Just how chikungunya went global in 10 years is a story of international travel, viral mutations and an accomplice with wings. Historical accounts suggest that the mosquito-borne virus has ventured from its natural home in Africa several times, even hitting North America in the 1820s. But apart from settling into Southeast Asia in the late 1950s, other sorties from Africa have fizzled.
Not this time. In 2005, chikungunya departed Kenya, hit several islands in the Indian Ocean and spread like a brush fire through India and Southeast Asia, where it lingers today. In 2013, the strain of chikungunya that had been ensconced in Asia since the 1950s found its way to the Caribbean and even nicked Florida in 2014.
It’s not unprecedented for a tropical disease to reach other warm regions. But one strain of the chikungunya virus has found a way to survive in mosquitoes that live in temperate zones, leading to recent forays into Italy and France. North America, China and Europe are now fair game.
That means chikungunya could be coming to a mosquito near you. The virus has not established long-term roots in temperate zones, and no one knows whether it has the chops to do so. But Stephen Higgs, a parasitologist and chikungunya expert at Kansas State University in Manhattan, says U.S. outbreaks are a real possibility.
Crossing the pond
The sleepy island of Réunion sits isolated in the Indian Ocean, far from major shipping lanes. It would seem like an ideal place to dodge global health problems.
But in 2005 and 2006, the French territory became a jumping-off point for the epidemic of chikungunya that sprang from Kenya and still churns in Asia today. The scourge devastated Réunion, racking up 266,000 cases on an island of roughly 800,000 people. At the height of the outbreak, patients were streaming into clinics at a rate of 40,000 per week. The virus also blew through Madagascar, Comoros, Mauritius and Seychelles. When it made landfall in India in late 2005, chikungunya hit the jackpot, causing close to 1.4 million infections. From India it crossed Southeast Asia, spawning outbreaks in Thailand, Cambodia, Malaysia and elsewhere.
This explosion of infections from a previously obscure virus stunned global health experts. India had a spotty history of chikungunya, but hadn’t had a case in 32 years. Réunion had never seen it before. Something had changed.
Story continues after interactive map
Western migration
Hot spots of chikungunya transmission have cropped up widely over the last 60 years, lately reaching the Western Hemisphere. The first U.S. outbreak affected a handful of people in Florida, but elsewhere, outbreaks have varied from hundreds to more than 1 million suspected cases.
SOURCES: M.C. ROBINSON/TRANS. ROYAL SOC. TROP. MED. HYG. 1955; K.A. TSETSARKIN ET AL/PLOS PATH. 2007; REZZA ET AL/LANCET 2007; S.-D. THIBERVILLE ET AL/PLOS NEGL. TROP. DIS. 2013; PAHO MAY 2015; M.L.G. FIGUEIREDO AND L.T.M. FIGUEIREDO/REVISTA DA SOCIEDADE BRASILEIRA DE MEDICINA TROPICAL2014; S. HIGGS AND D. VANLANDINGHAM/VECTOR-BORN ZOO. DIS. 2015; M. AUBRY ET AL/EMERG. INFECT. DIS. 2015; A. POWERS AND C. LOGUE/J. GEN. VIROL. 2007; S. WEAVER AND M. LECUIT/NEJM 2015; S. WEAVER/PLOS NEGL. TROP. DIS. 2014; MOYEN ET AL/PLOS ONE 2014
Réunion seemed an odd stopover for chikungunya because the island had little or no
Aedes aegypti, the tropical mosquito that typically carries the virus around Africa and Asia. Researchers soon figured out that the African chikungunya that hit Réunion had mutated to thrive inside a new carrier, the Asian tiger mosquito,
Aedes albopictus (
SN: 6/29/13, p. 26). Réunion, like many parts of the world, has tiger mosquitoes.
Before the virus mutated, the tiger mosquito couldn’t effectively spread chikungunya. But the mutation has rendered the virus 100 times as adaptable to the tiger mosquito’s innards as it once was. Specifically, the virus underwent a single amino acid change in one of its glycoproteins, a carbohydrate-protein mix called E1, making virus replication much easier in the tiger mosquito. When the mosquito takes a blood meal from a person carrying mutated chikungunya, the pathogen proliferates rapidly in the insect’s midgut and travels to its saliva. As a result, the mosquito’s next bite is like a hypodermic needle loaded with virus. Other mutations found later seemed to help this virus adapt to the tiger mosquito, its new host.
DRILLING DOWN One strain of chikungunya virus has found a way to hitchhike in the Asian tiger mosquito (bottom), which is found in much of the eastern United States. In the tropics, the most common chikungunya carrier is the Aedes aegypti mosquito (top).
BOTH: JAMES GATHANY/CDC
The tiger mosquito offered chikungunya what amounted to frequent flier miles on a fleet of jets bound for cooler climes. Within a few years the virus showed up in Italy and France, ferried from person to person by black-and-white striped tiger mosquitoes. Italy reported about 200 infections in 2007.
