Richard Elliott, virologist

Vincent and Richard ElliottVirologist Richard Elliott passed away on 5 June 2015. I have known Richard since 1979 and I would like to provide some personal recollections of this outstanding virologist. A summary of his work can be found at the MRC-University of Glasgow Centre for Virus Research science blog.

I first met Richard in 1979 when he joined Peter Palese’s laboratory at Mt. Sinai School of Medicine in New York City. We overlapped for only about a year but it was enough to get to know him: he was a hard-working, enthusiastic virologists and a good friend. We shared many beers in New York City. At the end of 1979 I went off to David Baltimore’s laboratory where in 1981 I produced an infectious DNA clone of poliovirus. It proved very difficult to make infectious DNAs of negative strand RNA viruses, and it was Richard who was the first to accomplish this feat in 1996 for a virus with a segmented genome. This work was very important as it showed that infectious DNA clones were not limited to RNA viruses with monopartite genomes.

I remained in contact with Richard over the years but I did not see him in person until the 2010 meeting in Edinburgh of the Society for General Microbiology. The following year he joined me, Connor Bamford, Wendy Barclay, and Ron Fouchier for TWiV #177 recorded in Dublin. Schmallenberg virus had just emerged as a new pathogen of livestock, and he discussed his work on this virus.

I next saw Richard in a 2011 meeting of the Brazilian Society for Virology. When I arrived in Brazil it was quite hot, and I found Richard sitting by the pool, reviewing manuscripts in his bathing suit. I snapped a few photos of him and put them on Facebook. Later that evening he said his laboratory had asked why pornographic photos of him were on the internet – he was shirtless in my pictures (with Grant McFadden in the photo).

Richard Elliott and Grant McFadden

Richard visited New York in the summer of 2014 but we were unable to connect. Early this year Richard had agreed to join TWiV again for an episode from Glasgow. Sadly he became too ill to participate and died on the Friday before I traveled to Scotland. While there I briefly visited the Elliott lab at the University of Glasgow MRC-Centre for Virus Research, nearly a week after his death. I’m happy that I made the lab members smile:

Elliott lab

I can still remember Richard telling me how to spell his name: two ls, two ts. Richard was an excellent virologist, mentor, and friend. I will miss him.

Update: Corrected to reflect the fact that Richard produced the first infectious DNA of a segmented (-) strand RNA virus.

Heartland virus disease

Amblyomma americanum

Six new cases of Heartland virus disease have been identified in residents of Missouri and Tennessee. The cause of this disease appears to be a member of the Phlebovirus genus in the Bunyaviridae family that was first identified in 2009 and appears to be transmitted by the Lone Star tick (Amblyomma americanum, pictured).

Heartland virus was first identified in two Missouri farmers who were hospitalized with fever, leukopenia (low numbers of white blood cells), and thrombocytopenia (low numbers of platelets). Both were males over 55 years old who reported being bitten by ticks in the week before disease onset. The novel virus was identified by electron microscopy, viral culture, and genome sequencing. For a complete discussion of this case, listen to This Week in Virology #199.

The tick A. americanum was implicated in transmission of Heartland virus because this species is extremely abundant in central and southern Missouri. However, virus was not isolated from ticks.

Since the description of the first two cases of Heartland virus disease, the Centers for Disease Control and Prevention have worked with state and local partners to develop diagnostic tests and identify additional cases. The six new cases were identified in 2012-13 in men over 50 years of age with fever, leukopenia, and thrombocytopenia. Presence of Heartland virus was determined by polymerase chain reaction using blood or tissue specimens, and by detecting a rise in antibodies against the virus in serum samples taken during and after illness. All six patients spent hours outdoors each day, and five reported tick bites in the two weeks preceding illness onset.

These studies strongly suggest but do not prove that Heartland virus was transmitted by ticks to these patients. One important piece of information will be finding Heartland virus in ticks. A first step is the identification of viral RNA sequences by polymerase chain reaction from ticks captured on the farms of the first two Missouri patients.

These findings raise several interesting questions. Why have the 8 patients with Heartland virus disease all been elderly males? Has this virus been present in the US for some time, and we have just detected it, or was it introduced from elsewhere? Does the virus circulate only in Missouri and Tennessee, and might it be found in other species of tick? Is there an animal reservoir as has been suggested? And what is the relationship of Heartland virus with the phlebovirus that causes severe fever with thrombocytopenia syndrome (SFTSV), an emerging disease in China that has also been detected in Japan and South Korea? Nucleotide sequence analysis reveals that Heartland viruses and SFTSV are highly related.

TWiV 221: Bunya there, done that

On episode #221 of the science show This Week in Virology, Vincent, Dickson, and Kathy review two emerging bunyaviruses, SFTSV and SBV.

You can find TWiV #221 at www.microbe.tv/twiv.

