Tag Archives: #dengue

Scientists Discover How Dengue Vaccine Fails to Protect Against Disease (Medicine)

UNC School of Medicine scientists led by Aravinda de Silva, PhD, identified the small subpopulation of antibodies in vaccinated children that correlate with protection against dengue fever. This research should help shape better vaccines for one of the most widespread infectious diseases in the world.

Developing a viable vaccine against dengue virus has proved difficult because the pathogen is actually four different virus types, or serotypes. Unless a vaccine protects against all four, a vaccine can wind up doing more harm than good.

To help vaccine developers overcome this hurdle, the UNC School of Medicine lab of Aravinda de Silva, PhD, professor in the UNC Department of Microbiology and Immunology, investigated samples from children enrolled in a dengue vaccine trial to identify the specific kinds of antibody responses that correlate with protection against dengue virus disease. In doing so, the researchers discovered that a small subpopulation of antibodies binding to unique sites on each serotype are linked to protection. The research, published in the Journal of Clinical Investigation, provides important information for vaccine developers to consider when creating a dengue vaccine, which has long eluded scientists.

Cameron Adams © UNC Health

The four dengue virus serotypes are mosquito-borne flaviviruses that infect hundreds of millions of individuals each year in Southeast Asia, western Pacific Islands, Africa, and Latin America. Nearly 100 million individuals report flu-like symptoms. Though rarely deadly, the virus can cause severe illness, especially when a person who was previously infected with one serotype (and recovers) is then infected by a second serotype. This happens because antibodies from the first infection help the virus replicate during the second infection through a process called antibody dependent enhancement. A dengue vaccine induced antibody response weighted towards a single dengue virus serotype can mimic this phenomenon.

Several vaccines have been in clinical development for years, and most show that they induce neutralizing antibodies against all four serotypes. Yet, research has also shown that the creation of neutralizing antibodies alone does not correlate to protection against clinical disease. The de Silva lab conducted experiments to compare the properties of antibodies against wild-type Dengue viruses and the properties of antibodies produced by a leading vaccine candidate – Dengvaxia – which the pharmaceutical company Sanofi Pasteur created using all four dengue virus serotypes in one formulation.

Experiments led by Sandra Henein, research associate in the UNC Department of Microbiology and

Sandra Henein © UNC Health

Immunology, and Cameron Adams, a medical and graduate student in the UNC Medical Scientist Training Program (MD/PhD), showed that wild type infections induced neutralizing and protective antibodies that recognized a part of the virus – an epitope – unique to each serotype. The vaccine, though, mainly stimulated neutralizing antibodies that recognized epitopes common among all serotypes. In vaccine trials, these antibodies did not protect children from dengue.   In the past, researchers have considered all dengue neutralizing antibodies to be protective in people. This appears to not be the case, according to this UNC-led research.

“Our results suggest that a safe and effective dengue virus vaccine needs to stimulate neutralizing antibodies targeting unique sites on each of the four dengue serotypes ,” Adams said. “Not merely the neutralizing antibodies against cross-reactive epitopes common to all four dengue types.”

Henein and Adams are co-first authors of the JCI paper, and de Silva is senior author. Other authors are Matthew Bonaparte, Janice Moser, Alina Munteanu, all from Sanofi Pasteur, and Ralph Baric, from UNC-Chapel Hill.

The National Institute of Allergy and Infectious Diseases funded this work through R01 grants AI107731 and AI125198.


Reference: Sandra Henein, … , Ralph Baric, Aravinda M. Desilva, “Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection”, J Clin Invest. 2021. https://doi.org/10.1172/JCI147066.


Provided by UNC Health

Scientists Identify Combination of Biological Markers Associated With Severe Dengue (Medicine)

New findings could improve the triage process for patients with dengue and help clinicians determine those who may be at risk of developing moderate to severe disease.

Researchers have identified a combination of biological markers in patients with dengue that could predict whether they go on to develop moderate to severe disease, according to a study published today in eLife.