That’s a modest number, but it established that chikungunya could successfully venture outside the tropics. “That was a game changer,” says Scott Weaver, a virologist at the University of Texas Medical Branch in Galveston.
Westward bound
A second surprise came in 2013 when chikungunya showed up on the sun-splashed Caribbean island of Saint Martin. A traveler — from the Far East according to genetic characteristics of the virus — apparently arrived in Saint Martin carrying the virus and was bitten by a local mosquito, which then spread it to other people, says Ann Powers, a molecular virologist at the Centers for Disease Control and Prevention in Fort Collins, Colo. This launched the epidemic in the West.
“Our luck ran out,” Weaver says. In the ensuing year and a half, chikungunya established a foothold in the Americas that it may never relinquish. Florida had 11 cases in 2014 transmitted by local mosquitoes. The warm Gulf Coast may be at risk since the tropical
Ae. aegypti,which appears to be driving the epidemic, can live there, says Higgs.
The good news for now is that the chikungunya strain that hit the Caribbean and Florida isn’t carried by the much-despised tiger mosquito, he adds. That’s probably why the Caribbean infections haven’t penetrated North America beyond Florida. If chikungunya were to catch on in Europe or the eastern United States, it would arrive in a sick traveler but would need to be a strain already adapted to the tiger mosquito.
Meanwhile,
Ae. aegypti is spreading the Asian strain of chikungunya in Latin America and the Caribbean, with tens of thousands of cases confirmed and more than 1 million suspected. The epidemic has stretched to Brazil, which has reported hundreds of cases of person-to-mosquito-to-person spread.
Much of Brazil is home to both the tiger mosquito and
Ae. aegypti, and scientists are trying to determine which insect is spreading the virus there. Brazil has a second two-headed problem: It has cases of the Asian strain of chikungunya that swept the Caribbean as well as the African strain of chikungunya that spilled into the Indian Ocean and learned to ride the tiger mosquito. Researchers don’t know yet if the African strain has mutated in Brazil as it did in Réunion and parts east.
If the virus in Brazil morphs, the West could face a worst-case scenario, because Panama, Mexico and many other countries also harbor both mosquitoes. The risk posed by having a version of chikungunya in the West that has adapted to temperate-zone carriers keeps U.S. infectious disease experts up at night.
“It’s certainly something I worry about,” says Mark Heise, a virologist at the University of North Carolina at Chapel Hill. There is plenty of air traffic between Brazil and North America, he says, and the tiger mosquito’s ever-expanding range includes much of the United States east of the Mississippi River.
To become contorted
The best that can be said about a case of chikungunya is that it confers lifetime immunity. People rarely get it twice. Once is bad enough.
Ann Powers first witnessed people with chikungunya in Comoros in the Indian Ocean, which was hit about the same time Réunion was. “It was incredible to see people in that much pain,” she says. Powers interviewed some patients as they lay down because their ankles were so inflamed they couldn’t stand. “Shaking hands hurt them,” she says.
In a long-term study of 102 Réunion patients, 60 percent still reported joint pain three years after contracting chikungunya, a French team
reported in
PLOS Neglected Tropical Diseases in 2013. In Italy, a one-year follow-up found nearly 67 percent of patients continued to have joint or muscle pain.
Why the virus goes after the joints is a mystery. Joints lack circulation, which might help the virus evade the immune system, Heise says.
The crippling joint symptoms can disable a whole community, says David Morens, a pediatric infectious disease physician at the National Institute of Allergy and Infectious Diseases in Bethesda, Md. “In Asia you see these really massive outbreaks where everybody gets sick at once. The whole town gets incapacitated. There are no taxicabs, no teachers.”
Pregnant women face special risks. Of 39 pregnant women in Réunion who had chikungunya fever around the time they were in labor, 19 had infected newborns. Ten of those infants developed serious complications, most with swelling of the brain. Four became disabled, a French research team
reported in
PLOS Medicine in 2008.
Treatment options are lacking. Aside from fever reducers and fluid replacement, the drug ribavirin shows some benefit. Antibodies from a recovered chikungunya patient might help an exposed person, but more testing is needed.
A
2013 study identified antibodies in mice that can neutralize chikungunya virus and prevent the animals from getting ill. The antibodies even worked when injected after the mice were exposed to the virus, but not if the animals were already showing symptoms, says Heise, who coauthored the report, in
PLOS Pathogens.
One of the problems with chikungunya is how little scientists know about it. In humans, the incubation period — time between exposure and first symptoms — is a guesstimate of one to 12 days. Lab tests show mosquitoes other than
Ae. aegypti and Asian tiger are capable of harboring the virus, but whether they do so extensively in the wild isn’t known. Chikungunya has circulated in Africa for hundreds of years. The natural reservoirs are understood to be nonhuman primates and maybe rodents or other animals. When a mosquito bites an infected animal, that infected blood can be transmitted to humans with the next bite. But even though Asia has millions of monkeys and a history of outbreaks, no wild reservoirs have been identified there.
