Researchers at Yale University's School of Medicine have discovered a novel mechanism by which viruses infect neighboring cells. Their discovery, appearing in this week's Nature Cell Biology could lead to new antiviral therapies.
Previous studies found that viruses are ferried from infected to healthy cells by dendritic cells, which are cells that can transport germs without becoming infected themselves. Cell-to-cell transfer of a virus (as opposed to a virus jumping from one infected cell to another) is believed to be as much as 1,000 times more effective at spreading pathogens.
The new study, led by Walter Mothes, a Yale microbial pathogens expert, involved creating one culture that mixed healthy rat cells with cells infected by the murine leukemia virus, a cancerous pathogen in rats and monkeys that is not known to affect humans. The researchers then watched as filopodialong, thin, short-lived filaments on the outside of uninfected cellslatched onto viral cells, stabilized and then allowed viral particles to shimmy across the makeshift spans to spread.
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"Who would have thought that viruses would induce long, thin cell fingers and walk along them?" says Mothes, who notes that the original purpose of this study was to visualize the infectious synapse mechanism, not to view an alternative method of viral transfer. "That the dynamic and short-lived filopodia can be transformed into long and stable bridges is amazing."
Filopodia have also been observed during wing formation in fruit flies. In this newly discovered viral infection mechanism, uninfected cells cast filopodia about in serum until they encounter cells expressing viral envelope protein. Signals from within the two cells then activate the protein actin, which elongates the bridge. Infected cells draw the filopodia in and actually suck in the tips of the filaments. Then, according to Mothes, "viruses 'surf' along filopodia to efficiently infect cells by using the underlying retrograde flow of actin."
Mothes does not believe this mechanismwhich the researchers showed also works with the HIV virus and avian leucosis (a pathogen that causes paralysis in poultry)is a substitute for infectious synapses. "Both must exist, but how they are related to each other needs to be figured out," he says. "Filopodial contacts may precede synapse formation." Thomas Hope, a molecular biologist at Northwestern University's Feinberg School of Medicine, believes that dendritic cells may explain the early stages of infection, while filopodial bridges could be the means by which viruses amplify. "I think [the filopodial mechanism] is pretty neat, but it wouldn't surprise me in the end if everything is [a] slightly different version of the same process," he says. "It's probably providing a more detailed look at things that have been seen before."
Mothes says researchers will do an entire culture to confirm their hypothesis that several cycles of viral transmission can result in the spread of an infection. He notes that the filopodial bridges would have to be transient to limit the amount of infection, because too much viral access would kill cells. "Understanding these details may lead to a new target for future antiviral therapies," Mothes adds. "If we find a kinase that regulates filopodial bridge formation or a kinase that facilitates virus surfing along a filopodium," he says, these enzymes can be targeted to thwart infection.