Biomarkers are used to identify the state or risk of a disease in patients. Examples of biomarkers can include naturally occurring molecules or genes in the vascular, inflammatory or other biological pathways. The new findings could aid the development of biomarker panels for clinical use and help improve triage and risk prediction in patients with dengue.

Dengue is the most common mosquito-borne viral disease to affect humans globally. In 2019, the World Health Organization identified dengue as one of the top 10 threats to global health, with transmission occurring in 129 countries and an estimated 3.9 billion people being at risk.

“While most symptomatic dengue infections are self-limiting, a small number of patients develop complications that usually occur at around four to six days from symptom onset,” explains first author Vuong Nguyen Lam, Researcher and PHD Student at Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam. “Large numbers of patients therefore need regular assessments to identify these complications. The accurate and early identification of such patients, particularly within the first three days of illness, should allow for the appropriate care to be provided.”

The role of blood biomarkers in predicting severe outcomes has been investigated in other studies, but mostly in the later stages of disease progression or at hospital admission. Many of these biomarkers either peak too late in the disease course or have too short a half-life to be clinically useful.

To address this, Vuong and colleagues selected 10 candidate biomarkers from vascular, immunological and inflammatory pathways that are associated with dengue disease pathogenesis. These biomarkers were: VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, and CRP. They were chosen based on their likelihood to be increased during the early stages of disease.

The team then conducted a study using samples and clinical information from a large multi-country observational study called ‘Clinical evaluation of dengue and identification of risk factors for severe disease’ (IDAMS study). Of the 2,694 laboratory-confirmed dengue cases included in the IDAMS study, 38 and 266 cases were classified as severe and moderate dengue, respectively.

For the current study, the researchers selected 281 cases in four countries – Vietnam, Cambodia, Malaysia and El Salvador – as the blood samples from these participants were stored at the OUCRU laboratory. For comparison, the team also selected 556 patients with uncomplicated dengue who shared similar geographies and demographic characteristics.

They measured the participants’ blood biomarkers at two different time points – one during the first three days of illness, and the second following recovery (10–31 days after symptom onset). They found that, during the first three days of illness, higher levels of any of the 10 biomarkers increased a patient’s risk of developing moderate to severe dengue.

They also identified a combination of six biomarkers that was best associated with severe disease in children, and a combination of seven biomarkers that was best associated with severe disease in adults. “This highlights how relationships between biomarkers and clinical outcome can differ between age groups,” Vuong says.

“Together, our findings should assist the development of biomarker panels to help improve future triage and early assessment of dengue patients,” concludes senior author Sophie Yacoub, Dengue Research Group Head at OUCRU. “This would help improve individual patient management and healthcare allocation, which would be of major public health benefit especially in outbreak settings.”

Featured image: Blood samples. Image credit: Public domain


Provided by Elife

A Missing Antibody Molecule May Indicate When Dengue Will Become Deadly (Medicine)

A first encounter with the dengue virus typically causes very mild symptoms; however, a subsequent infection is a different story. For a small proportion of people who are reinfected, the virus can cause severe symptomatic disease, which is often life-threatening.

“The main hypothesis for some time has been that antibodies generated the first time around, instead of providing protection against disease, can actually exacerbate it,” says Stylianos Bournazos, research assistant professor at Rockefeller. “But even in secondary infection, we see a wide range of symptoms—so the presence of antibodies alone cannot explain why only some cases turn deadly.”

Now new findings published in Science by the lab of Jeffrey V. Ravetch in collaboration with the Pasteur Institute in Cambodia suggest that the susceptibility and severity of dengue disease comes down to a particular type of antibody that is missing a specific sugar, fucose, on its stem. This impacts the antibody’s so-called Fc region, which is responsible for binding and passing instructions along to other immune cells.

Previously, researchers in the Ravetch lab found that patients with severe dengue disease have unusually high levels of these fucose-less antibodies. However, it was not clear whether the absence of fucose was the result of severe disease or its cause.