Outwitting a tricky virus
The molecular structure of chikungunya may provide more guidance — and a way to stop it. The virus relies on two glycoproteins, E1 and E2, to enter and infect a cell. It targets cells found in the blood, muscle, joints, lymph nodes and liver. Once inside a cell, E1, E2 and other viral proteins trigger a complex series of events that revs up manufacture of more virus. In the Réunion outbreak, the mutational change in the viral E1 glycoprotein put this process into overdrive in the Asian tiger mosquito, which spread it around the island, Higgs and his colleagues
reported in 2007 in
PLOS Pathogens.
DAZZLINGLY DANGEROUS A chikungunya virus particle comes studded with tools for infecting cells. The E2 glycoproteins (fuchsia) anchor the virus on cells by binding with protein docking stations called receptors. The E1 glycoproteins (red, blue and yellow) orchestrate cell penetration and virus replication. The viral membrane (green) encloses chikungunya’s genetic material. Once inside a cell, the virus induces its host to produce more virus.
FELIX REY/PASTEUR INSTITUTE
These same proteins might be turned against the virus in a vaccine. One candidate vaccine that contains E1, E2 and other chikungunya proteins can elicit an immune reaction in monkeys and people. In 25 volunteers, a three-shot regimen of these proteins triggered neutralizing antibodies against chikungunya after two doses, NIAID vaccine researcher Julie Ledgerwood and colleagues
reported December 6 in the
Lancet.
The protection remained for 44 weeks and probably lasts longer, she says. Vaccination helped turn the corner against yellow fever, another mosquito-borne virus. While yellow fever is deadlier, it has been suppressed by a long-lasting vaccine and now crops up only sporadically, usually in parts of Africa with low vaccination rates.
Another group is testing a chikungunya vaccine added to a measles shot. At the 2014 meeting of the American Society of Tropical Medicine and Hygiene in New Orleans, Erich Tauber of Themis Bioscience GmbH in Vienna, reported that 42 healthy volunteers given the vaccine produced a strong immune response after the second shot of a three-shot regimen. And Weaver and his colleagues
reported in the
Journal of Infectious Diseases in 2014 that a vaccine they developed showed strong protection against chikungunya in monkeys.
These vaccines are likely to protect against all three major strains of chikungunya, Ledgerwood says, including the morphed virus carried by the tiger mosquito. The greater challenge may be to find funding for testing and mass production. “We’re not short on ideas or tools,” Higgs says. “We’re short on investment.” Whether Big Pharma will go all in against an obscure virus with a funny name is anyone’s guess.
North versus south
How chikungunya will play out in cool climates is equally unclear. If the virus sparks new outbreaks in temperate regions, they will probably be summertime events, Powers says. Winter would douse the fire in North America. “You’re much more likely to have annual reintroduction of the virus” in warm months by travelers coming from endemic areas, she says, than year-round spread.
The use of bug spray and mosquito avoidance might — at least in developed countries — offset the growing reach of the Asian tiger mosquito and thwart chikungunya.
“My feeling is that people in countries like Italy and the United States are probably not exposed to mosquitoes enough,” Weaver says. “We might see small outbreaks but not major epidemics,” thanks mainly to air-conditioning and window screens. Whether those upgrades will be enough to stall the disease remains unknown.
Heise says a lack of these amenities in poor parts of cities could make them high-risk areas. The Asian tiger, he says, “is an incredibly aggressive mosquito.”
For people in the American tropics, the deal may be done. “I don’t see us, in these circumstances, driving chikungunya out of South and Central America,” Higgs says.
Some tropical countries with both kinds of mosquitoes lack good sanitation and have people housed in close urban quarters, a recipe for mosquito-borne disease transmission, Morens says. These conditions, often considered the price of finding work and getting ahead in life, are an ideal setting for disease spread. “Human progress creates opportunities for microbial progress to follow,” he says.
Others doubt that the disease will linger in the West. Historically, chikungunya (mistaken for dengue before the 1950s) may have emerged from Africa every 50 or 60 years, run rampant and burned itself out, says Scott Halstead, an infectious disease physician at the Uniformed Services University of the Health Sciences in Bethesda, Md. He was in Asia in the 1960s when the virus seemed to do just that, even though conditions were ideal for its continued spread. For this reason, Halstead doubts that the current global expansion is permanent.
Morens says that for the virus to stay in the West, it has to either adapt itself to humans or to wild animals. If it infects New World monkeys, as yellow fever did, chikungunya could linger under the radar and periodically jump to people. This is what chikungunya does in Africa. “The other possibility is more alarming,” he says. “The virus adapts itself to a new cycle, completely human-to-mosquito-to-human. Once in that cycle, it’s almost never going to go away.” This is how dengue fever established itself in the Americas, and it’s how chikungunya spreads in Asia.
Infection rates in Central America are down during the current dry season. But that’s about to change, Powers says. “Expect an increase in the number of cases in the near future.” The rainy season is right around the corner.
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