TWiV 311: Bulldogs go viral

17 November 2014

On episode #311 of the science show This Week in Virology, Vincent visits the University of Georgia where he speaks with Zhen Fu and Biao He about their work on rabies virus and paramyxoviruses.

You can find TWiV #311, audio and video versions, at www.twiv.tv.

Phycodnaviridae virionMany well-known human viruses, including poliovirus, rabies virus, West Nile virus, can infect cells of the nervous system, leading to alterations in the function of that organ. Could a virus that infects algae also cause human neurological alterations?

Chloroviruses are large DNA-containing viruses that infect unicellular algae called zoochlorellae (pictured: image credit, ViralZone). Unexpectedly, chlorovirus DNA sequences were found in the oropharynx of 40 of 92 individuals (43.5%) who had no known physical or psychiatric illness. The clinical specimens had been obtained as part of a study of cognitive function, and it was possible to determine that presence of chlorovirus DNA was associated with a slight but statistically significant decreased performance in tests for visual motor speed, delayed memory, and attention.

When mice were fed chlorovirus-infected algae, they showed decreased performance in tests of cognitive function, such as recognition memory and sensory-motor gating. Some of these animals developed antibodies against the virus, suggesting that viral replication took place. Furthermore, feeding of chlorovirus to mice was associated with changes in gene expression in the hippocampus, the part of the brain essential for learning, memory, and behavior.

It is not known if the chlorovirus replicates in humans or in mice; only viral nucleic acids were detected. No mention is made of attempts to isolate infectious chloroviruses from humans or mice. The amount of chlorovirus in the oropharynx is not known. However the results of sequence analysis, in which low numbers of sequences were found in each person suggest very low numbers of genomes. Of course, it is possible that virus replication took place some time ago, and its effects linger after replication has subsided.

Chloroviruses are commonly found in inland waters, and the subjects could have acquired the virus via inhalation or drinking contaminated water. It is entirely possible that the virus does not replicate in humans, but is present in the oropharynx as a common environmental contaminant. Many plant and insect virus sequences can be isolated from the human intestinal tract as a consequence of the food we ingest, but there is no evidence that they can replicate at that site. Consequently, chlorovirus might not have any role in the reduced cognitive functions observed in this study. It is possible that exposure to another factor together with chloroviruses, such as heavy metals, is responsible for the observed cognitive differences.

The suggestion that a virus infection might cause subtle cognitive defects is not outlandish. For example, lymphocytic choriomeningitis virus infects rodents congenitally or immediately after birth and establishes a persistent infection of virtually all tissues. These mice show no outward signs of illness, but careful study of infected animals reveals that they are less ‘smart’ than their uninfected peers.

The results are intriguing and warrant more study, including a determination of whether an infectious chlorovirus can be isolated from humans, whether this virus can replicate in human cells in culture, and how they differ from environmental isolates. It would also be important to determine if antibodies to chloroviruses are present in humans, and if they are associated with any diseases. It is too early to conclude that a virus of algae causes altered human neurological functions.

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transmission-image-ebolaAfter the governors of New York and New Jersey decided that health workers who have returned from the Ebola virus outbreak in West Africa should be subject to a 21-day quarantine, two Nobel laureates entered the fray. Bruce Beutler feels that the quarantine is the right thing to do, while Peter Doherty says it’s wrong. Which laureate is right?

The key issue in this debate is the assumption that someone who has been infected with Ebola virus, and does not display symptoms, is not contagious. Beutler doesn’t believe that there is enough evidence for this assumption: “People may have said that without symptoms you can’t transmit Ebola. I’m not sure about that being 100 percent true. There’s a lot of variation with viruses.” (source: NJ.com). On the other hand, Doherty says “the evidence-based consensus among the professionals seems to be that this is not necessary” (source: NJ.com).

As I’ve written before, our knowledge of the non-contagious nature of Ebola virus infected patients is based on experience with previous outbreaks.  To make sure I wasn’t missing anything that Beutler had noted, I examined the published summaries of the previous outbreaks of Ebolaviruses. There have been 24 outbreaks caused by these viruses, summarized in a table by CDC.  In poring over the outbreak data, I looked for information on how the virus is transmitted. These data are typically obtained by interviewing Ebola virus patients or their families, and constructing chains of transmission – who infected who, and how the infection was transmitted. Because it is not always possible to determine exactly how transmission took place, the interviewers attempt to determine what kinds of activities are most associated with acquiring infection. These activities are called ‘risk factors’.

I was particularly interested in determining if the following was a risk factor in any of the 23 previous outbreaks: some type of contact with a healthy person who subsequently developed Ebola hemorrhagic fever (EHF). I didn’t find any. All transmissions that could be assessed involved an obviously sick individual, and never from anyone who was healthy.