By analyzing samples from a variety of dengue patients early in the onset of their disease, the team found that those who eventually developed the most severe disease also had significantly higher levels of fucose-deficient antibodies at the time of hospital admission. As a result of this change to their structure, the antibodies bind too strongly to white blood cells, increasing inflammation and leading to the destruction of platelets crucial for blood clotting. The result is hemorrhagic fever and shock syndrome often seen in severe dengue disease.

The findings suggest that the fucose status of antibodies represents a robust prognostic tool, says Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology. “It can help us identify patients at risk of severe illness so they can receive appropriate medical care early on.”


Reference: Stylianos Bournazos et al., “Antibody fucosylation predicts disease severity in secondary dengue infection”, Science  04 Jun 2021: Vol. 372, Issue 6546, pp. 1102-1105 DOI: 10.1126/science.abc7303


Provided by Rockefeller University

People Who Have Had Dengue Are Twice As Likely To Develop Symptomatic COVID-19 (Biology)

A study published this May in the journal Clinical Infectious Diseases suggests that people who have had dengue in the past are twice as likely to develop symptoms of COVID-19 if they are infected by the novel coronavirus.

The findings of the study were based on an analysis of blood samples from 1,285 inhabitants of Mâncio Lima, a small town in the state of Acre, part of Brazil’s Amazon region. The principal investigator was Marcelo Urbano Ferreira, a professor at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP) in Brazil. The study was supported by FAPESP

“Our results show that the populations most exposed to dengue, possibly owing to socio-demographic factors, are precisely those that most risk falling very sick if they’re infected by SARS-CoV-2. This is an example of what has been called a syndemic [synergic interaction between two epidemic diseases so that one exacerbates the effects of the other]. On one hand, COVID-19 has hindered efforts to control dengue. On the other, the latter appears to increase the risk for those who contract the former,” Ferreira told Agência FAPESP.

For seven years Ferreira has been conducting research in Mâncio Lima with the aim of combating malaria. In 2018 he began work on a project involving a survey of 20% of the town’s population every six months. His team call on homes, apply questionnaires, and collect blood samples. In early 2020 the project received additional funding from FAPESP so that part of the research effort could be redirected to the monitoring and characterization of SARS-CoV-2 in the region (read more at: agencia.fapesp.br/34728). 

“In September 2020, a study by another group was published suggesting that areas with many cases of dengue were relatively little affected by COVID-19. Because we already had blood samples collected from inhabitants of Mâncio Lima before and after the first wave of the pandemic, we decided to use the material to test the hypothesis that prior infection by dengue virus conferred some degree of protection against SARS-CoV-2. What we found was exactly the opposite,” Ferreira said.

Methodology

The blood samples analyzed had been collected in November 2019 and November 2020. They were submitted to tests capable of detecting antibodies against all four dengue serotypes and against SARS-CoV-2.

The results showed that 37% of the cohort studied had contracted dengue before November 2019 and 35% had been infected by the novel coronavirus before November 2020. Clinical data (symptoms and outcomes) of the volunteers diagnosed with COVID-19 were also analyzed.

“We deployed statistical analysis to conclude that prior infection by dengue virus doesn’t alter the risk of being infected by SARS-CoV-2. On the other hand, our study also shows that people who have had dengue are more likely to have symptoms if they’re infected by SARS-CoV-2,” said Vanessa Nicolete, first author of the article. Nicolete is a researcher with a postdoctoral fellowship at ICB-USP.

The causes of the phenomenon described in the article are unclear. There may be a biological basis for it, in the sense that antibodies against dengue virus somehow exacerbate COVID-19, or it may simply be due to socio-demographic factors that make certain population groups more vulnerable to both diseases for various reasons.

“The results evidence the importance of reinforcing both the social distancing measures introduced to contain the spread of SARS-CoV-2 and efforts to control the dengue vector, as the two epidemics are occurring at the same time and affecting the same vulnerable population. This should be getting more attention from the federal government,” Ferreira said.

