Breaking News
September 26, 2018 - Horwitz Prize Awarded for Work on Hormones
September 26, 2018 - Genomic ‘islands’ evolved from viruses can be converted into ‘anti-bacterial drones’
September 26, 2018 - Most running injuries may be influenced by simple technique errors, finds study
September 26, 2018 - Optimizing dopaminergic treatment improves non-motor symptoms and quality of life
September 26, 2018 - NIRS-IVUS imaging identifies patients and plaques vulnerable to subsequent adverse cardiac events
September 26, 2018 - New insights into what drives organ transplant rejection
September 26, 2018 - Tiny Device Is a ‘Huge Advance’ for Treatment of Severe Heart Failure
September 26, 2018 - Research shows possibility to postpone cumbersome treatment for low-risk MDS patients
September 26, 2018 - CSU chemists may help in making extracorporeal life support devices more effective
September 26, 2018 - Brain marker linked with aggression in toddlers identified
September 26, 2018 - Blood-brain barrier can be important biomarker for early diagnosis of Alzheimer’s disease
September 26, 2018 - PCORI, AHRQ announce awards to support patient-centered outcomes research in learning health systems
September 26, 2018 - Scientists discover and characterize human skeletal stem cells
September 26, 2018 - Repeat CT Common in Peds Traumatic Epidural Hematoma
September 26, 2018 - Genetics Home Reference: bunion
September 26, 2018 - Increase observed in hearts from drug-intoxicated donors
September 26, 2018 - For Heart Failure Patients, Mitral Valve Procedure Improved Outcomes
September 26, 2018 - TINY cancer detection device shows promise as point-of-care detector of KSHV
September 26, 2018 - Women with non-small cell lung cancers live longer than their male counterparts
September 26, 2018 - KTU researchers engineer experimental bone to help treat osteoarthritis patients
September 26, 2018 - Foundation for a Smoke-Free World calls for proposals to implement Smoke-Free Index
September 26, 2018 - Functional Imagery Training helps lose five times more weight than talking therapy
September 26, 2018 - Fewer American Teens Having Sex, Most Using Birth Control
September 26, 2018 - We are predisposed to forgive, new research suggests
September 26, 2018 - Insomnia Exacts Heavy Toll on Quality of Life
September 26, 2018 - Clinical study shows efficacy, safety of novel drug-eluting stent with improved radiographic visibility
September 26, 2018 - Cytox, AIBL announce expanded agreement to assess genetic risk for Alzheimer’s
September 26, 2018 - Study finds persistent rate of lawnmower injury-related emergency department visits
September 26, 2018 - Researchers find molecule that halts, reverts neurodegeneration caused by Parkinson’s disease
September 26, 2018 - Novartis announces winners of 2018 eXcellence in Ophthalmology Vision Award
September 26, 2018 - New spinout company to tackle drug-resistant infections with novel antibiotics
September 26, 2018 - In depression the brain region for stress control is larger
September 26, 2018 - Smuggling RNA into cells can activate the immune system to fight cancer
September 26, 2018 - Special Focus Issue takes wide view of complementary and integrative medicine in cancer
September 26, 2018 - Researchers now confirm that genome duplication drives evolution of species
September 25, 2018 - Study provides evidence of beta lactamase producing, antimicrobial resistant E. coli in U.S. retail meat
September 25, 2018 - UCI study finds new cause of cerebral microbleeds
September 25, 2018 - Researchers propose mechanism by which ASTN2 protein defects lead to brain disorders
September 25, 2018 - Chinese and German researchers to cooperate more closely in future for better food
September 25, 2018 - Recent study helps predict probability of pregnant mothers to have child with autism
September 25, 2018 - New online, sound matching tool offers tinnitus sufferers potential treatment options
September 25, 2018 - UC Davis researchers take critical step in developing more effective Salmonella vaccine
September 25, 2018 - Antibiotics best paediatric treatment for children’s chronic wet cough
September 25, 2018 - Looking beyond opioids: Stanford pain psychologist briefs Congress
September 25, 2018 - Organs actively fighting back against autoimmune diseases, finds study
September 25, 2018 - Lancaster professor aims to understand how genes affect smoking cessation
September 25, 2018 - Human-oriented perspective needed to better understand Parkinson’s disease
September 25, 2018 - Physical activity may have beneficial effects for people with rare Alzheimer’s disease
September 25, 2018 - FDA Updates on Valsartan Recalls
September 25, 2018 - 3-D-printed tracheal splints used in groundbreaking pediatric surgery
September 25, 2018 - Who is the designated driver, or proxy, for your health decisions?
September 25, 2018 - New chemo-optogenetic method enables multi-directional activity control of cellular processes
September 25, 2018 - Study explores link between genetic predisposition to Alzheimer’s and cardiometabolic risk factors
September 25, 2018 - NeoTract presents new clinical data from studies of UroLift System for patients with BPH
September 25, 2018 - Patients with paralysis manage to walk thanks to new technology
September 25, 2018 - Statins Improve Long-Term Survival After AAA Repair
September 25, 2018 - Novel brain network linked to chronic pain in Parkinson’s disease
September 25, 2018 - Researchers reassess negative pressure wound therapy as its benefit and harm remain unclear
September 25, 2018 - Older adults with ‘fall plan of care’ less likely to suffer fall-related hospitalizations
September 25, 2018 - FDA lifts partial clinical hold that paused enrollment of new patients in tazemetosta clinical trials
September 25, 2018 - IME Medical Electrospinning establishes state-of-the-art manufacturing lab facilities
September 25, 2018 - Phase 1 and 2 clinical trials of entrectinib drug in ROS1-positive NSCLC show promising results
September 25, 2018 - How to Protect Your Eyesight
September 25, 2018 - Novel approach allows researchers to define how cells in the retina respond to diabetes
September 25, 2018 - Columbia University announces winners of 2018 Louisa Gross Horwitz Prize
September 25, 2018 - New model enables anyone to run powerful simulations, complex calculations easily
September 25, 2018 - Clinical trial investigators found non-compliant with requirement to report results on EU register
September 25, 2018 - Study analyzes quality of protein supplements in function of source, treatment and storage
September 25, 2018 - FDA grants Orphan Drug Designation to Myelo001 for treatment of Acute Radiation Syndrome
September 25, 2018 - U.S. Alzheimer’s Cases to Nearly Triple by 2060
September 25, 2018 - Improving cell replacement therapy for Parkinson’s disease
September 25, 2018 - Genervon reports new findings that drug candidate GM6 attenuates Alzheimer’s disease in mice model
September 25, 2018 - FDA approves new 5 mm diameter drug-eluting stent from Cook Medical
September 25, 2018 - New $17.8 million grant ensures USC at forefront of research on tobacco-related health risks
September 25, 2018 - Researchers analyze response to combination immunotherapy for patients with rare skin cancer
September 25, 2018 - Study sheds light on how brain protein may be involved neurodevelopmental disorders
September 25, 2018 - Where to draw the line on incentives
September 25, 2018 - Solid fuel use linked with increased risk of hospitalization or death from respiratory diseases
September 25, 2018 - ‘Trouble Brewing’ report highlights steps that governments can take to reduce alcohol-related harms
September 25, 2018 - Recurrence risk of VTE appears similar for patients with cancer and those with unprovoked VTE
Study uncovers mechanism that affects multiplication of dengue virus lineage