A new rhabdovirus from a patient with hemorrhagic fever

Viral hemorrhagic fevers in AfricaHemorrhagic fevers are among the most graphic viral diseases, inspiring movies, novels, and a general fear of infection. They are characterized by an abrupt onset and a striking clinical course involving bleeding from the nose and mouth, vomiting with blood, and bloody diarrhea. The most famous hemorrhagic fevers are produced by infection with filoviruses like Ebola virus, but members of three other viral families – Arenaviridae, Bunyaviridae, and Flaviviridae – can also cause this syndrome. The isolation of a novel rhabdovirus from an African with hemorrhagic fever suggests that members of a fifth viral family can also cause this disease.

Three cases of hemorrhagic fever that occurred in the spring of 2009 were noteworthy because none of the typical viral suspects could be detected in one patient. Two were young (13, 15 year old) students in the village of Mangala, Bas-Congo province, Democratic Republic of Congo. They lived near each other and went to the same school. Both arrived at the local health center with typical symptoms of hemorrhagic fever, and both died 2-3 days later. The third case was a 32 year old male nurse at the health center who was involved in the care of the other two patients. He developed symptoms of hemorrhagic fever but recovered within a few days.

Deep sequence analysis of RNA extracted from the serum of patient #3 revealed the presence of a novel rhabdovirus, provisionally named Bas-Congo virus (BASV). Phylogenetic analyses reveal that BASV is substantially diverged from the two main human rhabdoviruses, rabies virus and Chandipura virus (ten of the 160 known species of rhabdoviruses have been isolated from humans). BASV is more related to viruses of the Tibrogargan group and the Ephemerovirus genus, which contain arthropod-borne viruses that infect cattle, but clusters separately in an independent branch of the phylogenetic tree.

Antibodies to BASV were detected in the serum of patient #3 and also in the serum of an asymptomatic nurse who had cared for this patient. However, no antibodies to this virus were found in 43 other serum samples from individuals with hemorrhagic fever of unknown origin. These samples came from individuals who lived in 9 of the 11 provinces of the DRC, including Bas-Congo. Nor were antiviral antibodies detected in plasma from 50 random blood donors in one DRC province.

Although the viral genome sequence was determined from RNA extracted from patient serum (where there were 1 million copies per ml of the viral RNA), the virus did not replicate in cell cultures from monkey, rabbit, and mosquito, or in suckling mice. These findings are in contrast to those obtained with a newly discovered coronavirus in humans. It is likely that the samples had not been kept sufficiently cold to maintain viral infectivity. It should be possible to recover virus from a cloned DNA copy of the viral genome.

These data suggest, but do not prove, that BASV caused hemorrhagic fever in the 3 patients. All three cases occurred in a 3 week period within the same small village. BASV nucleic acid and antibodies were detected in the third patient. Given that viruses of the closely related Tibrogargan group and the Ephemerovirus genus are transmitted to cattle by biting midges, it is possible that the initial infections were transmitted by such an arthropod vector. Human to human transmission of the virus could have taken place when the nurse was infected by one or both pediatric patients. However, it should be noted that infection with BASV was not confirmed in either of the first two cases as no clinical samples were available. Other etiologies for this outbreak of hemorrhagic fever should not be ruled out.

Rhabdoviruses are known to cause encephalitis, vesicular stomatitis, or flu-like illness in humans, not hemorrhagic fevers. But these viruses clearly have the potential to cause this disease: members of the Novirhabdovirus genus cause hemorrhagic septicemia in fish. As long as there are viruses to discover, any rules we make about them should be considered breakable.

G Gerard, JN Fair, D Lee, E Silkas, I Steffen, J Muyembe, T Sittler, N Veerarghavan, J Ruby, C Wang, M Makuwa, P Mulembakani, R Tesh, J Mazet, A Rimoin, T Taylor, B Schneider, G Simmons, E Delwart, N Wolfe, C Chiu, E Leroy. 2012. A novel rhabdovirus associated with acute hemorrhagic fever in central Africa. PLoS Pathogens  8.

TWiV 199: Of mice, ticks, and pigs

On episode #199 of the science show This Week in Virology, Vincent, Alan, Rich, and Kathy discuss recent outbreaks of hantavirus pulmonary syndrome in Yosemite National Park and novel swine-origin influenza in the US midwest, and isolation of the Heartland virus from two patients in Missouri with severe febrile illness.

You can find TWiV #199 at www.microbe.tv/twiv.

Schmallenberg virus

On TWiV #186, in response to a request to talk about Schmallenberg virus, we directed the listener to our discussion of this new virus with Richard Elliott on TWiV #177 – Live in Dublin. At the same meeting (Society for General Microbiology Spring Conference 2012) Richard also gave a separate presentation on Schmallenberg virus, which can be viewed in the video below.

Update: Schmallenberg virus is a recombinant of two known orthobunyaviruses.

TWiV 177: Live in Dublin

On episode #177 of the science show This Week in Virology, Vincent, Connor Bamford, Wendy Barclay, and Ron Fouchier discussed avian influenza H5N1 transmission experiments in ferrets and novel bunyaviruses at the 2012 Spring Conference of the Society for General Microbiology in Dublin, Ireland.

You can find TWiV #177 at www.microbe.tv/twiv.