The article “Interacting epidemics in Amazonian Brazil: prior dengue infection associated with increased COVID-19 risk in a population-based cohort study” by Vanessa C. Nicolete, Priscila T. Rodrigues, Igor C. Johansen, Rodrigo M. Corder, Juliana Tonini, Marly A. Cardoso, Jaqueline G. de Jesus, Ingra M. Claro, Nuno R. Faria, Ester C. Sabino, Marcia C. Castro and Marcelo U. Ferreira is at: academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab410/6270997.

Featured image: This is the main finding of a study published in Clinical Infectious Diseases. The authors analyzed blood samples collected in a town in the Brazilian Amazon before and after the first wave of the pandemic to detect the presence of antibodies against dengue virus and SARS-CoV-2 (members of the research team during a household survey in Mâncio Lima, Acre; photo: Bárbara Prado/ICB-USP)


Provided by FAPESP

New Research Reveals How One Antibody Blocks Dangerous Effects of Dengue Virus Infection, Offering a Potential Path to Prevention

The research team used the Advanced Photon Source to confirm an effective antibody that prevents the dengue virus from infecting cells in mice, and may lead to treatments for this and similar diseases.

A team of researchers has discovered an antibody that blocks the ability of the dengue virus to cause disease in mice. The findings open the potential for developing effective treatments and designing a vaccine for dengue and similar diseases.

Researchers have revealed how one antibody (in green) is able to neutralize a protein that is central to the dengue virus’s ability to cause disease, by blocking the protein’s ability to interact with host cells. Image credit: Rajani Arora, U-M Life Sciences Institute

Dengue virus, a member of a group of viruses called flaviviruses, causes 50 to 100 million cases of dengue disease each year, with no effective treatment or vaccine. Other members of this group include the viruses that cause Zika, yellow fever and West Nile fever.

In a new study scheduled to publish Jan. 8 in the journal Science, researchers from the University of California, Berkeley, and the University of Michigan revealed how an antibody called 2B7 neutralizes one specific protein made by the virus—a protein that is key to the dengue virus’s ability to both replicate and cause disease.

The protein, called NS1 (short for “non-structural protein 1”) circulates in the patient’s blood and exacerbates disease by interacting directly with endothelial cells, the cells that form protective barriers around organs. By breaking apart the connections between endothelial cells, NS1 weakens this barrier, increasing permeability and contributing to increased vascular leak, which is the hallmark of severe dengue disease. This endothelial permeability may also enable the virus to more easily cross barriers to infect and damage target organs.

The authors and other researchers had previously demonstrated that this protein itself can cause leaks in the endothelial barrier, even in the absence of infectious viral particles. And in cases of dengue virus infection, the more NS1 found circulating in the host’s blood, the more severe the infection is likely to be.

“We think of bacterial toxins, but this idea of a viral toxin is a new concept,” said Eva Harris, a professor of infectious diseases and vaccinology at UC Berkeley’s School of Public Health and one of the study’s senior authors. “This is really an important protein in terms of creating new paradigms regarding how we think about viral proteins and their functions in disease.”

In this latest study, the researchers identified specific regions of the protein that are responsible for damaging the endothelial cells: a so-called wing region that allows the protein to connect to the host cells, and another region that triggers destructive events within the endothelial cells.

By analyzing the precise way that the 2B7 antibody attaches to the protein, they found that the antibody is able to neutralize both of these regions—simply by getting in the protein’s way. The antibody connects to NS1 in such a way that the wing regions cannot reach the endothelial cells, preventing the protein from latching onto (and thus interacting with and damaging) the endothelial cells.

“This collaborative approach gives us a lot of great insight into understanding the biology of this protein, its interactions with cells and its pathogenesis,” said David Akey, a researcher at the U-M Life Sciences Institute and a lead author of the study. “It’s an example of combining structure and function to open therapeutic avenues.”

