Researchers discover long sought after mechanism in human cells that could help treat diseases caused by viruses, including influenza and Ebola
A team of researchers, co-led by a University of California, Riverside professor, has found a long-sought-after mechanism in human cells that creates immunity to influenza A virus, which causes annual seasonal epidemics and occasional pandemics.
The research, outlined in a paper published online today in the journal Nature Microbiology, could have broad implications on the immunological understanding of human diseases caused by RNA viruses including influenza, Ebola, West Nile, and Zika viruses.
“This opens up a new way to understand how humans respond to viral infections and develop new methods to control viral infections,” said Shou-Wei Ding, a professor of plant pathology and microbiology at UC Riverside, who is the co-corresponding author of the paper.
The findings build on more than 20 years of research by Ding on antiviral RNA interference (RNAi), which involves an organism producing small interfering RNAs (siRNAs) to clear a virus.
His initial research showed that RNAi is a common antiviral defense in plants, insects and nematodes and that viral infections in these organisms require active suppression of RNAi by specific viral proteins. That work led him to study RNAi as an antiviral defense in mammals.
In a 2013 paper in the journal Science he outlined findings that show mice use RNAi to destroy viruses. But, it remained an open debate as to whether the same was true in humans.
That open debate led Ding back to a key 2004 paper in which he described a new activity of a protein (non-structural protein 1, or NS1) in the influenza virus that can block the antiviral function of RNAi in fruit flies, a common model system used by scientists.
In the current Nature Microbiology paper, the researchers demonstrated that human cells produce abundant siRNAs to target the influenza A virus when the viral NS1 is not active.
They showed that the creation of viral siRNAs in infected human cells is mediated by an enzyme known as Dicer and is potently suppressed by both the NS1 protein of influenza A virus and a protein (virion protein 35, or VP35) found in Ebola and Marburg viruses.
The researchers in the lab of the co-corresponding author, Kate L. Jeffrey, an investigator in the Massachusetts General Hospital gastrointestinal unit and an assistant professor of medicine at Harvard Medical School, further demonstrated that the infections of mature mammal cells by influenza A virus and other RNA viruses are inhibited naturally by RNAi, using mice cells specifically defective in RNAi.
“Our studies show that the antiviral function of RNAi is conserved in mammals against distinct RNA viruses, suggesting an immediate need to assess the role of antiviral RNAi in human infectious diseases caused by RNA viruses, including Ebola, West Nile, and Zika viruses,” Jeffrey said.
The Nature Microbiology paper is called “Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells.”
Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year.
Dengue vaccine development is challenging because of the need to induce simultaneous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial efficacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been precisely molded using Particle Replication in Non-wetting Template (PRINT) technology.
Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE), purified and adsorbed to poly (lactic-co-glycolic acid) (PLGA) nanoparticles of different sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika.
Dengue virus (DENV) is transmitted by mosquitoes and is endemic in over 120 countries, causing over 350 million infections yearly. Most infections are clinically unapparent, but under specific conditions, dengue can cause severe and lethal disease. DENV has 4 distinct serotypes and secondary DENV infections are associated with hemorrhagic fever and dengue shock syndrome. This enhancement of infection complicates vaccine development and makes it necessary to induce protective immunity against all 4 serotypes. Since whole virus vaccine candidates struggle to induce protective immunity, we are developing a nanoparticle display vaccine approach. We have expressed, purified and characterized a soluble recombinant E-protein (sRecE). Regardless of nanoparticle shape or size, particulation of sRecE enhances DENV specific IgG titers and induces a robust, long lasting neutralizing antibody response and by adsorbing sRecE to the nanoparticles, we prolong the exposure of sRecE to the immune system.
Nanoparticle display shows great promise in dengue vaccine development and possibly other mosquito-borne viruses like zika virus.
Discovery shows existing drugs can treat virus
A team of researchers from Florida State University, Johns Hopkins University and the National Institutes of Health has found existing drug compounds that can both stop Zika from replicating in the body and from damaging the crucial fetal brain cells that lead to birth defects in newborns.
