The new research provides hope for identifying
future therapeutic approaches
KANSAS
CITY, Mo., July 22, 2024 /PRNewswire/ --
Mosquito-borne viral infections once confined to tropical regions
are spreading. Dengue virus infects up to 400 million people
worldwide each year according to World Health Organization
estimates, and no available treatments exist for this disease. Now,
research from the Stowers Institute for Medical Research has
uncovered surprising strategies for how dengue and hundreds of
other viruses replicate in their hosts, with the potential to aid
in developing novel antiviral treatments and vaccines.
"We need to start thinking very seriously
about how to combat dengue and other mosquito-borne viral
infections."
Led by Stowers Predoctoral Researcher Luciana Castellano in the
lab of Associate Investigator Ariel
Bazzini, Ph.D., the study, published in Molecular
Systems Biology on July 22,
2024, revealed that the dengue virus genome uses less
efficient codons, or "vocabulary," to make its own proteins
using the host's machinery to replicate, and spread. A codon
is a sequence of three nucleotides, or "words" in the genetic code
that help make proteins. The researchers found that hundreds of
other viruses also use "words" in their genetic code that are less
efficient in their mosquito and human hosts.
"Now that we know what dengue and other viruses use when they
infect our cells, we have clues for how we may be able to help
prevent these deadly diseases," said Bazzini.
"During infection, host cells and viral invaders are at war,"
said Castellano. "Like building weapons, both viruses and cells
need to build proteins to fight and defend themselves."
Dengue virus needs the proteins encoded in its single-stranded
RNA genome to propagate, but the virus can't produce them on its
own. The virus must use the host cell's protein production
machinery, so the researchers hypothesized that dengue virus would
use codons or "vocabulary" similar to that of mosquitos and
humans.
"The genetic code is universal for all living organisms and
contains 64 codons, the three-nucleotide 'words' of RNA, that
specify the amino acids that make up proteins," said Bazzini.
The nature of the genetic code allows for more than one codon to
specify the same amino acid. Functioning like synonyms in language,
codons that specify the same amino acid are called synonymous
codons.
But just as each synonym is a distinct word, each synonymous
codon has individual properties that can impact a cell's efficiency
for manufacturing proteins as well as the stability of RNA. In
addition, a particular synonymous codon can be efficient and
optimal in one species but inefficient and nonoptimal in another.
This concept is called codon optimality. The Bazzini Lab studies
the codon optimality code in humans and other vertebrates, and in
this study, the researchers identified for the first time that the
mosquito genome also follows its own optimality code.
The researchers found that dengue virus tends to use synonymous
codons that are deemed less optimal in their mosquito and human
hosts, contrary to their original prediction.
"We were surprised to find that dengue virus preferentially uses
the host's less efficient codons, possibly as a strategy to evade
an antiviral response by the host," said Castellano.
"Viruses accumulate mutations during infection of their hosts.
We were surprised to find that mutations in the dengue virus genome
toward these less efficient codons increased dengue virus fitness
in both mosquito and human cells," said Ryan McNamara, a Bioinformatics Analyst in the
Bazzini Lab whose contribution was key to this work.
The team analyzed hundreds of other human-infecting viruses and
found that many of them, including HIV and SARS-CoV-2,
preferentially use less efficient codons relative to humans,
suggesting they have evolved an "inefficient" genome as a strategy
to use host cell resources in a way that benefits the virus. The
conserved preference among viruses has implications to understand
not only how viruses evolve but also how the host-pathogen
relationship changes over time.
"Fundamentally, this work has altered how we think about the
relationship between a virus and a host cell," said Bazzini.
"In the future, we hope to better understand the mechanism by
which viruses are benefitting from using these inefficient codons,
and which molecules viruses may be manipulating to gain control,"
said Castellano.
The Centers for Disease Control and Prevention reported that
cases of dengue have doubled since just last year in the Americas,
and warn of an increased risk of infection in the U.S.
"As mosquitos are spreading to broader, more global regions, we
need to start thinking very seriously for how to combat dengue and
other mosquito-borne viral infections," said Bazzini.
Additional authors include Horacio Pallarés, Ph.D., from the
Stowers Institute; Andrea Gamarnik,
Ph.D., from Fundación Instituto Leloir-CONICET, Argentina; and Diego
Alvarez, Ph.D., from Universidad Nacional de San
Martín-CONICET, Argentina.
This work was funded by the National Institute of General
Medical Sciences of the National Institutes of Health (NIH) (award:
R01GM136849), the NIH Office of the Director (award: R21OD034161),
the PEW Innovation Fund award, and institutional support from the
Stowers Institute for Medical Research. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the NIH.
About the Stowers Institute for Medical Research
Founded in 1994 through the generosity of Jim Stowers, founder of American Century
Investments, and his wife, Virginia, the Stowers Institute for
Medical Research is a non-profit, biomedical research organization
with a focus on foundational research. Its mission is to expand our
understanding of the secrets of life and improve life's quality
through innovative approaches to the causes, treatment, and
prevention of diseases.
The Institute consists of 21 independent research programs. Of
the approximately 500 members, over 370 are scientific staff that
include principal investigators, technology center directors,
postdoctoral scientists, graduate students, and technical support
staff. Learn more about the Institute at www.stowers.org and about
its graduate program at www.stowers.org/gradschool.
Media Contact:
Joe
Chiodo, Head of Media Relations
724.462.8529
press@stowers.org
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SOURCE Stowers Institute for Medical Research