TWiV 215: Illuminating rabies and unwrapping a SARI

On episode #215 of the science show This Week in Virology, Vincent, Alan, and Kathy review the finding that rabies virus infection alters but does not kill neurons, and provide an update on the novel coronavirus in the Middle East.

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TWiV 212: Apocalypse TWiV 122112 212

On episode #212 of the science show This Week in Virology, the TWiVerers answer listener email about genetically modified chickens, a hendra vaccine for horses, online education, curing color blindness, Roosevelt and polio, Th cells, and much more.

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TWiV 207: Silk sheets and viral infidelity

On episode #207 of the science show This Week in Virology, Vincent, Alan, Matt, and Kathy review the use of silk to stabilize antibiotics and a viral vaccine, and an impaired-fidelity vaccine against SARS coronavirus.

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TWiV 204: M m m my corona

On episode #204 of the science show This Week in Virology, Vincent, Alan, Matt and Kathy review isolation of a new coronavirus from two patients in the Middle East, and expansion of the enteric virome during simian AIDS.

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No further evidence of novel coronavirus

disease timelineThere is no evidence for further spread among humans of a novel coronavirus recently isolated from two individuals with severe respiratory illness. This conclusion has been drawn after scrutinizing the travels (figure) and contacts of a Qatari adult who was transferred to intensive care in London.

While in Saudi Arabia the 49 year old male patient developed mild respiratory illness (rhinorrhea and fever). These symptoms resolved several days after his return to Qatar on 18 August. At the beginning of September he developed another respiratory illness which worsened and required his transport to London. Later that month the novel coronavirus was detected in his respiratory tract.

This timeline suggests that the patient acquired the viral infection in Qatar, as he was there for 16 days prior to illness. How he obtained the infection is not known. He did spend time on a Qatari farm where sheep and camels are kept. The SARS coronavirus is believed to have originated in bats and spread to humans either directly or through animals in meat markets, and the new coronavirus is related to bat coronaviruses.

Sixty-four close contacts were identified among the patient’s health care workers, friends, and family during his stay in the United Kingdom. None of these have developed severe disease, while 13 have displayed mild respiratory symptoms, and the new coronavirus was not detected 10 of these individuals.

These results show that no human to human transmission of the novel coronavirus has taken place that resulted in mild or severe disease. Serological testing for anti-viral antibodies must be done to determine if asymptomatic infections have occurred. It will also be important to conduct serological surveys to determine whether there is evidence for infection in the general populations of Qatar and Saudi Arabia. It is also likely that animal surveys will be done to identify potential reservoirs for the virus.

RG Pebody et al. 2012. The United Kingdom public health response to an imported laboratory confirmed case of a novel coronavirus in September 2012. Eurosurveillance, Volume 17, Issue 40.

Update: A third human infection with the novel coronavirus was confirmed on 4 November 2012 in Saudi Arabia.

A new coronavirus isolated from humans

Coronavirus virionA new coronavirus has been isolated from two individuals with severe respiratory illness. It is different from the SARS coronavirus, but health officials are nonetheless preparing for a rapid response should the virus be detected elsewhere.

The novel coronavirus was first reported by Ali Mohamed Zaki on ProMED-mail on 15 September 2012, from a 60 year old male patient in Saudi Arabia with pneumonia and acute renal failure who died in July. The virus was isolated by culturing sputum on Vero and LLC-MK2 cells, and identified as a coronavirus by polymerase chain reaction. Dr. Zaki sent the virus to Ron Fouchier in the Netherlands who sequenced its genome and confirmed that it is a beta-coronavirus closely related to bat coronaviruses.

At the beginning of September 2012 a 49 year old male Qatari national who had previously traveled to Saudi Arabia was admitted to an intensive care unit in Doha with severe respiratory illness. He was moved to the United Kingdom where laboratory tests confirmed the presence of the novel coronavirus. Comparison of a 200 nucleotide genome sequence with that from the Saudi national revealed 99.5% identity (one mismatch). Alignment of this sequence with that of other coronaviruses shows that the new virus is related to bat coronaviruses.

