A research team from several institutions
being led by the University of California San Diego has deciphered a key
component behind a rising epidemic of pathogens that the World Health
Organization (WHO) recently added to its list of critical emerging
diseases.
New research published July 12 in the journal PLOS Pathogens uncovered
a protein enabling the replication of arenaviruses, pathogens carried
by rodents that can infect humans and cause lethal hemorrhagic fevers.
According to the WHO, the Lassa virus -- an arenavirus with symptoms
similar to the Ebola virus -- is currently widespread in West Africa,
with nearly 300,000 infections and more than 5,000 deaths reported per
year. Research and identification of clinical targets to combat these
diseases are urgently needed, the WHO has indicated.
Research led by Elina Zúñiga's laboratory in UC San Diego's Division
of Biological Sciences identified DDX3, a protein involved in RNA
metabolism, as a key factor promoting arenavirus multiplication through
its unexpected ability to promote viral RNA synthesis and dismantle
normal human immune system defenses.
The study, led by María Eugenia Loureiro and Andre
Zorzetto-Fernandes, two postdoctoral fellows in Zúñiga's lab, may pave
the way to new therapeutic treatments for arenaviruses and hemorrhagic
fever.
"Our results uncover novel mechanisms used by arenavirus to exploit
the host machinery and subvert immunity, singling out DDX3 as a
potential host target for developing new therapies against highly
pathogenic arenaviruses," the authors write in the study.
"Mortality due to Lassa fever can rise up to 50 percent for
hospitalized patients in some outbreaks and to 90 percent for women in
the last month of pregnancy," said Zúñiga. "Currently there is no
vaccine and no effective treatment for this virus. Therefore,
understanding how arenaviruses exploit the host molecules is important
and may lead to new treatments to fight these deadly infections."
As part of the search for new drug targets, Zúñiga's research team
focused on arenavirus nucleoproteins, which play important roles in the
viral life cycle and evasion of the immune system. The researchers
analyzed protein interactions in a human cell line expressing the Lassa
virus nucleoprotein. This revealed several candidate human proteins,
whose roles were then investigated in loss-of-function experiments in
infected cells. DDX3 emerged as a human protein that enhances viral
growth.
Further experiments with Lassa virus and Junín virus, an arenavirus
endemic in Argentina, confirmed the importance of DDX3 in arenavirus
infection of human cells. The results suggest that DDX3 may have two
distinct roles. First, it suppresses the production of type I
interferons, key proteins needed for a robust antiviral state and immune
response to infection. DDX3 also appears to enhance synthesis of
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.
"This work was the result of a team effort from scientists at several
institutions and raises new important questions on the mechanisms by
which DDX3 favors arenavirus RNA synthesis and suppression of
interferons," said Zúñiga. "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."
Story Source:
https://ucsdnews.ucsd.edu/pressrelease/scientists_id_protein_exploited_by_virus_ravaging_west_africa" rel="nofollow - Materials provided by http://www.ucsd.edu" rel="nofollow - University of California - San Diego . Original written by Mario Aguilera. Note: Content may be edited for style and length.