West Nile complications: bad luck?

Human infection with West Nile Virus (WNV) first made its appearance in the US in 1999 in, of all places, Queens, New York. Humans are an incidental host of the virus which circulates in small land based birds, passing between them via mosquitoes. It's hard to find a place to bite a bird if you are a mosquito, but a number of species know just where to look. There is a rim around the eye, for example, where the bird's blood is accessible via a bite. The female mosquito needs the protein in blood to ovulate. Sometimes the mosquito also bites a human and a WNV infection can occur in a human, but we don't build up enough virus in our blood, although we are infected, to make passage between humans via mosquitoes happen. So it's a bird disease that some unlucky humans get "accidentally." Unfortunately the number of such "accidents" has gotten fairly large. While most WNV infections are mild or even asymptomatic, this year it's estimated there will be some 4000 to 5000 serious WNV infections.

Serious here usually means neurological complications, where the virus gets into the nervous system causing a meningoencephalitis, an inflammation of the brain matter and its covering membranes; or an acute flaccid paralysis, where one or more arms or legs go limp and become unresponsive. WNV is the most common cause of viral encephalitis in the US. Encephalitis occurs more commonly in the elderly or those with impaired immune systems, while acute flaccid paralysis can occurs in younger and immunocompetent patients as well. This epidemiological difference suggested something different might be going on. For encephalitis cases, the virus is able to breach the natural barrier protecting the central nervous system (CNS), the so-called blood-brain barrier. In people with depressed immunity the virus may build to a higher level or the barrier itself may be somehow impaired. Either way, once inside the CNS it can infect nerve cells. Headaches, seizures, coma or death are some of the outcomes. Not good. For patients with acute flaccid paralysis with or without encephalitis something else seems to be going on. A new paper (PNAS, Samuel et al.) suggests one element might be really, really bad luck.

Researchers at Washington University in St. Louis have now showed that WNV can spread in both directions along a neuron in culture. Neurons (nerve cells) can be very long, extending from the spinal cord all the way to the muscles in a limb and all the way from low in the spine up to the brain. A virus introduced into such a long fiber will move both toward and away from the CNS and spinal cord, traveling rapidly in little membrane capsules called vesicles. The rapid transport in the vesicle is characteristic of flow in the nerve cell and is passive as far as the virus is concerned. The virus has no motive power of its own. Infected nerves also shed virus that could infect other nerves to which they were connected in the nervous system network.

To show that what happens in culture is relevant to what goes on in a whole animal, a nerve which goes to the hamster hindlimb from its spinal cord was tied off and WNV injected below or above the tie. Virus injected below the tie produced acute flaccid paralysis, above the tie encephalitis. In other words the virus was blocked by the tie in each case and only produced infections in the accessible direction. Where does bad luck come in?

An untreated human patient's chances of developing flaccid paralysis from West Nile may come down to a roll of the dice, [Washington University's Michael] Diamond speculates. To break through the blood-brain barrier and cause encephalitis, high levels of the virus have to build up in the blood. In the elderly or patients with weakened immune systems, West Nile is able to replicate relatively freely in areas like the skin and lymph tissues, providing additional copies of the virus that build up in the blood. "Paralysis might not require such high levels of infection," he theorizes. "What may happen instead is if a mosquito bites you and the virus is able to replicate in the vicinity of a nerve, by the time the immune system has cleared the infection in the skin, a small amount of virus may already be following the nerve back to the spinal cord. Unless you have a robust antibody response, you're probably not going to clear that fast enough, and you might get paralysis." (Medilexicon.com)

This is pretty interesting work but it sounds like there is a lot more to learn. It may come down to where you are bitten, how much virus gets regurgitated by the mosquito at that point, how fast and how vigorously your immune reaction is and whether it wins the race between the virus crawling up your neuron and your system's ability to clear it before it infects a bunch of other nerve cells.

We may be Hostages to Fortune, but if you don't get bitten in the first place, none of the rest matters.

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