One reason no effective therapeutic has been found for dengue is that the disease can be caused by one of four different virus strains (dengue virus 1, 2, 3 or 4). Having antibodies against one strain of the virus can actually increase severity of a subsequent infection from another strain, a phenomenon called antibody-dependent enhancement.

By binding only to the NS1 protein and not to the virus particle itself, however, the 2B7 antibody does not lead to antibody-dependent enhancement of the infection.

“These findings tell us that we can really have an effect on the virus’s pathogenesis by blocking these sites on just the circulating proteins,” said Janet Smith, a professor at the U-M Life Sciences Institute and U-M Medical School. “It offers a strategy not only for a therapy to treat an infection, but also for a vaccine to prevent infection.”

And because the NS1 protein is produced by many flaviviruses, the scientists believe the antibody that targets NS1 may be useful in treating or preventing multiple flaviviruses.

“We were able to show not only the mechanism of how the antibody protects the host cells, but also the actual mechanism of pathogenesis of this protein that is conserved across other flaviviruses,” Harris said.

“I think the fact that this antibody is cross-reactive with other flavivirus NS1 proteins is one of the most exciting elements of this work,” said Scott Biering, a postdoctoral researcher in Harris’s lab and a lead author of the study. “This research is the proof of concept that you can target this one protein for multiple flaviviruses to protect against pathogenesis. It opens a lot of avenues not only for better understanding the mechanics of this virus, but also for developing effective therapeutics.”

The research was supported by the National Institutes of Health.

Study authors are: Scott B. Biering, Marcus P. Wong, Nicholas T.N. Lo, Henry Puerta-Guardo, Francielle Tramontini Gomes de Sousa, Chunling Wang, Diego A. Espinosa, Dustin R. Glasner, Jeffrey Li, Sophie F. Blanc, Evan Y. Juan, P. Robert Beatty and Eva Harris of the University of California, Berkeley; David L. Akey, W. Clay Brown, Jamie R. Konwerski, Nicholas J. Bockhaus and Janet L. Smith of the University of Michigan; Stephen J. Elledge of Brigham and Women’s Hospital, the Howard Hughes Medical Institute and Harvard Medical School; and Michael J. Mina of the Harvard T.H. Chan School of Public Health.

“Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction,” Science. DOI: 10.1126/science.abc0476. Once the embargo lifts, the paper will be available at https://science.sciencemag.org/cgi/doi/10.1126/science.abc0476

Provided by University of Michigan

New Defence Against Dengue And Emerging Mosquito-borne Viruses (Biology)

New treatments to cut the global death rate from dengue, Zika and West Nile viruses could result from research led by The University of Queensland.

Image depicts the 1G5.3 antibody (green) bound to both Zika (red) and dengue (blue) NS1 proteins. It’s based on structural data but idealised to showing binding to both viral proteins simultaneously. Credit: Associate Professor Daniel Watterson

Associate Professor Daniel Watterson from UQ’s School of Chemistry and Molecular Biosciences said the team identified an antibody that improved survival rates in laboratory trials and reduced the presence of virus in the blood.

“We made a discovery in 2015 in the wake of the Zika outbreak that identified a new target for flavivirus treatments, a viral protein called NS1,” Dr Watterson said.

“Now we’ve shown for the first time that a single NS1 antibody can be protective against multiple flaviviruses including dengue, Zika and West Nile.

“No other antibody reported has shown such a broad range of protection.

“The improved protection we saw compared to existing treatments was really unexpected.”

An estimated 390 million people are infected with dengue globally each year, particularly in tropical and sub-tropical areas.

Of those cases, about half a million people develop a more severe form of the disease, which can be fatal.

Dr Watterson said the discovery was important, as the development of a vaccine for viruses like dengue is an unmet global challenge.

“Creating vaccines and therapies has been greatly hindered because antibodies that target the main viral envelope protein can also enhance disease.