This new virus is not the SARS coronavirus, but because it is related to bat coronaviruses there is concern that it could spread rapidly among humans and cause serious respiratory disease. This is why WHO has placed health officials in its six regions on alert, and has issued a case definition so that the disease may be readily detected. The definition comprises: acute respiratory syndrome which may include fever (≥ 38°C , 100.4°F) and cough requiring hospitalization or with suspicion of lower airway involvement (clinical or radiological evidence of consolidation) not explained by any other infection or any other aetiology; and close contact within the last 10 days before onset of illness with a probable or confirmed case of novel coronavirus infection while the case-contact was ill, or travel to or residence in an area where infection with novel coronavirus has recently been reported or where transmission could have occurred.

Ron Fouchier doesn’t believe that we should become overly worried about these cases:

There are now six known human coronaviruses; one of them is SARS, but four cause the common cold and are quite innocuous. So let’s keep both feet on the ground and not blow this out of proportion.

The fact that the virus has been isolated from individuals with severe respiratory disease does not mean that it is the causative agent. To prove this requires additional work, as Fouchier notes:

 For starters, we’ll find out whether animals get sick from this virus. You can isolate a virus from a patient, but that does not mean they died from it; to show that it causes disease you need to fulfill Koch’s postulates. That’s what we did for SARS, and it’s what we hope to do here; we’ve applied for emergency ethical approval. The most obvious animal species to put this virus in are mice, ferrets, and perhaps monkeys.

Proof that the new coronavirus is an agent of respiratory disease would come from its isolation from additional patients with the disease. An outbreak of severe respiratory disease in Jordan in April of 2012 is now being reviewed for evidence of the novel coronavirus.

Coronaviruses are composed of enveloped virions that contain a positive strand RNA genome. Human coronaviruses may cause the common cold or severe respiratory illness. In 2002 the SARS coronavirus emerged in China and spread globally, infecting over 8000 individuals and killing more than 900. The SARS coronavirus is believed to have originated in bats and spread to humans either directly or through animals in meat markets. Because the new coronavirus isolated from two patients is related to bat coronaviruses, there is concern that a scenario similar to the SARS outbreak is in the making. Whether or not this is true will be revealed in the coming weeks.

Update. Eurosurveillance has published communications on how to detect the novel coronavirus by real-time polymerase chain reaction; and the case definition and public health measures. The authors conclude:

There is strong evidence that a novel virus caused the severe disease in the two patients. Based on this assumption it can be concluded that the virus poses an as yet poorly defined level of threat to people’s health. There may have been other cases in the past that were missed and serological testing of stored sera and other specimens from such cases will be important. […] Our assessment, based on the limited information currently available, is that the risk of wide spread transmission resulting in severe disease is low. However, the emergence of a novel coronavirus requires a thorough assessment which is currently being coordinated at international level.

Update 2. CDC has published a travel advisory:

At this time CDC, does not recommend that travelers change their travel plans.

TWiV 155: XXII Brazilian National Virology Meeting

sbv_logoenv2011Hosts: Vincent Racaniello, Grant McFadden, Eurico de Arruda Neto, Paulo Eduardo Brandão, Francisco Murilo Zerbini, and Janice Reis Ciacci Zanella

Vincent, Grant, Eurico, Paulo, Francisco and Janice discuss their work on bocavirus, infectious bronchitis virus, begomoviruses, and circoviruses at the Brazilian Virology Society meeting in Atibaia, São Paulo, Brazil.

Click the arrow above to play, or right-click to download TWiV 155 (56 MB .mp3, 93 minutes).

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Bats harbor many viral sequences

How large is the zoonotic pool – all the animal viruses that could one day infect humans? Assuming that there are 50,000 vertebrates on earth, each with 20 viruses, the number is one million – probably a vast underestimate. Determining just how many viruses exist in a variety of animal species is technically feasible, limited only by the number of hosts that can be sampled. A study of the virome of several North America bats reveals that these animals – which constitute 25% of all the known mammalian species – harbor a very large collection of viral sequences.