TWiV 127: Viruses are no joke

cold chainHosts: Vincent Racaniello, Alan Dove, and Rich Condit

Vincent, Alan, and Rich explore a novel bunyavirus isolated in China, the recent polio outbreak in Republic of the Congo, and cell to cell transmission of a retrovirus by biofilm-like extracellular assemblies.

Click the arrow above to play, or right-click to download TWiV #127 (62 MB .mp3, 86 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

Weekly Science Picks

Rich – Should smallpox be destroyed? (Emerging Infectious Diseases)
Alan – Zoology of the Beagle images
Vincent – Vaccines and Your Child by Paul Offit and Charlotte Moser

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

Could Rift Valley fever come to the US?

rift-valleyIn an NYTimes Op-Ed article called “The Scary Caterpillar”, Jeffrey Lockwood wrote about potential use of a virus as a weapon of bioterrorism:

What if a terrorist group announced that their operatives had introduced Rift Valley fever into the United States? This mosquito-borne disease would make West Nile virus look like a case of the sniffles. Given that virtually every corner of America has a native species of mosquito capable of transmitting the virus, Rift Valley fever could spread across the nation. Hundreds of thousands of people could be sickened, with thousands dying and many more falling blind. The livestock industry could lose billions of dollars as animals aborted their fetuses and succumbed to bloody diarrhea. Imagine the fear if every mosquito bite this summer could be the precursor of a disease that would cause your brain to become inflamed or your internal organs to hemorrhage?

To me it reads like a movie script, not a serious assessment. Let’s dissect the statement and find out the truth.

Rift Valley fever virus (RVFV) is a member of the Bunyaviridae, a large family of enveloped, RNA containing viruses that includes the well known hantaviruses. The virus was first isolated in 1930 from a lamb during investigation of a disease that was causing abortion and mortality in Kenyan sheep. Since then the virus has caused large outbreaks of disease in livestock. Because infection may lead to high rates of abortion and death, the virus has substantial economic impact. The virus is transmitted among livestock by mosquito vectors. Epizootics often occur when precipitation is high, favoring mosquito breeding.

Outbreaks were confined to livestock in Africa until September 2000 when the disease was observed in Saudi Arabia and Yemen. These epidemics were believed to be a consequence of more abundant mosquito populations that resulted from heavy rain and flooding near the Asir mountains. There is some concern that the virus might spread to Europe, but that has not been observed.

RVFV may also infect humans; in the vast majority of such cases, transmission occurs by direct contact with the blood or organs of infected animals. Some infections are transmitted by mosquitoes, but this is certainly not the main route of human infection.

How serious is human disease caused by RVFV? Most cases are mild, and involve non-specific symptoms including fever, muscle and joint pain, and headache; neck stiffness and vomiting may also occur. About 1% of infected patients may develop more serious disease including eye infection, meningoencephalitis, and hemorrhagic fever. Fatality is typically less than 1%, although in the outbreak in Yemen and Saudi Arabia it was 12%.

What mosquitoes are known to carry RVFV? The principal vector appears to be mosquitoes of the Aedes genus, although Culex species have been shown to transmit the virus in the laboratory. However, the particular species known to transmit RVFV in Africa are not the predominant type of mosquito in the US.

It is clear that nearly every statement in the paragraph reproduced above from “The Scary Caterpillar” is an exaggeration. Rift Valley disease usually does not make West Nile encephalitis look like a case of the sniffles; every corner of America does not have a mosquito capable of transmitting the virus, and the disease severity is overstated. Whether or not the virus could be entrenched in the US is not known  – we might not have the proper climate for the levels of mosquito infestation that is required for transmission. Like all viruses, RVFV is capable of changing so that it could cause extensive human disease in the US – but our current understanding of the viral disease is completely inconsistent with Lockwood’s description.

There are other bothersome errors in the passage. The writer calls Rift Valley Fever a ‘mosquito borne disease’, but readers of virology blog know that it is the virus that is borne by the mosquito, not the disease. And the terrorists would not be introducing the disease into the US – they would introduce the virus. Finally, the sentence “This mosquito-borne disease would make West Nile virus look like a case of the sniffles” just isn’t right – you can’t compare a disease with a virus. But these are small errors when compared with the outright exaggerations of the article.

Perhaps the fact that the author of the Times piece, Jeffrey A. Lockwood, is not a virologist, but a professor of natural sciences and humanities at the University of Wyoming, explains why he does not understand the biology of Rift Valley fever virus.

Moutailler, S., Krida, G., Schaffner, F., Vazeille, M., & Failloux, A. (2008). Potential Vectors of Rift Valley Fever Virus in the Mediterranean Region Vector-Borne and Zoonotic Diseases, 8 (6), 749-754 DOI: 10.1089/vbz.2008.0009

Turell, M., Dohm, D., Mores, C., Terracina, L., Wallette, D., Hribar, L., Pecor, J., & Blow, J. (2008). Potential for North American Mosquitoes to Transmit Rift Valley Fever Virus Journal of the American Mosquito Control Association, 24 (4), 502-507 DOI: 10.2987/08-5791.1