“This phenomenon is called antibody dependent enhancement (ADE), and contributed to the complications arising from large-scale roll-out of the first licensed dengue vaccine.

“But because NS1 antibodies don’t drive ADE, our findings provide the blueprint for new and safe broad-spectrum vaccines against multiple flaviviruses, including dengue.”

Lead author UQ’s Dr Naphak Modhiran said the antibody could also provide the first line of defence in future viral outbreaks across the world.

“The antibody binds to a wide range of flaviviruses including Usuto virus in Europe, and Rocio and Ilheus viruses in South America,” Dr Modhiran said.

“These viruses have already caused local outbreaks in the past and have the potential to be the next Zika.”

Co-author Professor Paul Young said the antibodies were first developed in his group more than 30 years ago.

“Since then, they have provided numerous insights into the biology of the dengue viruses and have been employed in the development of new diagnostics,” Professor Young said.

“It’s great to see them now progressing as potential templates for therapeutics.

“This highlights the critical nature of discovery research in providing the foundation for translation into clinical practice.”

The UQ team worked in collaboration with Professor George Gao, Professor Yi Shi and Dr Hao Song at the Institute of Microbiology, Chinese Academy of Sciences.

The work was supported by the Australian Government National Health and Medical Research Council (NHMRC).

The research has been published in Science (DOI: 10.1126/science.abb9425).

Provided by University of Queensland

New Research Reveals How One Antibody Blocks Dangerous Effects of Dengue Virus Infection, Offering a Potential Path to Prevention

A team of researchers has discovered an antibody that blocks the ability of the dengue virus to cause disease in mice. The findings open the potential for developing effective treatments and designing a vaccine for dengue and similar diseases.

Dengue virus, a member of a group of viruses called flaviviruses, causes 50 to 100 million cases of dengue disease each year, with no effective treatment or vaccine. Other members of this group include the viruses that cause Zika, yellow fever and West Nile fever.

In a new study scheduled to publish Jan. 8 in the journal Science, researchers from the University of California, Berkeley, and the University of Michigan revealed how an antibody called 2B7 neutralizes one specific protein made by the virus–a protein that is key to the dengue virus’s ability to both replicate and cause disease.

The protein, called NS1 (short for “non-structural protein 1”) circulates in the patient’s blood and exacerbates disease by interacting directly with endothelial cells, the cells that form protective barriers around organs. By breaking apart the connections between endothelial cells, NS1 weakens this barrier, increasing permeability and contributing to increased vascular leak, which is the hallmark of severe dengue disease. This endothelial permeability may also enable the virus to more easily cross barriers to infect and damage target organs.

The authors and other researchers had previously demonstrated that this protein itself can cause leaks in the endothelial barrier, even in the absence of infectious viral particles. And in cases of dengue virus infection, the more NS1 found circulating in the host’s blood, the more severe the infection is likely to be.

“We think of bacterial toxins, but this idea of a viral toxin is a new concept,” said Eva Harris, a professor of infectious diseases and vaccinology at UC Berkeley’s School of Public Health and one of the study’s senior authors. “This is really an important protein in terms of creating new paradigms regarding how we think about viral proteins and their functions in disease.”

In this latest study, the researchers identified specific regions of the protein that are responsible for damaging the endothelial cells: a so-called wing region that allows the protein to connect to the host cells, and another region that triggers destructive events within the endothelial cells.

By analyzing the precise way that the 2B7 antibody attaches to the protein, they found that the antibody is able to neutralize both of these regions–simply by getting in the protein’s way. The antibody connects to NS1 in such a way that the wing regions cannot reach the endothelial cells, preventing the protein from latching onto (and thus interacting with and damaging) the endothelial cells.

“This collaborative approach gives us a lot of great insight into understanding the biology of this protein, its interactions with cells and its pathogenesis,” said David Akey, a researcher at the U-M Life Sciences Institute and a lead author of the study. “It’s an example of combining structure and function to open therapeutic avenues.”

