Henipavirus glycoprotein architecture suggests therapeutic strategies
Cryoelectron microscopy studies of Nipah and Hendra viruses may provide blueprints for vaccine design and antibody treatments

Date:
March 4, 2022
Source:
University of Washington School of Medicine/UW Medicine
Summary:
3D structural findings are reported on a critical component of the
Nipah virus' infection mechanism, and how antibodies home in on
an important part of the machinery that attaches the virus to host
cells. The results point to multipronged strategies for preventing
and treating the deadly Nipah and Hendra viruses, which are carried
by bats, but which have jumped species to infect other animals and
people. The results of this latest research suggest a blueprint
for computer-engineered, next- generation vaccine candidates,


FULL STORY ========================================================================== Recent molecular findings offer new details on how Nipah and Hendra
viruses attack cells, and the immune responses that try to counter this onslaught. The results point toward multi-pronged tactics to prevent
and treat these deadly illnesses.


==========================================================================
This research is reported today inScienceas a First Release peer-reviewed paper, published rapidly online.

Both Nipah virus and Hendra virus are carried by bats native to certain
parts of the world. These henipaviruses jump species and can infect many
other mammals, including humans. The viruses cause brain inflammation
and respiratory symptoms. People acquiring either of these diseases
stand a 50% to 100% chance of succumbing.

There is a vaccine approved for use in horses and a modified version
entered a human clinical trial.

Horses can spread Hendra, possibly contracted from eating bat-contaminated fruit, to their caretakers through saliva and nasal secretions. An experimental, but not yet approved, cross-reactive antibody expected to
work against both Nipah and Hendra viruses has been given to fifteen
people who had a high-risk exposure. This was done under emergency compassionate use guidelines. This antibody is in a clinical trial in Australia, where it has just completed the Phase 1 stage of testing. There
are no approved vaccines or therapies for use in humans against these henipaviruses, other than supportive care in the limited hope that the
patient can overcome the virus.

New attempts to design life-saving preventatives and treatments became
even more urgent after a new strain of Hendra was discovered a few
months ago.

Outbreaks of Nipah virus have appeared nearly every year over the past
two decades in Bangladesh. The disease also has been seen in India and
the Philippines. Henipavirus antibodies have been detected in people
and Pteropus bats in Africa. It's estimated that 2 billion people live
in the parts of the world where henipavirus spillovers from bats, or intermediary animal vectors, could be a threat.



==========================================================================
The senior author of the latest henipavirus paper in Science is David
Veesler, associate professor of biochemistry at the University of
Washington School of Medicine and a Howard Hughes Medical Investigator. He studies bat immunity to many dangerous viruses, and conducts molecular structure and function studies of the infectivity machinery in
coronaviruses, other related viruses, and henipaviruses. His lab also researches antibody and virus interactions that hold clues for designing antivirals and vaccines for these two families of viruses.

The lead author is Zhaoqian Wang, a UW graduate student in biochemistry.

Christopher Broder's lab collaborated on the research at the Uniformed
Services University and the Henry M. Jackson Foundation for the
Advancement of Military Medicine.

The researchers explained that Nipah and Hendra viruses enter into
cells through attachment and fusion glycoproteins, which work in a
coordinated fashion. These glycoproteins are the key targets for the
antibody defense system.

Through cryoelectron microscopy, the scientists were able to determine
the structure of a critical component of the Nipah viruses' infection
mechanism in an interaction with a fragment of a broadly neutralizing
antibody. They also observed that a mixture or "cocktail" of antibodies
work better together to disarm Nipah viruses. Similar synergistic effects
were seen in a set of antibodies against Hendra viruses. This combining
of forces also helped keep escape mutants from emerging to sidestep the antibody response.

Examining the antibody response in laboratory animals inoculated with a critical section of the Nipah virus infection machinery provided vital information. The analysis indicated which area of the virus receptor
binding protein was dominant in eliciting an immune response.



========================================================================== Before this study, the researchers said, nothing was available on the
structure of a critical portion of henipaviruses responsible for eliciting antibody response, called the HNV G protein. This lack of information
was an obstacle to understanding immunity and to improving the design
of vaccine candidates.

Now that the researchers have uncovered the 3D organization and some of
the conformational dynamics of the HNV G protein, science may be closer
to creating a template for building new and improved vaccines.

In a simplified description of the more complex findings, an important
part of the attachment structure has a neck and four heads. Only one
of the four heads turns its receptor binding site in the direction of
the potential host cell; the other three turn away toward the virus'
membrane. This gives the viral structure the freedom to re-orient the
head domain to engage with the host receptor.

The scientists noted that the architecture then "adopts a unique two
heads up and two heads down conformation that is different from any other paramyxovirus attachment glycoprotein." The paramyxovirus is a large
family of single-strand RNA viruses. They cause several distinct types
of diseases, most of which are transmitted on respiratory droplets. They include measles, mumps, distemper, parainfluenza, and the henipavirus
diseases that have more recently crossed from animals to humans.

In investigating the nature of antibody responses to the Nipah virus
and Hendra virus attachment protein G, the scientists examined two
animals that were immunized with that glycoprotein. A potent, diverse neutralizing antibody response ensued. The head domain was found to be
the main, if not exclusive target, of the immunization-induced antibody neutralization, even though the full tetramer was used. This indicated
that the antibody response narrowed in on the receptor-binding area.

These findings, the researchers noted, "provide a blueprint for
engineering next-generation vaccine candidates with improved stability
and immunogenicity." The s would focus on the vulnerability of the
head domain. They anticipate a design approach like that employed for
newer computer-engineered SARS-CoV-2 and respiratory syncytial virus candidates. A mosaic of head antigens would be presented to the body in
an ordered array on a multivalent display. Using only the head domain
rather than the full G protein could also make manufacturing large
supplies of vaccine simpler.

This study was supported by the National Institute of Allergy and
Infectious Diseases (DP1AI158186 and HHSN272201700059C, AI077995,
U19AI142764), the National Institute of Health Cellular and Molecular
Biology Training Grant (T32GM007270), a Pew Biomedical Scholars Award,
an Investigators in the Pathogenesis of Infectious Disease Awards from
the Burroughs Wellcome Fund, the University of Washington Arnold and
Mabel Beckman cryoEM center and a National Institute of Health grant S10OD032290 (to D.V.). The scientists also acknowledged the Coalition
for Epidemic Preparedness Innovations (CEPI) for their support of the
Nipah virus vaccine program.

========================================================================== Story Source: Materials provided by University_of_Washington_School_of_Medicine/UW_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zhaoqian Wang, Moushimi Amaya, Amin Addetia, Ha V. Dang, Gabriella
Reggiano, Lianying Yan, Andrew C. Hickey, Frank DiMaio,
Christopher C.

Broder and David Veesler. Architecture and antigenicity of
the Nipah virus attachment glycoprotein. Science, 2022 DOI:
10.1126/science.abm5561 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220304090347.htm

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