One of the drugs is already on the market as a treatment for tapeworm.
“We focused on compounds that have the shortest path to clinical use,” said FSU Professor of Biological Science Hengli Tang. “This is a first step toward a therapeutic that can stop transmission of this disease.”
Tang, along with Johns Hopkins Professors Guo-Li Ming and Hongjun Song and National Institutes of Health scientist Wei Zheng identified two different groups of compounds that could potentially be used to treat Zika — one that stops the virus from replicating and the other that stops the virus from killing fetal brain cells, also called neuroprogenitor cells.
One of the identified compounds is the basis for a drug called Nicolsamide, a U.S. Food and Drug Administration approved drug that showed no danger to pregnant women in animal studies. It is commonly used to treat tapeworm.
This could be prescribed by a doctor today, though tests are still needed to determine a specific treatment regimen for the infection.
Their work is outlined in an article published Monday by Nature Medicine.
Though the Zika virus was discovered in 1947, there was little known about how it worked and its potential health implications — especially among pregnant women — until an outbreak occurred in South America last year. In the United States, there have been 529 cases of pregnant women contracting Zika, though most of those are travel related. As of Aug. 24, there have been 42 of locally transmitted cases in Florida.
The virus, among other diseases, can cause microcephaly in fetuses leading them to be born with severe birth defects.
“It’s so dramatic and irreversible,” Tang said. “The probability of Zika-induced microcephaly occurring doesn’t appear to be that high, but when it does, the damage is horrible.”
Researchers around the world have been feverishly working to better understand the disease — which can be transmitted both by mosquito bite and through a sexual partner — and also to develop medical treatments.
Tang, Ming and Song first met in graduate school 20 years ago and got in contact in January because Tang, a virologist, had access to the virus and Ming and Song, neurologists, had cortical stem cells that scientists needed to test.
The group worked at a breakneck pace with researchers from Ming and Song’s lab, traveling back and forth between Baltimore and Tang’s lab in Tallahassee where they had infected the cells with the virus.
In early March, the group was the first team to show that Zika indeed caused cellular phenotypes consistent with microcephaly, a severe birth defect where babies are born with a much smaller head and brain than normal.
They immediately delved into follow-up work and teamed with NIH’s Zheng, an expert on drug compounds, to find potential treatments for the disease.
Researchers screened 6,000 compounds that were either already approved by the FDA or were in the process of a clinical trial because they could be made more quickly available to people infected by Zika.
“It takes years if not decades to develop a new drug,” Song said. “In this sort of global health emergency, we don’t have time. So instead of using new drugs, we chose to screen existing drugs. In this way, we hope to create a therapy much more quickly.”
All of the researchers are continuing the work on the compounds and hope to begin testing the drugs on animals infected with Zika in the near future.
Learn more: FSU research team makes Zika drug breakthrough
Anxiety over the Zika virus is growing as the Olympic Games in Rio de Janeiro approach. To better diagnose and track the disease, scientists are now reporting in ACS’ journal Analytical Chemistry a new $2 test that in the lab can accurately detect low levels of the virus in saliva.
The World Health Organization (WHO) recently announced that there was no need to postpone or move the Olympics due to Zika’s presence, but concern over the virus’ spread and its link to serious birth defects is far from allayed. Public health experts debate whether WHO made the right call. But while the discussion continues, scientists are working on new tools to help manage the outbreak. Current gold-standard tests to detect the virus require expensive lab equipment and trained personnel. Low-cost diagnostic methods have been reported but can’t detect low levels of the disease or don’t distinguish between Zika and similar viruses such as dengue. Changchun Liu and colleagues wanted to design a rapid, low-cost, and more reliable point-of-care detection test.
Researchers at the University of Wisconsin–Madison have confirmed that a benign bacterium called Wolbachia pipientis can completely block transmission of Zika virus in Aedes aegypti, the mosquito species responsible for passing the virus to humans.
