image: This is DDX3 promoted LASV growth in human cells. DDX3 ko-1, DDX3 ko-2 and WT A549 cells were infected with LASV (strain Josiah) at low M.O.I. (0.01, 0.05 and 0.1) for 48h or at high M.O.I. (0.5 and 3) for 24h. view more
Credit: Sheli Radoshitzky Molecular and Translational Sciences Division, US Army Medical Research Institute of Infectious Diseases
A protein known as DDX3 promoted viral multiplication in cells from a human cell line that were infected with viruses from the arenavirus family, according to new research presented by María Eugenia Loureiro, Andre Zorzetto-Fernandes, Elina Isabel Zuniga of the University of California, San Diego, and colleagues in PLOS Pathogens.
Arenaviruses primarily infect rodents, but some can infect and cause severe hemorrhagic fever in humans. These include Lassa virus, which kills 5,000 people each year in West Africa, and Junín virus, which primarily infects residents of rural Argentina. The World Health Organization has stated that research into arenaviruses and potential new drug targets is urgently needed.
As part of the search for new arenavirus drug targets, Dr. Zuniga's research team focused on viral proteins known as arenavirus nucleoproteins, which are known to play important roles in the viral life cycle and evasion of the immune system. Targeting interactions between arenavirus nucleoproteins and human proteins could be a central focus of novel treatment strategies.
To identify human proteins that interact with arenavirus nucleoproteins, the researchers analyzed protein interactions in cells from a human cell line expressing Lassa virus nucleoprotein. This revealed several candidate human proteins, whose roles were then investigated in loss-of-function experiments in infected cells. DDX3, which is involved in RNA processes, emerged as a human protein that may enhance viral growth.
Further experiments with Lassa and Junín virus confirmed the importance of DDX3 in arenavirus infection of human cells. The results suggest that DDX3 suppresses the production of type I interferons, key proteins needed for a robust immune response to infection. DDX3 also appears to enhance synthesis of new arenavirus RNA, an important step in viral multiplication. These two DDX3-dependent arenavirus exploitation strategies were previously undiscovered.
Overall, these findings reveal the importance of DDX3 in arenavirus infection and identify it as a potential target for new anti-arenavirus strategies.
Dr. Zuniga concludes, "This work was the result of a team effort from scientists in several institutions and raises new important questions on the mechanisms by which DDX3 favors arenavirus RNA synthesis and suppression of interferons"
Zuniga continues, "We are excited to continue this line of research to further evaluate in animal models the potential of targeting DDX3 to counteract infections with arenaviruses and perhaps other hemorrhagic fever viruses."
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Journal
PLoS Pathogens