The first two recognized outbreaks of infection were in 1976 in Zaire (Ebola virus) and in Sudan (Sudan virus). The former comprised 318 cases, and infection was spread by close contact with patients and by using contaminated needles. The Sudan oubreak of 284 cases started in workers of a cotton factory, and was amplified by transmission in a hospital. Transmission required close contact with an acute case, usually the act of nursing a patient.

Sudan, 1979 (Sudan virus, 34 cases) The index case worked in a textile factory. Virus was then introduced into 4 families from the local hospital. Every case, except the index patient, could be traced to a human source of infection. Twenty-nine cases occurred in chains of secondary spread in 4 families, all from direct physical contact. No illness was observed among persons who were exposed to cases in confined spaces, but without physical contact.

Gabon, 1994 (Ebola virus, 52 cases) This outbreak began in three different gold mining camps. A second wave of infections outside the camp was initiated by contact with a hospitalized patient from first wave.

DRC, 1995 (Ebola virus, 315 cases) The index case was a charcoal worker, with no known contacts with other EHF patients, probably infected in a charcoal pit or on his farm. He infected 3 members of his family and 10 secondary cases occurred among his family members. Some of these individuals introduced virus into a maternity hospital, and then a general hospital. Prior contact with a suspected patient was reported by 93.5% (159/170) of case-patients for whom data were available. Eleven patients reported receiving an injection within 3 weeks of symptom onset. No role for airborne transmission was observed in human-to-human transmission. Sleeping in the same room with patient not a risk factor.

Gabon, 1996 (Ebola virus, 37 cases) A chimpanzee found dead in the forest was eaten by people hunting for food. Eighteen people who were involved in butchering the animal became ill. Ten other cases occured in their family members. Of 190 individuals who contacted sick people, none developed EHF.

Gabon, 1996-97 (Ebola virus, 60 cases) The index case was a hunter who lived in a forest camp. A dead chimpanzee found in the forest at the time was determined to be infected with Ebola virus. Disease was spread by close contact with infected persons. This outbreak was not well documented.

South Africa, 1996 (Ebola virus, 2 cases) A nurse in South Africa developed EHF; she had been previously exposed to the blood of a sick doctor brought from Gabon. This doctor had treated EV infected patients.

Uganda, 2000-2001 (Sudan virus, 425 cases) The three most important risk factors identified: attending funerals of EHF patients; interfamilial or nosocomial transmission.  The source of infection of primary patients could not be identified. The transmission risk factors among 83 contacts were determined. The most important risk factor was direct repeated contact with a sick person’s body fluids, as occurs during care. Risk of infection was higher during late stage of disease. Simple physical contact with sick person was neither necessary nor sufficient for developing EHF. Transmission through contaminated fomites is possible – such as sleeping on the same mat, or sharing meals with a sick person. Having washed the clothing of a sick person was not a risk factor. There was no evidence for airborne transmission during this outbreak – sleeping in the same hut as an infected person was not a risk factor.

Gabon, 2001-2002 and Republic of Congo (Ebola virus, 65 and 67 cases, respectively)  All but two cases were linked to recognized chains of transmission. There were six different introductions of virus into humans during the outbreak, each related to a hunting episode. An unusually high number of animals were found dead in the rainforest at this time, mainly gorillas, chimps, and monkeys. Ebola virus was detected in the carcass of a gorilla that had been butchered by one of the index cases shortly before onset of illness. The vast majority of secondary cases were related to community based transmission, and health care workers caring for infected patients included.

Republic of Congo 2002-03 (Ebola virus, 143 cases)  Risk factors in this outbreak were determined to be participating in the funeral/burial ritual of a patient, and providing nursing care to an individual with EHF. Quote from the paper: ‘There is no contamination by air or just handshake’.

Republic of Congo 2003 (Ebola virus, 35 cases)  Risk factors in this outbreak were determined to be participating in the funeral/burial ritual of a patient, and providing nursing care to an individual with EHF.

Sudan, 2004 (Sudan virus, 17 cases)  Risk factors in this outbreak were determined to be participating in the funeral/burial ritual of a patient, and providing nursing care to an individual with EHF. There was one introduction of virus into the index case-patient, who had been hunting baboons in forest, and was in contact with fresh monkey meat 5 days before onset of symptoms. All cases were epidemiologically linked, with 4 generations of transmission observed.

Democratic Republic of Congo, 2007 (Ebola virus, 264 cases) Index case-patient bought freshly killed fruit bats from hunters for consumption. She infected 11 family members who provided care, who in turn passed infection to others in a chain of transmission.

