The first human virus discovered

PlaqueOn the wall of a Columbia University Medical Center building just across the street from my laboratory is a plaque commemorating two participants in the discovery of a mosquito vector for yellow fever virus.

The plaque reads:

Aristides Agramonte, Jesse William Lazear, Graduates of the Columbia University College of Physicians and Surgeons, class of 1892. Acting Assistant Surgeons, U.S. Army. Members of the USA Yellow Fever Commission with Drs. Walter Reed and James Carroll. Through devotion and self-sacrifice they helped to eradicate a pestilence of man.

Yellow fever, known in tropical countries since the 15th century, was responsible for devastating epidemics associated with high rates of mortality. The disease can be mild, with symptoms that include fever and nausea, but more severe cases are accompanied by major organ failure. The name of the illness is derived from yellowing of the skin (jaundice) caused by destruction of the liver. For most of its history, little was known about how yellow fever was spread, although it was clear that the disease was not transferred directly from person to person.

Cuban physician Carlos Juan Finlay proposed in 1880 that a bloodsucking insect, probably a mosquito, was involved in yellow fever transmission. The United States Army Yellow Fever Commission was formed in 1899 to study the disease, in part because of its high incidence among soldiers occupying Cuba. Also known as the Reed Commission, it comprised four infectious disease specialists: U.S. Army Colonel Walter Reed (who was the chair); Columbia graduates Lazear and Agramonte, and James Carroll. Lazear confirmed Finlay’s hypothesis in 1900 when he acquired yellow fever after being experimentally  bitten by mosquitos who had fed on sick patients. Days later, he died of the disease.

The results of the Reed Commission’s study proved conclusively that mosquitoes are the vectors for this disease. Aggressive mosquito control in Cuba led to a drastic decline in cases by 1902.

The nature of the yellow fever agent was established in 1901, when Reed and Carroll injected filtered serum from the blood of a yellow fever patient into three healthy individuals. Two of the volunteers developed yellow fever, causing Reed and Carroll to conclude that a “filterable agent,” which we now know as yellow fever virus, was the cause of the disease.

Sometimes you don’t have to wander far to find some virology history.

Update 6/16/17: The statement on the plaque that Agramonte and Lazear “helped to eradicate a pestilence of man” is of course incorrect, as yellow fever has never been eradicated. Recent large outbreaks of yellow fever in Brazil and Angola are examples of the continuing threat the virus poses, despite the availability of a vaccine since 1938.

TWiV 429: Zika Experimental Science Team

Vincent meets with members of team ZEST at the University of Wisconsin Madison to discuss their macaque model for Zika virus pathogenesis.

You can find TWiV #429 at microbe.tv/twiv, or listen/watch right here.

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TWiV 422: Watching the icosahedron drop

The TWiVestigators wrap up 2016 with a discussion of the year’s ten compelling virology stories.

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TWiV 410: Hurricane Zika

Sharon and Scott join the TWiV team to talk about their work on dengue antibody-dependent enhancement of Zika virus infection, and identifying the virus in mosquitoes from Miami.

You can find TWiV #410 at microbe.tv/twiv, or listen below.

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TWiV 405: All the world’s a phage

The TWiXers discuss a study on vertical transmission of Zika virus by Aedes mosquitoes, and uncovering Earth’s virome by mining existing metagenomic sequence data.

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TWiV 401: Vector victorious

Zika virus spreads in the USA, a Zika virus DNA vaccine goes into phase I trials, and how mosquito bites enhance virus replication and disease, from the friendly TWiFolk Vincent, Dickson, Alan, and Kathy.

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Mosquito saliva enhances virus replication and disease

Biting mosquitoMosquito saliva, which is injected into the host as a mosquito probes for a blood vessel, contains a collection of chemicals which include anticoagulants to prevent blood clotting, vasodilators to keep blood vessels wide, and anesthetics to prevent us from sensing the mosquito. Saliva also contains components that enhance viral replication, dissemination, and pathogenesis by inducing an inflammatory response that inadvertently promotes infection by providing new cell targets for infection (paper link).

To separate the bite from virus inoculation, mice were first exposed to Aedes aegyptii mosquitoes, and then infected at the bite site with two different mosquito transmitted viruses, Semliki Forest virus or Bunyamwera virus. Mosquito bites caused more virus replication at the inoculation site, greater dissemination of virus, and more lethality compared with control mice that received only virus.

How does mosquito saliva enhance virus replication and dissemination? Part of the story is that as the mosquito probes for a blood vessel, it causes damage that leads to vascular leakage and accumulation of fluid (edema) which inhibits movement of virus to draining lymph nodes.

But delaying dissemination of virus alone does not promote infection and disease. Mosquito bites cause an infiltration of neutrophils (a type of white blood cell) into the bite site. The edema at the bite site is enhanced by neutrophils, because depleting these cells from mice greatly reduced edema. This depletion also returned viremia to levels observed in unbitten control mice, and restored dissemination of virus to draining lymph nodes. Neutrophils are not susceptible to infection with Semliki Forest virus, and therefore cannot explain the increase in virus replication at the bite site.