Advances in nucleotide sequencing technologies (deep sequencing) have made it possible in recent years to study the virome – the genomes of all viruses in a host – in human blood, diarrhea, and respiratory secretions; grapevines, and feces of horses and bats. The latter mammals are a particularly important subject because it is known that they harbor the predecessors of several important human viruses, including SARS coronavirus, ebolavirus, marburgvirus, Nipah, Hendra, and rabies viruses. Since there are about 1200 known species of bats, the potential for future human zoonoses is significant.

A multicenter group comprising virologists* and chiropterists (scientists who study bats) has examined the virome of three North American bat species: big brown bats (Eptesicus fuscus), tri-colored bats (Perimyotis subflavus), and little brown myotis (Myotis lucifugus). Deep sequencing was used to analyze fecal and oral samples from 41 bats captured on one night in Western Maryland. The results provide a comprehensive glimpse of the bat virome.

The 576,624 sequence ‘reads’ (a read is the result of a single sequence reaction, in this study ~250 nucleotides) on six pools of fecal samples revealed an amazing diversity of viral sequences (figure), with representatives of human, other mammals, insect, bacteriophage, fish, shrimp, protist, reptile, plant, avian, fungi, algae, and marine viruses. Among the interesting findings are sequences of three novel coronaviruses from big brown bats. Many coronaviruses have previously been found in bats; the results of this study provide more evidence that these mammals are likely to be sources of future human infections.

Novel viruses of plants and insects were also identified in fecal samples from all bats. This observation can be explained by the bats’ prodigious appetite for insects, which harbor both insect or plant viruses (the latter transmitted to plants by insect vectors). It seems unlikely that these viruses replicate in bats, but pass through the gastrointestinal tract into the feces.

Perhaps not surprisingly (given the diversity of bacteria that colonize mammalian intestinal tracts), sequences of novel bacteriophages were also identified in fecal samples. One appears to have high sequence identity with a bacteriophage that infects the plague bacterium Yersina pestis. Curiously, such bacteria are not known to colonies animals in the northeastern United States. A second bacteriophage infects strains of E. coli associated with human illnesses. These findings suggest that bats could be involved in the spread of human bacterial pathogens.

The main viral sequences identified in pooled oral samples were of a novel cytomegalovirus. These viruses appear to be common in bats, and have been been detected in many previous studies.

One question that arises from these findings is whether bats are unique in harboring a large collection of diverse viruses. The answer to this question awaits studies of the viromes of other wild animals.

Viral discovery by massive sequencing will no doubt identify many new viruses in a wide range of species. However, this technology cannot answer some of the more intriguing biological questions, such as which hosts support viral replication, and whether it is associated with disease. Answers to these questions will require construction of complete DNA copies of viral genomes and recovery of infectious viruses by transfection of cells in culture.

The title of this post is ‘Bats harbor many viral sequences’, not ‘many viruses’. That’s because no infectious viruses were identified – only parts of their genomes. If you wish to conclude that a certain virus infects bats, you must either isolate the virus in cell culture, or show that the entire viral genome is present in tissues or fluids.

*including Eric F. Donaldson and Matt Frieman, who spoke about this work on TWiV 90 and 65.

Donaldson EF, Haskew AN, Gates JE, Huynh J, Moore CJ, & Frieman MB (2010). Metagenomic Analysis of the Virome of three North American Bat Species: Viral Diversity Between Different Bat Species that Share a Common Habitat. Journal of virology PMID: 20926577

TWiV 83: An hour with Dr. Kiki

Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Kirsten Sanford

On episode #83 of the podcast This Week in Virology, Vincent, Alan, Rich, and special guest Dr. Kirsten Sanford talk about her career in science media, then consider whether smallpox eradication led to the AIDS pandemic, high fidelity RNA synthesis, and a new Ebola virus vaccine.

This episode is sponsored by Data Robotics Inc. Use the promotion code TWIVPOD to receive $75-$500 off a Drobo.

Win a free Drobo S! Contest rules here.

Click the arrow above to play, or right-click to download TWiV #83 (66 MB .mp3, 91 minutes)

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Zinc and the common cold

cold-eezeShortly after I developed sore throat, cough, and congestion last week, a package of ‘Cold – Eeze’ materialized on my kitchen counter. The writing on the package of zinc-laden lozenges promised to ‘shorten your cold’, and noted that they were ‘clinically proven to reduce the duration of the common cold’. Do zinc lozenges have any effect on the common cold?