Study uncovers mechanism that affects multiplication of dengue virus lineage

image_pdfDownload PDFimage_print

A lineage of type 1 dengue virus found in Brazil is able to prevail over another even though it multiplies less in vector mosquitoes and infected human cells. This discovery was made under the scope of a Thematic Project supported by the São Paulo Research Foundation – FAPESP involving several Brazilian institutions as well as a university in the United States.

According to the study, the lineage activates a weaker immune response in the patient and is less strongly combated. As a result, the virus is able to multiply more in the organism and is more likely to be transmitted to others via infected mosquitoes, so that this lineage supersedes the other owing to its significantly greater overall capacity to multiply in mosquitoes and patients.

The researchers studied lineages 1 and 6 (L1 and L6) of type 1 dengue, which affect the population of São José do Rio Preto, São Paulo State, Brazil. Their findings showed that while L1 had a superior capacity to multiply in mosquitoes and cells, L6 was able to minimize and even deactivate the human immune response, so that this lineage ended up replacing L1.

“There were three approaches to investigating the situations in which dengue virus multiplies and to explain why one lineage supersedes another. Our research brought to light a new phenomenon that explains how a virus survives in a population,” said Maurício Lacerda Nogueira, a professor at the São José do Rio Preto Medical School (FAMERP), head of its Dermatological Disease Department’s Virology Research Laboratory, and co-author of an article that published the results of the study in PLOS Neglected Tropical Diseases . Nogueira also chairs the Brazilian Society for Virology.

“However, knowing whether the virus multiplies more or less in mosquitoes or human cells isn’t enough to understand why one lineage replaces another. We also need to know how the virus interacts with the human organism as a whole,” said Nogueira.

The study produced vital new knowledge for the production of dengue vaccines. “A global understanding of how the virus interacts with the population helps us understand how vaccines work and is fundamental to our ability to design them,” he said.

Type 1 dengue virus has been circulating in Brazil since the mid-1980s. Three lineages (L1, L3 and L6, all belonging to the same genotype) were introduced at different times. L6 was initially observed in São José do Rio Preto, where it began circulating in 2008. L1 was first identified in the city in 2010. These two lineages cocirculated for a period.

L1 was expected to display a higher capacity to multiply in cells and in the vector mosquito, Aedes aegypti, since it arrived after L6 and its viral fitness appeared to be superior to that of L6. L1 was therefore expected to replace L6 as the dominant strain, but it began to decline in 2013 and eventually disappeared.

