Rabies Vulnerability Unlocked by Molecular Science

UAB Researchers Target Virus’s Replication Shield

A silent threat, rabies infiltrates the body through a bite or scratch, often proving fatal once symptoms manifest. This dangerous virus, present even in regions like Alabama, poses a significant public health challenge due to its intricate molecular defenses that make effective treatment incredibly difficult after initial infection.

Targeting the Virus’s Engine

For over three decades, structural biologist and virologist Todd Green, Ph.D., has dedicated his research to understanding the viral proteins crucial for rabies replication. His work at the University of Alabama at Birmingham (UAB) Department of Microbiology aims to identify vulnerabilities in the virus’s complex machinery, paving the way for novel therapeutics to combat outbreaks before they escalate.

Rabies, along with other negative-strand RNA viruses (NSVs), exhibits a replication cycle distinct from many viruses. These NSVs depend on specific surface proteins for cellular interaction and unique enzymes to direct transcription and replication. A key characteristic is the tight binding of their genetic material to nucleocapsid (N) proteins, forming a complex that serves as the blueprint for viral multiplication.

“The rabies virus and all negative-strand RNA viruses, or NSVs, have distinctive replication cycles. They rely on surface proteins that interact with various cell types and unique enzymes that drive transcription and replication.”

—Todd Green, Ph.D., Associate Professor, UAB Department of Microbiology

This process requires the virus to first transcribe its genetic material into messenger RNA before producing proteins. Dr. Green suggests this early stage offers a critical window for intervention, potentially leading to the development of antivirals specifically designed to halt replication, rather than relying on broad-spectrum treatments.

Unmasking a Key Weakness

A significant vulnerability has emerged from decoding the rabies virus’s replication pathway: a specialized polymerase enzyme essential for its survival and proliferation. Unlike other viruses, NSVs like rabies depend on this enzyme to generate messenger RNA and duplicate their genetic material.

“Two unique features of the polymerase are that it recognizes a protein-RNA complex as the viable template for both transcription and replication, and polymerases of NSVs have a different mechanism for capping viral mRNA,” Dr. Green explained. “Capping is necessary for the stability of mRNA and efficient translation of mRNA to protein.”

The polymerase possesses a distinct region that performs this capping function through a process separate from human cellular mechanisms. This molecular insight provides a promising target for developing antiviral drugs that can disrupt the virus without harming host cells.

Pioneering Research at UAB

UAB has been instrumental in advancing NSV research, with former faculty members Gail Wertz, Ph.D., and Andrew L. Ball, Ph.D., pioneering reverse genetics systems for NSVs in the late 1980s and early 1990s. These tools revolutionized the study of viral behavior by enabling targeted modifications to viral genomes.

“My work has focused on the structural biology of two related rhabdoviruses: vesicular stomatitis virus, or VSV, and rabies virus,” stated Dr. Green. He collaborated with the late Ming Luo, Ph.D., to determine the structure of the VSV nucleocapsid protein bound to RNA and subsequently studied its interaction with the phosphoprotein.

Dr. Green‘s laboratory has since defined crucial parts of the polymerase structure and developed models for polymerase complexes in VSV and rabies viruses. This extensive research has meticulously mapped the structures and interactions of all major viral proteins, significantly deepening the understanding of how these viruses assemble, replicate, and transcribe their genetic information.

The department continues to build on this foundational work, expanding its influence in viral research and antiviral development. According to the Centers for Disease Control and Prevention (CDC), the United States averages fewer than three human rabies cases annually, largely due to effective post-exposure prophylaxis and animal vaccination programs, but global efforts remain critical (CDC).

“By studying the detailed molecular makeup of viruses, researchers in our department can illuminate new paths for targeted antiviral therapies. Their studies on virus replication mechanisms and structural vulnerabilities offer hope for the possible development of future treatments that could transform once-untreatable threats into preventable diseases.”

—J. Victor Garcia-Martinez, Ph.D., CPC, Charles H. McCauley Endowed Chair in Microbiology

This deep dive into the intricate molecular architecture of viruses offers promising avenues for developing targeted antiviral therapies. The ongoing research into viral replication mechanisms and structural weaknesses at UAB provides a hopeful outlook for future treatments that could convert currently formidable threats into manageable, preventable conditions.