One reason no effective therapeutic has been found for dengue is that the disease can be caused by one of four different virus strains (dengue virus 1, 2, 3 or 4). Having antibodies against one strain of the virus can actually increase severity of a subsequent infection from another strain, a phenomenon called antibody-dependent enhancement.

By binding only to the NS1 protein and not to the virus particle itself, however, the 2B7 antibody does not lead to antibody-dependent enhancement of the infection.

“These findings tell us that we can really have an effect on the virus’s pathogenesis by blocking these sites on just the circulating proteins,” said Janet Smith, a professor at the U-M Life Sciences Institute and U-M Medical School. “It offers a strategy not only for a therapy to treat an infection, but also for a vaccine to prevent infection.”

And because the NS1 protein is produced by many flaviviruses, the scientists believe the antibody that targets NS1 may be useful in treating or preventing multiple flaviviruses.

“We were able to show not only the mechanism of how the antibody protects the host cells, but also the actual mechanism of pathogenesis of this protein that is conserved across other flaviviruses,” Harris said.

“I think the fact that this antibody is cross-reactive with other flavivirus NS1 proteins is one of the most exciting elements of this work,” said Scott Biering, a postdoctoral researcher in Harris’s lab and a lead author of the study. “This research is the proof of concept that you can target this one protein for multiple flaviviruses to protect against pathogenesis. It opens a lot of avenues not only for better understanding the mechanics of this virus, but also for developing effective therapeutics.”

Reference: Scott B. Biering, Marcus P. Wong, Nicholas T.N. Lo, Henry Puerta-Guardo, Francielle Tramontini Gomes de Sousa, Chunling Wang, Diego A. Espinosa, Dustin R. Glasner, Jeffrey Li, Sophie F. Blanc, Evan Y. Juan, P. Robert Beatty and Eva Harris of the University of California, Berkeley; David L. Akey, W. Clay Brown, Jamie R. Konwerski, Nicholas J. Bockhaus, Janet L. Smith and Michael J. Mina, “Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction,” Science. DOI: 10.1126/science.abc0476. Once the embargo lifts, the paper will be available at https://science.sciencemag.org/cgi/doi/10.1126/science.abc0476

Provided by University of Michigan

Sugar-coated Viral Proteins Hijack And Hitch A Ride Out Of Cells (Biology)

Researchers from the Universities of Melbourne, York, Warwick and Oxford have shed light on how encapsulated viruses like hepatitis B, dengue and SARS-CoV-2 hijack the protein manufacturing and distribution pathways in the cell – they have also identified a potential broad spectrum anti-viral drug target to stop them in their tracks.

3D structure of human endo-α-mannosidase (MANEA), with a sugar bound. Image: Łukasz F. Sobala

The findings have been published in PNAS today and are important to efforts to develop broad-spectrum antiviral agents.

Professor Spencer Williams from the School of Chemistry at Bio21 said the research will help define a new ‘host-directed’ approach for treating infections by encapsulated viruses.

“One approach to treating viral infections is to make a new drug for each virus that comes along. But it is slow. An alternative and attractive approach is to make a drug against a human target that viruses need to replicate. The same drug can then be used and reused against many different viruses, even ones that have yet to emerge,” he said.

The findings result from work by Professor Gideon Davies and his UK team who clarified how the structure of the catalytic domain of human enzyme that trims sugar molecules from proteins during their production and Professor Williams’ and his Bio21 team, who developed a series of inhibitors to block the enzyme.

When tested in human cell lines, these inhibitors where shown to reduce infection in dengue viruses.

“Encapsulated viruses tend to harness the ‘glycosylation’ step of protein production, whereby glycans, or sugar molecules coat newly assembled proteins,” said Professor Williams.

“The sugar molecules provide instructions for proteins to fold into their correct 3D structure as well as transport instructions for the protein to be brought to its next destination within the cell. Glycosylation is facilitated by various enzymes that synthesize, trim, check and modify these sugar molecules.”

