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Sussing out the enemy’s tactics with dengue
04-25-2017
by Jeffrey Bouley  |  Email the author
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NEW YORK—Whether we’re trying to figure out our life partners, children, relatives, friends or co-workers—or that person you want to ask out but have yet to introduce yourself to—it's often about the signals. What signals are being sent, what message is being received.
 
And, as the Mount Sinai Health System pointed out recently with regard to some recent research around the dengue virus (DENV), “for the human body to mount an immune response to a viral infection, host cells must identify the viral invader and trigger a signaling pathway. This signal then prompts the immune system to attack and subdue the pathogen.”
 
With that in mind, and using DENV as a model, researchers from the Icahn School of Medicine at Mount Sinai have reportedly identified the “viral sensor” that initiates an immune response and have also described how the virus counteracts this mechanism and evades immune detection.
 
The paper describing these findings was published in the journal Nature Microbiology, and the findings in it may help give greater understanding to the issue of patient susceptibility to disease severity, in addition to the more direct and obvious insights the findings might offer to vaccine design and potential treatments for DENV infection and perhaps other infectious diseases.
 
In addition, understanding how host cells signal the need for an immune response and the sophisticated mechanisms viruses use to avoid recognition could also inform techniques to dampen unwanted pro-inflammatory responses associated with autoimmune diseases, according to Mount Sinai.
 
“Previous studies have shown that human viruses have acquired specific mechanisms to strategically avoid detection by the innate immune system. Active strategies are used by viruses to minimize the ability of cells to detect and respond to infection, allowing sufficient time for the production of viral progeny,” said last author of the study Dr. Ana Fernandez-Sesma, a professor of microbiology at Icahn. “Our study shows how dengue virus, which affects people around the globe, employs multiple techniques to avoid detection. We shed light on the mechanisms cells use to recognize the traces of viral infection within a cell and the methods viruses have acquired to obstruct them. It is this recognition that eventually leads to an immune response.”
 
Researchers identified cyclic GMP-AMP synthase (cGAS) as the protein responsible for initially detecting viral infection—cGAS, a cytosolic DNA sensor, recognizes DNA that has escaped the nucleus or mitochondria of a cell and entered the cytoplasm, an unusual occurrence. In the case of DENV infection, cGAS recognizes traces of mitochondrial DNA released into the cytoplasm as a consequence of the beginning stages of the infection; it does not recognize the viral particles themselves. Once cGAS binds to DNA, it activates a series of cascading chemical triggers known as the cGAS/cGAMP/STING sensing pathway, which induces type I interferon (IFN) signaling and begins the immune response. Although cGAS has been characterized as a DNA sensor, it has antiviral properties against different positive-strand RNA viruses, like DENV—a characteristic that has not yet been fully explored Mount Sinai points out.
 
DENV in turn reduces the likelihood of triggering the cGAS/cGAMP/STING pathway by degrading cGAS and preventing it from binding with mitochondrial DNA in the cytoplasm of the cell, Mount Sinai further explains. The DENV-encoded protease cofactor NS2B promotes cGAS degradation in an autophagy-lysosome-dependent mechanism.
 
“Previous research from this group has shown that DENV cleaves to STING, an endoplasmic reticulum resident host protein, to prevent type I IFN signaling. Uncovering the role DENV plays in degrading cGAS and stopping the preliminary step of the immune-signaling pathway confirms two separate but coordinated mechanisms the virus uses to thwart a host immune response,” Mount Sinai adds.
 
Interest has been growing in terms of learning more about the interplay between DENV and the mitochondria, and this recent paper “describes a novel mechanism by which human cells can detect damage generated during the early stages of an infection.”
 
“Mapping how cGAS recognizes DENV and the role mitochondrial DNA plays in creating an immune response is another novel insight of this study,” Fernandez-Sesma said. “Until now, it has not been understood how cGAS can play such a critical role in identifying these RNA viruses. Our data strongly suggest that mitochondrial damage and the release of mitochondrial DNA are intrinsic collateral damage during DENV infection and prompt cGAS to activate the necessary immune signaling pathways.”
 
The importance of this work is significant, of course, given that almost half of the people living on Earth are in areas where mosquito species can transmit dangerous viruses like dengue, yellow fever and Zika, among others. Finding new ways to combat DENV and similar viruses can play a crucial role in lessening the enormous global health burden they represent, Mount Sinai notes--further, charting the strategies viruses use to counteract the immune system can be used as a platform for the design of chemical compounds that can mimic this inhibitory effect and address the inflammatory process observed in many autoimmune diseases.
 
The importance of better understanding these related infectious disease is highlighted further by some other Icahn-related research at Mount Sinai, reported in early April this year, that pre-existing immunity to dengue and West Nile viruses may cause increased risk in Zika-infected people.
 
“Recent studies have shown that the Zika virus protein is structured similarly to that of dengue and West Nile," said the study’s co-author, Dr. Adolfo García-Sastre, who is the Irene and Dr. Arthur M. Fishberg Professor of Medicine, professor of microbiology and infectious diseases and director of the Global Health and Emerging Pathogens Institute at Icahn. “Our study is the first large-scale analysis of Zika virus enhancement in individuals infected with dengue and West Nile.”
 
Using blood samples from individuals infected with dengue and West Nile, researchers identified enhancement of Zika virus growth in cell cultures. The dengue- and West Nile-infected plasma was then administered to mice engineered to be susceptible to the Zika virus, resulting in increased mortality and morbidity, including fever and viral loads in the spinal cords and testes of the mice upon virus infection.
 
“We believe the antibody-dependent enhancement may explain the severe disease manifestations associated with recent Zika virus outbreaks, and highlights the need for great caution when designing vaccines for Zika and other flaviviruses,” said co-author Dr. Jean Lim, PhD, an assistant professor of microbiology at Icahn. “Further understanding of pre-existing immunity is a high priority in the development of a vaccine that works.”
 
“We found that the antibody-dependent enhancement effect was dependent on the dose of plasma administered,” added co-author Dr. Florian Krammer, an associate professor of microbiology. “Low concentrations of cross-reactive antibodies clearly enhanced disease.”
 
The studies showed that high concentrations of dengue immune plasma resulted in protection against Zika infection, with 100-percent survival, no weight loss, and decreased symptoms. It was the lower concentrations that resulted in enhanced morbidity and mortality, highlighting that antibody-dependent enhancement is a particular worry in individuals with waning antibody levels.
 
Code: E04261703

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