NIAID-NCATS Collaboration Identifies Potential Viral Treatment

NIAID-NCATS Collaboration Identifies Potential Viral Treatment
Screened from 3,800 Compounds, Rottlerin Found to Inhibit LACV

Note: a similar version of this blog appears in Nature’s Microbiology blog.

Outside of the preventive measure of vaccination, there are ony limited methods or therapeutics for treating viral infections. Indeed, for viruses that infect the central nervous system and cause encephalitis, the main treatment is palliative care: providing comfort, hydration and pain relief. Thus, there is an urgent need to develop, identify, and validate drugs that can inhibit virus infection or suppress virus replication.

A key source for identifying new antivirals is screening existing drugs for their ability to inhibit the virus of interest. A new NIAID study published in Nature Microbiology involved screening thousands of drugs through a collaboration with the Therapeutic Development Branch at NIH’s National Center for Advancing Translational Sciences (NCATS). The study, from the laboratory of Dr. Karin Peterson at NIAID’s Rocky Mountain Laboratories, aimed to determine whether any existing drugs would inhibit La Crosse virus (LACV) and potentially could be repurposed. LACV is transmitted by mosquitos and is the primary cause of arboviral pediatric encephalitis in the United States. LACV was first isolated in the early 1960s near La Crosse, Wisconsin. Since then, LACV encephalitis cases have been found in more than 20 states, mostly in the basins of the Mississippi and Ohio rivers.
 
The virus also is something familiar to Dr. Peterson, who grew up in Wisconsin and at some point was infected with the virus – her case was asymptomatic, though she carries antibodies to the virus.

The NCATS collaboration allowed scientists to screen 3,833 FDA-approved drugs and small molecules. Vital to the project was technology that provided easy-to-read “colorimetrics,” a fluorescent readout showing cells that survive viral infection.

After the group’s initial screen, 38 compounds showed some level of viral inhibition. Further analysis narrowed the field to 10 compounds, and finally to three selected for further validation. Only one of these, Rottlerin, consistently inhibited LACV-induced cell death and virus replication in human and mouse neuronal cell lines. Rottlerin is a natural compound isolated from the Kamala tree.

To determine if Rottlerin was effective at inhibiting LACV in a more complex model, the scientists used human cerebral organoids, which contain neurons in different stages of development. This allowed the group to test whether Rottlerin could inhibit LACV infection and neuron death in an environment with cell-to-cell contact between neurons.

The most important aspect for any therapeutic drug is whether it helps at the stage of a virus being present and causing damage to an organ or tissue. With most encephalitic viruses, disease is not detected or diagnosed until after the virus already has entered the brain and caused inflammation. So the scientists tested Rottlerin in a mouse model of disease that mimics the key aspects of LACV-encephalitis in humans. They treated mice with Rottlerin three days after being infected, to ensure that virus would already be found in neurons in the brain. The researchers found that Rottlerin significantly inhibited LACV-induced neuronal disease in the mice.

Despite the encouraging results, the scientists stress that the data do not replace a double-blinded clinical trial to determine whether Rottlerin would have efficacy in an LACV-encephalitis patient. One of the challenges of testing therapeutics for diseases such as LACV encephalitis is that patient cases often are widely dispersed from year-to-year in different states and are not always diagnosed until later stages of disease. But these challenges also reinforce the need to develop potential drugs like Rottlerin.

Reference: D Ojha, et al. Rottlerin inhibits La Crosse virus-induced encephalitis in mice and blocks release of replicating virus from the Golgi body in neurons. Nature Microbiology DOI: 10.1038/s41564-021-00968-y (2021).