Uganda 2007-08 (Bundibugyo virus, 149 cases) Identified a chain of transmission from a prominent individual in the community to 27 others; they had contact with him before or after his death.

I did not find risk factor analysis for outbreaks in Democratic Republic of Congo, 2008-2009 (Ebola virus, 32 cases) ; Uganda, 2012 (Sudan virus, 11 cases; and Democratic Republic of Congo, 2012 (Bundibugyo virus, 36 cases). Transmission studies on the recent Ebola virus outbreak in West Africa has not yet been published. However the recent outbreak of Ebola virus in Nigeria was traced from an index case who traveled there from Liberia, where he had cared for a sibling who died of EHD. Upon receiving medical attention in Nigeria, he infected health care workers and the disease spread further. Few of the 898 contacts linked to this index case became infected.

From this analysis it is clear that contact with an asymptomatic individual, who subsequently developed EHV, is not a risk factor for disease. All risk factors involve close contact with sick individuals, such as would occur in a health care facility, among family members caring for a sick individual, and during funeral proceedings.

I am aware that not all of the cases in these outbreaks could be traced and assigned risk factors for infection. One could argue that among these cases, some might have been acquired by contact with an individual in the incubation period. However it makes no sense that these individuals would have been missed in all of the outbreaks. The more likely conclusion is that during the incubation period, patients infected with Ebola virus are not contagious.

There is one more piece of information to support the conclusion that there is no transmission during the Ebola virus incubation period. During the Ebola virus outbreak of 2000-2001 in Uganda, blood samples were collected from health care workers who became symptomatic with EHF; of these, 27 died and 18 survived. Ebola virus RNA could be detected in the blood on the first day that symptoms were observed, at levels just above the detection threshold (illustrated; image credit). Each day thereafter, the virus load increased, much more substantially in patients with a fatal outcome. While no viral loads were determined before the onset of symptoms, it is reasonable to predict that viral loads would be even lower. This conclusion is consistent with the observation that infected patients do not transmit infection before the onset of symptoms, probably because the levels of virus that they produce are too low. The results of this study are also consistent with observations from some outbreaks that the risk of transmission is increased later in disease, when more virus is present in the blood.

These data lead to the conclusion that Ebola virus transmission does not occur during the incubation period. Therefore it is not necessary to quarantine those who might have had contact with Ebola virus infected individuals. Daily reporting of temperature and other vital signs should be sufficient to allow detection of the onset of disease.

In other words, I disagree with Dr. Beutler’s statement that there are no good data supporting lack of Ebola virus transmission during the incubation period. The fact that Dr. Doherty disagrees with Dr. Beutler just goes to show that having a Nobel Prize doesn’t mean you are always right.

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TWiV 309: Ebola email

2 November 2014

On episode #309 of the science show This Week in Virology, the TWiVocytes answer questions about Ebola virus, including mode of transmission, quarantine, incubation period, immunity, and much more.

You can find TWiV #309 at www.twiv.tv.

I usually don’t post TWiM episodes here, but #90 has a lot of virology. In this episode, recorded in La Jolla, CA at the annual meeting of the Southern California Branch of the American Society for Microbiology, I first speak with Laurene Mascola, Chief of Acute Communicable Diseases at the Los Angeles County Department of Public Health. Dr. Mascola talks about how Los Angeles county has prepared for an outbreak of Ebola virus. Next up is David Persing, Executive Vice President and Chief Medical and Technology Officer at Cepheid. His company has developed an amazing, modular PCR machine that is brining rapid diagnosis everywhere, including the United States Post Office. And it might even be available on your refrigerator one day.

Watch TWiM #90 below, or listen at microbeworld.org/twim or iTunes.

 

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The Wild Types

29 October 2014

The Wild Types is an interview show about scientists hosted by Ushma Neill and Richard White. Ushma interviewed me for episode #2. The show name doesn’t refer to the fact that all scientists are wild (some are; I am not) but the genetic term referring to the strain or organism that is compared with mutants. As in, ‘the wild type virus was compared with the mutant virus that transmits among ferrets by the airborne route’.

 

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Peter L. SalkJonas Salk, who lead the team that developed the first poliovirus vaccine, was born 100 years ago today, 28 October 1914, in New York City. Numerous sites across the country have convened symposia in his honor. Last week City College of New York, where Salk earned a bachelor’s degree, held a centennial celebration. The photo shows Salk’s son Peter speaking at the celebration. New York University Medical Center, where Salk obtained his MD degree, also had a celebration last week. The Salk Institute, founded by Jonas Salk, will hold a celebration on 13 November. And today’s Google Doodle is in honor of Dr. Salk.

