A drug that blocks danger signals that can lead to harmful inflammation could help reduce COVID-19 lung damage, a new study from NIAID scientists and colleagues has found. Scientists from NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, and the University of Utah completed the project, published online in JCI Insights.

Though they completed the study in laboratory mice modified to model COVID-19 in people, the scientists think their findings are important enough to pursue further studies of the drug, FPS-ZM1, to determine dosing and timing strategies for possible human clinical trials. FPS-ZM1 is an immune modulatory therapeutic – the drug is designed to prevent a specific immune system response from occurring. The investigational therapy has been evaluated in preclinical studies to treat conditions such as diabetes, lung injury and stroke. In their study, the scientists used FPS-ZM1 to block the “receptor for advanced glycation end products” (RAGE), which senses danger signals and can generate inflammation and coagulation known to damage the lungs of COVID-19 patients. 

Therapeutic treatment with FPS-ZM1 during the study improved survival in mice infected with SARS-CoV-2, the virus that causes COVID-19. Further, FPS-ZM1 specifically reduced damage to the lung vasculature, an important system for circulating blood through the lungs that becomes damaged during SARS-CoV-2 infection. FPS-ZM1 also has shown in other rodent studies that it can protect against injury in disease models of brain injury, sepsis, asthma, diabetes, acute lung injury and ischemic/reperfusion (organ damage due to blood flow).

The study also identified two distinct phases of COVID-19 disease development in the mice. The scientists want to further explore those phases as potential guides for treatment strategies. For example, FPS-ZM1 limited specific types of inflammation and tissue damage, so it would likely be most effective if administered during the intermediate to later stages of SARS-CoV-2 infection, whereas antiviral treatment may be most effective when given early following infection.

Reference: F Jessop, et al. Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection. JCI Insights DOI: https://doi.org/10.1172/jci.insight.155896. (2022).
 

COVID-19 Respiratory Treatment Effective in Encephalitis Study

Molnupiravir Reduced Viral Brain Disease in Mice

NIAID research into finding broad uses for existing drug treatments has a potential new success story: Molnupiravir, a relatively new antiviral developed to treat respiratory diseases – such as COVID-19 – reduced brain swelling in study mice infected with a pathogen dangerous to children, La Crosse virus (LACV).

The new study, from NIAID scientists and colleagues at the University of North Carolina and Emory University, is published in PLOS Pathogens. LACV, which is spread by mosquitos, can cause brain inflammation in children. 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 and throughout the Appalachian Mountains.

Most LACV infections in people are mild, but the virus sometimes – particularly in children – enters the brain, infects neurons and causes disease that can result in learning and memory difficulties, paralysis, seizures and death. Between 30 and 90 cases of severe LACV – those that affect the central nervous system (CNS) – are reported each year, though the Centers for Disease Control and Prevention believes many mild cases occur but are not diagnosed.

The study used a new strategy to test three antiviral drugs – N4-Hydroxycytidine (NHC, the active metabolite of the prodrug molnupiravir), ribavirin and favipiravir– for treatment against LACV infection. The scientists chose LACV because it broadly represents several RNA viruses that cause disease in the CNS, including Jamestown Canyon and Cache Valley viruses – which also were part of the study – and rabies, polio, West Nile, Nipah and several other viruses not part of the study.

The three antiviral drugs were tested in a cell culture system to examine an antiviral strategy called lethal mutagenesis. This approach increases the number of errors in the viral genome that RNA viruses make when they replicate, weakening the resulting viruses. By incorporating the drug, more errors are induced in the viral genome and more weakened viruses emerge, providing the host an opportunity to recover.

Ribavirin and favipiravir used in cell treatment studies did not produce potent enough results to justify testing in mice. The NHC prodrug molnupiravir, however, was used in two different mouse study models. Oral treatment with molnupiravir reduced brain disease in mice by 32% when LACV infection was started by an injection in the abdomen, and by 23% when the infection was started in the nose, offering easy access to the brain.

Also noteworthy: The researchers tested NHC against LACV and found it effective in the cell and mouse models, as well as in cell models using Jamestown Canyon and Cache Valley viruses. This showed that the drug treatment strategy could be successful against viruses related to LACV and supports the idea that this strategy could be used against a broader group of encephalitic RNA viruses.

The researchers say more study is needed to see how these drugs counter RNA viruses, particularly to determine whether injecting the drug directly into cerebrospinal fluid would provide better results and possibly reduce adverse side effects.

Reference:

D Ojha et al. N⁴-Hydroxycytidine/Molnupiravir Inhibits RNA Virus-Induced Encephalitis by Producing Less Fit Mutated Viruses. PLOS Pathogens DOI: 10.1371/journal.ppat.1012574 (2024).