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According to a study conducted by researchers at Stanford University and the University of California at San Francisco, temporarily disabling a single protein in our cells could protect us from colds and other viral diseases.
The results were performed in human cell cultures and in mice.
"Our grannies have always asked us," If you're so smart, why do not you come up with a cure for colds? "Said Jan Carette, PhD, associate professor of microbiology and immunology." Now we have a new way of doing that. "
The approach of targeting proteins in our own cells has also helped stop the viruses associated with asthma, encephalitis and polio.
Colds, or upper respiratory tract infections unrelated to influenza, are usually harmful for a week. It is also the most prevalent infectious disease in the world, costing the US economy about $ 40 billion a year. At least half of the colds are the result of rhinovirus infections. There are about 160 known types of rhinovirus, which partly explains why catching a cold does not prevent you from catching another one a month later. Worse, rhinoviruses are very susceptible to mutations and, therefore, rapidly develop drug resistance, and escape immune surveillance caused by previous exposure or vaccine.
In a study published online September 16 in Microbiology of natureCarette and her associates have found a way to prevent a large number of enteroviruses, including rhinoviruses, from replicating within cultured human cells as well as in mice. They accomplished this feat by disabling a protein in mammalian cells that all enteroviruses seem to need to replicate.
Carette shares the lead author role with Or Gozani, MD, PhD, professor of biology at Stanford and biology professor Dr. Morris Herzstein; Raul Andino, PhD, Professor of Microbiology and Immunology at UCSF; and Nevan Krogan, PhD, Professor of Cellular and Molecular Pharmacology at UCSF. The lead authors are Jonathan Diep, a former Stanford graduate student, PhD, and Stanford postdoctoral fellows Yaw Shin Ooi, PhD, and Alex Wilkinson, PhD.
Well known and feared
The poliovirus is one of the best known and most feared enteroviruses. Until the advent of an effective vaccine in the 1950s, the virus resulted in paralysis and death for several thousand children each year, just in the United States. Since 2014, another type of enterovirus, EV-D68, has been implicated in biennial riddles of a polio-like disease, acute flaccid myelitis, in the United States and Europe. Other enteroviruses can cause encephalitis and myocarditis – an inflammation of the brain and heart, respectively.
Like all viruses, enteroviruses travel slightly. To replicate, they exploit the proteins present in the cells they infect.
To determine which proteins in human cells are essential for enteroviral fecundity, the researchers used a genomic screen developed by Carette's lab. They generated a human cell line in culture that enteroviruses could infect. The researchers then used gene editing to randomly disable a single gene in each of the cells. The resulting culture contained, in the aggregate, cells lacking one or the other of the genes of our genome.
Scientists infected the culture with RV-C15, a rhinovirus known to exacerbate asthma in children, and then with EV-C68, implicated in acute flaccid myelitis. In each case, some cells managed to survive the infection and to spawn colonies. Scientists were able to determine which gene from each surviving colony had been decommissioned. While RV-C15 and EV-D68 are both enteroviruses, they are taxonomically distinct and require different proteins from the host cell to execute their replication strategies. Thus, most of the human genes encoding the proteins that each type of virus needed to thrive were also different. But there were only a few genes whose absence prevented the two types from entering cells, replicating, leaving their cell room and invading new ones. One of these genes in particular is demarcated. This gene encodes an enzyme called SETD3. "It was clearly essential to viral success, but little was known about it," Carette said.
The scientists generated a culture of human cells lacking SETD3 and tried to infect them with several different types of enterovirus – EV-D68, poliovirus, three different types of rhinovirus and two varieties of Coxsackie virus that can cause myocarditis. None of these viruses could replicate in SETD3 deficient cells, although all were found to be able to loot cells whose SETD3 production capacity had been restored.
The researchers observed a 1000-fold reduction in the measurement of viral replication in human cells lacking SETD3, compared with controls. Inactivation of SETD3 function in human bronchial epithelial cells infected with various rhinoviruses or by replication reduced by EV-D68 about 100-fold.
Waterproof mice
The transgenic mice lacking SETD3 reached apparently healthy adult age and were fertile, but they were insensitive to infection by two distinct enteroviruses that could cause fatal and paralytic encephalitis, even when these viruses were injected directly in the mouse brain shortly after birth. .
"Unlike normal mice, SETD3-deficient mice were absolutely unaffected by the virus," Carette said. "It was the virus that had died in the water, not the mouse."
Scientists have learned that enteroviruses have no utility for the SETD3 section that cells use for their routine enzymatic activity. Instead, enteroviruses surround a protein whose interaction with a different part of the SETD3 molecule, in yet unknown ways, is necessary for their replication.
"This gives us hope that we will be able to develop a drug with extended antiviral activity not only against the common cold, but perhaps against all enteroviruses, without even disrupting the normal functioning of SETD3 in our cells," said Carette.
Carette and Gozani are members of Stanford Bio-X and the Stanford Institute for Maternal and Child Health Research, as well as Stanford ChEM-H faculty members. Gozani is a member of the Stanford Cancer Institute.
The other Stanford co-authors are graduate student Christine Peters; postdoctoral scholar James Zengel, PhD; Siyuan Ding, PhD, Gastroenterology and Hepatology Medical Instructor; researcher in basic life sciences, Kuo-Feng Weng, PhD; Kristi Kobluk, DMM; Joshua Elias, PhD, Assistant Professor of Chemical Biology and Systems; Peter Sarnow, PhD, Professor of Microbiology and Immunology; Harry Greenberg, MD, Professor of Gastroenterology and Hepatology and Microbiology and Immunology; and Claude Nagamine, PhD, DVM, Associate Professor of Comparative Medicine.
Researchers from Biohub Chan Zuckerberg and the VA Palo Alto Health System also contributed to the work.
Stanford's Departments of Microbiology, Immunology and Biology also supported the work.
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