA and prevents the release of interferon by the host's immune system, which would otherwise inhibit viral replication. "Once we confirm the importance of this structural information, we should be able to design drugs to block this action," explains Prasad. "There are other things the protein could do to interfere with different immune mechanisms. We don't know if this is the only mechanism or if there are others that also come into play during influenza virus infection." Indeed, Prasad and Bornholdt also believe that cellular factor binding sites found on the surface of the tubules play a role in deceiving the immune system. This is only one structure after all, concedes Prasad, "We now need to see if this holds up with other NS1 structures from other influenza viruses." Bornholdt's technique for crystallizing the protein will prove valuable in pursuing this work, he adds. He asks whether this is a common mechanism used by such viruses to elude the immune system's defences. If it is, then Prasad hopes to build a library of NS1 structures to facilitate future studies designed to fight influenza worldwide. Currently, H5N1 is not a human transmissible virus, but some researchers suggest that it could at some point in the future undergo an exchange of genetic information with strains that are. This might flip the biomolecular switch enabling human-to-human infection and with the assistance of international airtravel and virally permeable border controls help spread the disease rapidly across the globe. Others suggest that the transition to a human transmissible form might reduce overall virulence. Nevertheless, it is worth pursuing leads for drugs that can inhibit the unique characteristics of H5N1 as it might remain our best pharmaceutical defence against the disease regardless of the relative virulence. Related links:
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Prasad, tubular research could save us from flu flap |