In honor of Salk’s memory, I’ve included below my interview with his son, Peter, and a list of all the articles on poliovirus from virology blog. If you can only read one, make it Dreaming of inactivated poliovirus vaccine. Then realize that WHO has called for a switch to Salk’s IPV.

Oral polio vaccine-associated paralysis in a child despite previous immunization with inactivated virus

Poliovirus escapes antibodies

Implications of finding poliovirus in sewers of Brazil and Israel

Polio-like paralysis in California

India has been free of polio for three years

World Polio Day

Poliovirus silently (and not so silently) spreads

The wall of polio

Poliovirus on Time

WHO will switch to type 2 inactivated poliovirus vaccine

Virology lecture: Picornaviruses

World Polio Day

Can India remain polio-free?

India polio-free for one year

Wild poliovirus in China

Transgenic mice susceptible to poliovirus

Poliomyelitis after a twelve year incubation period

Poliovirus vaccine safety

Is bivalent poliovirus vaccine a good idea?

Viruses and journalism: Poliovirus, HIV, and sperm

Poliovirus on BBC radio

Poliovirus type 2 returns

Polio returns to Minnesota

Poliovirus vaccine litigation

Polio among the Amish

Dreaming of inactivated poliovirus vaccine

Polio in Nigeria

Polio and Nobel Prizes

Polio in Pakistan and Afghanistan

Jonas Salk’s Poliovaccine

Poliovirus

Poliovirus is IRESistable

Vaccines lecture, 2014 (YouTube)

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On episode #308 of the science show This Week in Virology, Tom Solomon, an infectious disease doctor from Liverpool, talks with Vincent about viral central nervous system infections of global importance, Ebola virus, and running the fastest marathon dressed as a doctor.

You can find TWiV #308 at www.twiv.tv.

This morning I received this email from President Lee Bollinger:

Dear fellow members of the Columbia community:

As you may have seen in the media, Dr. Craig Spencer is being treated for Ebola at Bellevue Hospital in Manhattan. Dr. Spencer, an emergency department physician at NewYork-Presbyterian/Columbia University Medical Center, recently returned from a humanitarian mission with Doctors Without Borders to one of the outbreak areas in Western Africa. We admire and appreciate all of those willing to do this vital and selfless public health work around the globe.

It’s critical to bear in mind what our public health and infectious disease experts have emphasized – that the risk to people in New York City and at Columbia remains extremely low. If you or anyone has any concerns, please visit the University’s Ebola Preparedness site or the New York City Department of Health Ebola update page. You may also contact Student Health Services or Workforce Health and Safety for Faculty/Staff with Hospital Responsibilities.

We must keep Dr. Spencer in our thoughts and wish him a full and speedy recovery, as we do the vulnerable populations he serves. We will also continue to keep the Columbia community informed as we learn more from City, State, and Federal health officials.

Sincerely,
Lee C. Bollinger

The transition between incubation period (when there are no symptoms) and the first clinical signs is a dangerous period. During this time the patient may continue to move around in public despite having fever and other indications of infection. It will be important to trace as many of this physician’s contacts as possible, a difficult task in a city of over 8 million people. Apparently the physician traveled around the city, using the subways, the night before having a fever. Whether any virus is shed during this time, in amounts sufficient to infect others, is unknown, but could be determined by studying the contacts of such infected individuals.

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crab eating macaqueI have received many questions about whether immunizing with Reston virus could protect against infection with Ebola virus. Usually the question comes together with the statement ‘because Reston virus does not cause disease in humans’. I can think of two reasons why a Reston virus vaccine is not a good idea.

There have been very few confirmed human infections with Reston virus (4 according to Fields Virology 6th Edition), and although these individuals did not show signs of disease, the number is too small to make any conclusions. For example, if the case fatality ratio of Reston virus in humans were 1%, we might not have yet seen any deaths due to the small number of confirmed infections. However if we were to immunize a million people with a Reston virus vaccine, and the case fatality ratio were 1%, there would be 10,000 deaths, obviously an unacceptable rate for a vaccine. As the virus causes disease in nonhuman primates, and there are so few human infections, it is not possible to know the case fatality ratio.

The other problem is that in general, infection with one of the Ebolaviruses does not confer protection against the others*. For example, animals that survive challenge with Ebola virus (Zaire) are not protected from infection with Sudan virus. For this reason, vaccines need to be prepared against representatives of all the species. I am not aware of any animal studies that have assessed whether Reston virus infection protects from infection with the other Ebolaviruses, but there is no reason to believe that such cross-protection would be achieved.

Vaccines are currently being tested against Ebola virus (species Zaire ebolavirus), cause of the outbreak in west Africa.

*Thanks to Andrea Marzi for information on cross-protection.

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