Senior Scholar Award in Global Infectious Disease
Alexander Rich, M.D.
Massachusetts Institute of Technology

Viral Pathogenic Mechanisms Involving Z-DNA Binding Proteins

When a virus infects a mammal, a number of different processes occur that determine the success of the viral infection. The host (sometimes a human) immediately mounts an anti-viral response, creating a number of substances that are designed to disarm the virus and prevent it from replicating or producing materials that harm the host. However, the virus has had a long history of attacking mammals, and it has developed many mechanisms that work to disarm the defenses of the host cell. At the molecular level an intense form of warfare exists between virus and host.

Recently, this laboratory has uncovered a new mechanism that is used by poxviruses such as vaccinia or its cousin variola, the agent of smallpox. This mechanism is used by the virus to disarm the host cell. When the host cell manufactures proteins used for fighting the infection, it turns on genes that are found in its DNA. When genes express proteins, a segment of the DNA is often twisted into a left-handed fold, as opposed to normal, relaxed DNA which twists in a right-handed manner. The segments of DNA that twist left-handed are often near the beginnings of genes. These viruses have discovered that if they make proteins that bind to these left-handed-twisting segments, they can block the host cell from synthesizing some of the proteins used to fight infection.

The question we are asking in this research is whether this mechanism, which was identified in poxviruses, is also found in other viral systems. We will analyze other viruses to see if they make some proteins that bind to left-handed-twisting DNA since they may also act to prevent the host from responding to the infection. Uncovering these proteins will be of great value as they can then be used as targets, that is, drugs can then be developed that attach to the proteins, preventing them from binding to the left-handed DNA molecules. In this way the host defense machinery is not blocked, and it can then mount an effective response against the virus. This may result in the development of new therapies for viral diseases.