This fact contradicted existing scientific knowledge about the prevalence of one lineage over another – a phenomenon called clade replacement (a clade is a branch of a phylogenetic tree comprising all organisms that have evolved from a common ancestor).

Clade replacement occurs if a lineage multiplies more in human cells after being introduced than another lineage that was already living in the same environment, or if a lineage that arrives later multiplies more in the mosquito. In both cases, the lineage that supersedes the other is said to have a higher level of viral fitness.

Epidemiological fitness

A third explanation arose from a 2015 study conducted in Puerto Rico, where a lineage of dengue virus was found to have a lower level of viral fitness than the lineages that were already in the environment yet eventually replaced them. Scientists discovered that this lineage inhibited the interferon system, which acts as the first line of defense against viruses in mammals (interferons are a complex of proteins that interfere with viral replication and protect cells from infection). This phenomenon is called epidemiological fitness – the capacity of a virus to become dominant in the field during epidemic outbreaks.

In the Brazilian case, none of this happened. The researchers first sequenced the genomes of the two viral lineages, which were found to have 47 different amino acids. Despite this significant genetic distance, L6 won the competition between them.

“Based on the information available at the time, it was assumed that L6 multiplied better and therefore became dominant, but when we looked at contaminated human and monkey cells, we found that L1 multiplied ten times more on average than L6,” said the coordinator for the FAPESP Thematic Project.

The next hypothesis was that L6’s higher viral fitness might be due to its higher multiplication rate in the mosquito. The researchers therefore infected captive mosquitoes (bred for use in scientific experiments) orally, having them feed by biting a membrane that contained mouse blood contaminated with dengue virus L1 and L6. “Again, L1 multiplied ten times better than L6 in the mosquito,” Nogueira said.

The researchers then investigated the possibility that the captive mosquitoes were somehow different from those found in the environment. In a new experiment, mosquito eggs were collected in the environment and hatched in the laboratory. The result was the same: L1 continued to be more efficient than L6 in terms of multiplication, although studies showed that patients infected with L6 had a far higher viral load than those infected with L1.

This evidence left the epidemiological fitness hypothesis, as had been the case in Puerto Rico, where a dengue virus that encoded interferon-inhibiting RNA had been found. Interference was not confirmed in the Brazilian case. “We then realized we were dealing with a mechanism that differed from the three known ones,” Nogueira said.

To solve the mystery, the researchers began studying the immunological aspects of the virus’s interaction with the organism. Using computational prediction systems, they found that L1 was far more likely than L6 to activate B and T lymphocytes, the main cellular components of the adaptive immune response.

Next, in studies involving mice and cells donated by people infected with the virus, the scientists succeeded in stimulating and measuring the activation of the response by B cells and T cells, observing that L6 activated a weaker response than L1. They also measured the level of cytokines present in the patients’ serum. Cytokines are signaling molecules that mediate and regulate immunity.

“Generally speaking, we observed that L1 multiplies much better but also strongly activates the immune system in both humans and mice,” Nogueira said. “In other words, L1 induces a very robust response against the virus by the organism, whereas L6 multiplies less but either inhibits the immune response or stimulates it little or not at all, so the organism takes longer to recognize the virus.”

As a result, the number of L6 viruses in the human organism is tenfold the number of L1 viruses on average, found the FAPESP-supported study. They also observed that L1 multiplies much more in the mosquito and replicates far more locally when it infects a person. This vigorous replication triggers strong activation of B and T cells, leading to an increase in cytokines, and this strong immune response inhibits systemic replication by the virus in the organism. As a result, the viral load is lower and dissemination to mosquitoes is reduced, so that fewer people will be infected by L1.

Despite the lower capacity of L6 to multiply in the mosquito and at the site of initial replication after a person is bitten, it produces only weak activation of B and T cells and stimulates the secretion of cytokines that inhibit the immune response instead of stimulating it.

“So systemic replication in people is much greater,” Nogueira said. “This means the number of viruses in the population is higher, and more mosquitoes will be infected. We therefore concluded that the epidemiological fitness of L6 is higher than that of L1, whereas the viral fitness of L1 is higher than that of L6.”

The research lasted two and a half years and involved a group of 24 scientists at several Brazilian higher education institutions in addition to FAMERP – Oswaldo Cruz Foundation, the Federal Universities of Rio de Janeiro (UFRJ) and Minas Gerais (UFMG), and São Paulo State University (UNESP) – as well as foreign collaborator Nikos Vasilakis, also a coauthor of the article and a researcher at the Center for Tropical Diseases, University of Texas Medical Branch, in Galveston (USA).

“Using epidemiological, phylogenetic, molecular and immunological analysis, the authors of the research showed that differences in the host’s immune response determine the dynamics of circulation in two lineages of dengue virus found in the city, suggesting that the factors that influence the dynamics of dengue transmission are far more complex than was previously thought,” Vasilakis said.

Source:

http://agencia.fapesp.br/mechanism-that-affects-multiplication-of-dengue-virus-lineage-is-discovered/28462/

Tagged with:

About author

Related Articles