Study shows how critical Lassa virus protein drives infection

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Lassa fever is a viral disease far too common in West Africa. Although it can have a mortality rate of 15% in severe cases, up to 90% in pregnant women, and causes deafness in a quarter of survivors, there is no vaccine or antiviral for it. protect against the Lassa virus. To save lives, scientists at the La Jolla Institute for Immunology (LJI) and Scripps Research are working to understand exactly how the Lassa virus replicates in human hosts.

In a new study published in Proceedings of the National Academy of Sciences, researchers show how a critical Lassa virus protein, called a polymerase, causes infection by harnessing a cellular protein in human hosts. Their work suggests that future therapies could target this interaction to treat patients.

There are no antiviral drugs that specifically target the Lassa virus. This is why it is important for researchers to identify potential drug targets on this virus to fight the infection. »


Jingru Fang, Study First Author, Joint LJI and Scripps Research Graduate Student

The Lassa virus only codes for four viral proteins. One of them, the polymerase, directs the process of viral genome replication and gene expression to produce the materials the virus needs to spread to new host cells. If we can stop the viral polymerase, we can stop the infection.

Together with the study’s lead authors, LJI President and CEO Erica Ollmann Saphire, Ph.D., and Scripps Research Professor Juan De La Torre, Ph.D., Fang led the hunt for host cell proteins that could act as Lassa polymerase’s partners in crime.

Lassa’s Helper Hunt

Fang and his colleagues engineered the Lassa virus polymerase to carry an enzymatic tag that marks host proteins interacting with the polymerase with a special chemical handle. The researchers then fished out the host proteins with this chemical handle and used a technique called mass spectrometry to identify those host proteins that interact with the Lassa virus polymerase.

“It’s like defining the Lassa polymerase virus social network, which allows you to search for partners,” says De La Torre.

Working with Professor Alexander Bukreyev, Ph.D., and colleagues at the University of Texas Medical Branch (UTMB), the team made a “working screen” using live Lassa virus. This work, performed in a high-containment laboratory, revealed which of these host proteins might be important for Lassa infection. Among a total of 42 host proteins that interact with Lassa polymerase, the team focused on one drug target: GSPT1. The team showed that GSPT1 is physically and functionally linked to Lassa virus polymerase and can facilitate Lassa virus infection.

This study is the first to uncover molecular interactions between the Lassa virus polymerase and cellular proteins. However, this is the second time the host protein GSPT1 has been linked to viral infection. The first was recent Cell reports study showing the diversion of the viral polymerase GSPT1 in Ebola virus infections; research also conducted by Saphire, De La Torre and Fang.

“If we could find a way to disrupt the link between GSPT1 and Lassa polymerase, or if we could just delete the GSPT1 protein, we could stop the Lassa virus infection,” Fang says.

Considering a new drug for Lassa

To their surprise, the team discovered a drug candidate, called CC-90009, which has been shown to destroy GSPT1 proteins and is currently being investigated as a cancer treatment in clinical trials.

To see if they can reuse the existing GSPT1 inhibitor against Lassa infection, research associate Colette Pietzsch, of the Bukreyev group at UTMB, added CC-90009 to Lassa-infected human liver cells in a high containment laboratory. This experiment showed that CC-90009 treatment significantly reduced Lassa virus growth without obvious cellular toxicity.

The researchers say it’s possible this same small-molecule drug could serve as a treatment for Ebola, and their Cell reports data suggest that CC-90009 may reduce virus titer at later times of Ebola virus infection.

“Translating this finding into therapeutic interventions will still take time,” says Fang. “We need to confirm that CC-90009 can inhibit Lassa and Ebola virus replication in animal models of infection, but at least we have a starting point.”

Source:

Journal reference:

Fang, J. et al. (2022) Lassa polymerase proximity interactome analysis reveals that eRF3a/GSPT1 is a drug target for host-directed antivirals. PNAS. doi.org/10.1073/pnas.2201208119.

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