Our body’s cells contain around 42 million protein molecules. Protein production is a complex, multi-step process within the cell. Like products on a factory assembly-line, all proteins pass through ‘quality control’ check points where they are inspected before they are transported to their destination, to carry out their functions.

Viruses are not living organisms, but biological programs encoded in ribonucleic acid (RNA) or deoxyribonucleic acid (DNA).

They come to life when they enter a living cell and hijack the protein production systems. Viruses use the cell’s machinery to copy their DNA or RNA (in the case of SARS-CoV2, it’s RNA) and to produce the proteins they need to make copies of themselves.

The viral proteins produced in an infected cell undergo the ‘glycosylation’ and then pass through the quality control steps, which involves ‘trimming’ by an enzyme called ‘MANEA’.

“Trimming is a crucial quality control step and when it does not occur, client proteins are marked for degradation. MANEA represents a key target for broad spectrum drug development against encapsulated viruses, as inhibitors will trigger destruction of their proteins,” said Professor Davies.

Because viruses hijack this unusual biosynthetic pathway, it makes it a good potential drug target.

Reference: Łukasz F. Sobala, Pearl Z. Fernandes, Zalihe Hakki, Andrew J. Thompson, Jonathon D. Howe, Michelle Hill, Nicole Zitzmann, Scott Davies, Zania Stamataki, Terry D. Butters, Dominic S. Alonzi, Spencer J. Williams, and Gideon J. Davies, “Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target”, Proc Natl Acad Sci USA first published November 5, 2020. https://doi.org/10.1073/pnas.2013620117 https://www.pnas.org/search/Structure%252Bof%252Bhuman%252Bendo-%25CE%25B1-1%252C2-mannosidase%252B%2528MANEA%2529%252C%252Ban%252Bantiviral%252Bhost-glycosylation%252Btarget%20content_type%3Ajournal

Provided by University of Melbourne

These Companies Are Working Hard To Fight Against Mosquito-Borne Diseases With “Mosquitoes” (Biology)

For decades, researchers have scratched their heads over how to combat deadly mosquito-borne diseases such as dengue fever. But, could a solution come from producing mosquitoes?? Yeah that’s what’s, Australian research World Mosquito Program (WMP) think.

They uses Wolbachia-carrying mosquitoes to naturally prevent the transmission of mosquito-borne diseases, including dengue, Zika, chikungunya and yellow fever. They release both female and male mosquitoes each week for several months, which facilitates the establishment of Wolbachia into the Aedes aegypti mosquito population. Since Wolbachia-carrying mosquitoes can’t transmit diseases, the incidence of mosquito-borne diseases reduces or is eliminated in areas where Wolbachia is established at high levels.

But, what if I say it actually worked?? Yes guys, in Indonesia, an impact study carried out on 300,000 people demonstrated that dengue infection rates decreased by 77 percent in regions where these modified mosquitoes were introduced.

And now, the French company InnovaFeed, specialised in the production of insects to feed livestock, is partnering with the Australian research World Mosquito Program (WMP) to develop what it says is the first industrial-level production of mosquitoes. Their partnership take this method to another level of grandeur.

Another company Oxitec, based in the UK but financed by American funds, got the green light from the US agency for the protection of the environment to release its lab-modified mosquitoes in Florida.

“Oxitec’s safe, non-biting male mosquitoes are designed to suppress local wild populations of disease-spreading mosquitoes,” a spokesperson for the company told AFP.

“The mosquitoes carry a self-limiting gene which means that when our mosquito males mate with wild females, their offspring inherit a copy of this gene, which prevents females from surviving to adulthood,” Oxitec added.

As a consequence, “there is a reduction in the wild pest population,” Oxitec said.

Around 750 million genetically mosquitoes will be released to battle natural mosquitoes under Florida’s blue sky.

Scientists warn that global warming could trigger major outbreaks of dengue, chikungunya or zika in the future, as mosquitoes thrive in warm temperatures and have longer breeding periods.