Enhanced virus replication in the skin occurs because the neutrophils elaborate chemokines that attract macrophages, which can be infected by Semliki Forest virus and Bunyamwera virus. One of the chemokines produced by neutrophils that is a macrophage attractant – CCL2 – binds a receptor on macrophages. Mice lacking the gene encoding the CCL2 receptor are protected from bite enhancement of Semliki Forest virus enhancement.

When a mosquito bites a host, it delivers saliva along with a virus. The saliva induces an inflammatory response and attracts neutrophils into the bite site. The resulting edema holds virus at the bite site until chemokines produced by neutrophils attract macrophages, which are then infected. The virus produced disseminates widely, reaching secondary tissues and causing disease.

It seems likely that the ability to replicate in macrophages that are recruited to the bite site is a property that was selected during evolution of mosquito-transmitted viruses. By replicating in macrophages, the amount of virus in the blood is increased, as well as the likelihood that the virus will be picked up by another mosquito and transmitted to a new host – a powerful selection mechanism. The down side – increased disease in the mammalian host – is an accidental side effect.

Think about that the next time you are scratching that raised bump on your skin caused by a mosquito bite.

Zika virus and mosquito eradication

Aedes aegyptiThe Aedes aegypti eradication campaign coordinated by the Pan American Health Organization led by 1962 to elimination of this mosquito from 18 countries, including Brazil. Ae. aegypti transmits not only Zika virus, but dengue virus, chikungunya virus, and yellow fever virus. Could control measures be implemented today to achieve similar control of this mosquito? Two articles in PLoS Neglected Tropical Diseases revisit the successful PAHO mosquito control campaign and suggest that its approaches should be revived.

The elimination of Ae. aegypti in 18 countries, which was accompanied by a marked reduction in dengue hemorrhagic fever, was achieved by removing mosquito breeding sites or spraying them with DDT. Determining whether households harbored such breeding sites was essential for the effectiveness of the campaign.

The United States did not participate in the PAHO campaign, even though Ae. aegypti was (and still is) present in that country, and was a vector for outbreaks of dengue fever from the 1920s through the 1940s. Peter Hotez (link to paper) cites a “lack of funds and political will” and “logistical difficulties due to lack of access to private homes or cultural norms of privacy in the US”. As a consequence, by 1970 the US became one of the last reservoirs of Ae. aegypti in the Americas.

Eventually the PAHO campaign fell apart and Ae. aegypti returned, followed by outbreaks of dengue fever in the 1980s in Latin America and the Caribbean, and Chikungunya virus and Zika virus in 2013.

Hotez argues that while control of Ae. aegypti is labor intensive and involves house-to-house spraying, PAHO demonstrated its feasibility. He further suggests that by not participating in the PAHO campaign, the US failed to establish a generation of mosquito control expertise, which is now needed as Zika virus and other mosquito-borne viruses threaten to spread. He calls for an “unprecedented campaign against the Ae. aegypti mosquito”. However, he does not specify exactly what kind of control should be implemented, only saying that “these activities might not closely resemble the Latin American programs of the 1960s”.

Paul Reiter (link to paper) believes that the success of the PAHO campaign “can be attributed to a single aspect of the behavior of the mosquitoes: female Ae. aegypti do not lay all their eggs in one basket”, but rather place them at multiple locations. During the PAHO campaign, infested containers were identified and sprayed with DDT, increasing the likelihood that a female would lay eggs at a site that had been treated. This approach is called perifocal.

The current use of fogging machines to spray residential areas with insecticides has a low impact on mosquito populations, according to Reiter, because they only work for a few minutes when the droplets are airborne. He believes that we should return to perifocal treatments to eliminate mosquitoes, but not using DDT. Rather he suggests the use of other, novel insecticides, such as crystals of deltamethrin embedded in a rain and sun-proof polymer that ensures release for three months.

Reiter acknowledges that long-term use of insecticides leads to resistance, in which case we should turn to the new anti-mosquito approaches that are being developed, including the release of mosquitoes containing Wolbachia bacteria or a lethal gene. But he indicates that these approaches “are some way from mass application”, and meanwhile, perifocal approaches could reduce mosquito populations (although the newer insecticides would first need to be tested).

The best way to prevent viral infection is with a vaccine, but one for Zika virus is likely years away. Meanwhile, mosquito control can make a difference, as it could for the next emerging virus well before a vaccine can be developed.

Virus Watch: How mosquitoes spread viruses

In this episode of Virus Watch, I explain how mosquitoes spread viruses. We’ll look at how a mosquito finds a host, how it finds a blood vessel, and how it delivers viruses to a new host. Don’t blame mosquitoes for viral diseases: it’s not their fault!

TWiV 392: Zika virus!

Four virologists discuss our current understanding of Zika virus biology, pathogenesis, transmission, and prevention, in this special live episode recorded at the American Society for Microbiology in Washington, DC.

You can find TWiV #392 at microbe.tv/twiv, or listen/watch below.

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