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Defending against viruses is one of the thorniest problems in medicine. Vaccines have been a major success story but can still only fend off a fraction of known viruses. They work by “teaching” our immune system to recognize a specific virus so it can mount an effective immune response if it spots that invader in future. Another approach is the use of antivirals, which prevent viruses from replicating and can be used to treat a current infection if administered quickly. Developing safe antivirals is difficult, however, because viruses hijack the host’s own cellular machinery in order to replicate, so interfering can also harm host cells.
A problem for both approaches is the huge diversity of viral pathogens. For instance, the viral group responsible for at least half of all cases of the common cold—rhinovirus–has at least 160 different types. Developing more than 100 vaccines to cure one illness is obviously not practical, and in any case, other viruses also cause colds. Complicating matters further, many viruses can mutate in ways that make them resistant to drugs or capable of overcoming immunity. All of which is why an important goal in virology is the development of “broad spectrum” antivirals that are effective against many viruses simultaneously.
In a study published Monday in Nature Microbiology, microbiologist Jan Carette of Stanford University and his colleagues report they have found a human gene that produces a protein essential to the function of numerous enteroviruses, a genus that includes rhinoviruses. Experiments in human cells and mice showed a range of enteroviruses cannot replicate without this host protein. The work could pave the way for antivirals effective against multiple illnesses—including most cases of the common cold—and sheds new light on how viruses exploit their host’s own cellular material. Carette and his colleagues have “done a tour de force here, to find this gene and characterize it,” says Ann Palmenberg, a virologist at the University of Wisconsin-Madison, who provided some advice and materials for the study but was not directly involved in it. “It’s a beautiful piece of work.”
Enteroviruses also include poliovirus, coxsackievirus (which causes myocarditis, or heart inflammation) and EV-D68, a virus that has been linked to acute flaccid myelitis . To search for commonalities between these viruses, the researchers used cutting-edge gene-editing technology to inactivate single genes from human cells grown in a lab dish. First they created a bank of cells that each lacked a different gene, spanning the whole human genome. Then they infected these cells with two enteroviruses: EV-D68 and a “type-C” rhinovirus called RV-C15. The latter is a fairly newly discovered rhinovirus type that can seriously exacerbate asthma symptoms and increase the risk of infected infants developing asthma and chronic obstructive pulmonary disease. Although they are both enteroviruses, EV-D68 and RV-C15 are relatively distant relations that mostly make use of different host-cell proteins. The team then looked at which genes were missing in cells that continued to flourish after infection, focusing on the few whose absence thwarted both viruses. In addition to two genes that produce proteins known to be needed by enteroviruses, one little known one stood out: SETD3, which makes a protein of the same name. Carette and his colleagues next investigated how widely enteroviruses, in general, depend on the protein SETD3. They created cells lacking SETD3 and infected them with seven viruses representative of the different species of human enteroviruses: one of each of the three types of rhinovirus (A, B and C), poliovirus, two types of Coxsackievirus and EV-D68. None of these could flourish in SETD3-deficient cells—their replication rate was reduced 1,000-fold as compared with control cells that possessed the gene....
Original findings published on September 16, 2019 in Nature Microbiology:
https://doi.org/10.1038/s41564-019-0551-1