Matthew Aliota, a scientist at the UW–Madison School of Veterinary Medicine(SVM) and first author of the paper — published today (July 1, 2016) in the journal Scientific Reports — says the bacteria could present a “novel biological control mechanism,” aiding efforts to stop the spread of Zika virus.
Thirty-nine countries and territories in the Americas have been affected by the Zika epidemic, and it is expected that at least 4 million people will be infected by the end of the year. Scientists believe the virus is responsible for a host of brain defects in developing fetuses, including microcephaly, and has contributed to an uptick in cases of a neurological disorder called Guillain-Barre syndrome. There are not yet any approved Zika virus vaccines or antiviral medications, and ongoing mosquito control strategies have not been adequate to contain the spread of the virus.
Researchers led by Jorge Osorio, a UW–Madison professor of pathobiological sciences, and Scott O’Neill of the the Eliminate Dengue Program (EDP) and Monash University in Melbourne, Australia, are already releasing mosquitoes harboring the Wolbachia bacterium in pilot studies in Colombia, Brazil, Australia, Vietnam and Indonesia to help control the spread of dengue virus. Their work is supported by the Bill and Melinda Gates Foundation.
An important feature of Wolbachia is that it is self-sustainable, making it a very low-cost approach for controlling mosquito-borne viral diseases that are affecting many tropical countries around the world.
Scientists at The University of Texas at Austin have developed a new method to rapidly detect a single virus in urine, as reported this week in the journalProceedings of the National Academy of Sciences.
Although the technique presently works on just one virus, scientists say it could be adapted to detect a range of viruses that plague humans including Ebola, Zika and HIV.
“The ultimate goal is to build a cheap, easy-to-use device to take into the field and measure the presence of a virus like Ebola in people on the spot,” says Jeffrey Dick, a chemistry graduate student and co-lead author of the study. “While we are still pretty far from this, this work is a leap in the right direction.”
The other co-lead author is Adam Hilterbrand, a microbiology graduate student.
The new method is highly specific, meaning it is only sensitive to one type of virus, filtering out possible false negatives caused by other viruses or contaminants.
There are two other commonly used methods for detecting viruses in biological samples, but they have drawbacks. One requires a much higher concentration of viruses, and the other requires samples to be purified to remove contaminants. The new method, however, can be used with urine straight from a person or animal.
A novel, inexpensive method for detecting the Zika virus could help slow spread of outbreak, and potentially other future pandemic diseases
An international, multi-institutional team of researchers led by synthetic biologist James Collins, Ph.D., at the Wyss Institute for Biologically Inspired Engineering at Harvard University, has developed a low-cost, rapid paper-based diagnostic system for strain-specific detection of the Zika virus, with the goal that it could soon be used in the field to screen blood, urine, or saliva samples.
“The growing global health crisis caused by the Zika virus propelled us to leverage novel technologies we have developed in the lab and use them to create a workflow that could diagnose a patient with Zika, in the field, within 2-3 hours,” said Collins, who is a Wyss Core Faculty member, and Termeer Professor of Medical Engineering & Science and Professor of Biological Engineering at the Massachusetts Institute of Technology (MIT)’s Department of Biological Engineering.
Building off previous work done at Harvard’s Wyss Institute by Collins and his team, along with collaborators from Massachusetts Institute of Technology (MIT), the Broad Institute of Harvard and MIT, Harvard Medical School (HMS), University of Toronto, Arizona State University (ASU), University of Wisconsin-Madison (UW-Madison), Boston University (BU), Cornell University, and Addgene, joined their efforts to quickly prototype the rapid diagnostic test and describe their methods in a study published online May 6 in the journal Cell, all within a matter of six weeks. Collins is the paper’s corresponding author.
Emerging innovation during the Ebola health crisis
In October 2014, Collins’ team developed a breakthrough method for embedding synthetic gene networks — which could be used as programmable diagnostics and sensors – on portable, small discs of ordinary paper.