The common cold is the primary cause of doctor visits in the United States, leading to 189 million lost school days each year. But it’s important to point out that the common cold can be caused by a number of different viruses, including rhinovirus, coronavirus, influenza virus, adenovirus, and paramyxovirus. Rhinoviruses are responsible for over half of all common colds.

The idea that zinc could be used to treat the common cold originated from a 1974 paper in Nature which showed that zinc blocks the replication of rhinoviruses in cell culture. Viral plaque formation was inhibited over 99% when 0.1 millimolar zinc chloride was included in the agar overlay. However, this concentration of zinc is too high for therapeutic use, and subsequent studies showed that levels compatible with use of the metal ion in humans minimally inhibited rhinovirus replication in cell culture. Zinc does not readily pass through the cell membrane, explaining why high concentrations are required to produce an antiviral effect.

Many trials have been conducted to determine if zinc – taken as a lozenge, nasal spray, or ointment – has any effect on the common cold in humans. In one study, 200 children were given 15 mg zinc daily by mouth for seven months. The mean number of colds in the treated children was 1.2 compared with 1.7 in the untreated children – statistically significant but not therapeutically useful. Many studies have evaluated the effectiveness of zinc containing lozenges. In one, 65 people took one lozenge containing 23 mg zinc every two hours while awake. After one week, 86% of the treated group were free of cold symptoms, compared with 46% of the placebo group. In another similar study, the duration of cold symptoms was reduced in the zinc group versus the placebo group – 4.5 days compared with 8.1 days. However, as many studies have lead to the conclusion that zinc lozenges – as well as zinc administered intransally or in a gel – have no effect on severity or duration of the common cold. A good summary of many of these trials can be found in the Alternative Medicine Review cited below.

It’s important to note that in these studies the virus responsible for the colds is not identified. Given the prevalence of rhinoviruses it is appropriate to assume that these viruses are involved in over half of the colds observed. Nevertheless, the extreme variability in the trial results may in part reflect the fact that various etiologic agents are involved, some of which might not be susceptible to inhibition by zinc. Other possible explanations for the inconsistent results include differences in the zinc preparations used (zinc gluconate and zinc acetate), the quantity of zinc administered, and the composition of the lozenge.

Although inhibition of rhinovirus replication by zinc was reported in 1974, the mechanism is not understood. It is believed that zinc enters the cell and binds to the rhinovirus protein that will form the capsid. This interaction blocks cleavage of the protein, thereby inhibiting production of infectious virus. Consistent with this proposed mechanism is the observation that zinc ionophores – compounds that allow the uptake of zinc into cells – have recently been shown to inhibit rhinovirus replication. The effectiveness of such compounds, which include pyrithione and hinokitiol, for treating the common cold is currently being investigated.

Although zinc does inhibit rhinovirus replication, this activity might not account for the effect on the common cold. It has been suggested that zinc reduces inflammation in the respiratory tract, which would explain the observed decrease in symptoms observed in some trials.

As for the Cold-eeze on my kitchen counter – the package was never opened. The unimpressive results of clinical trials made the idea of taking 6-8 lozenges a day for several days less appealing than enduring sore throat, cough, and congestion for less than a week. But the lozenges served a different purpose – I am now very interested in the revealing the mechanism of zinc inhibition of rhinovirus replication. I have begun experiments in my lab to solve this problem, and I’ll write about what I discover.

Korant BD, Kauer JC, & Butterworth BE (1974). Zinc ions inhibit replication of rhinoviruses. Nature, 248 (449), 588-90 PMID: 4363085

Geist FC, Bateman JA, & Hayden FG (1987). In vitro activity of zinc salts against human rhinoviruses. Antimicrobial agents and chemotherapy, 31 (4), 622-4 PMID: 3038000

Krenn, B., Gaudernak, E., Holzer, B., Lanke, K., Van Kuppeveld, F., & Seipelt, J. (2008). Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections Journal of Virology, 83 (1), 58-64 DOI: 10.1128/JVI.01543-08

Roxas M, & Jurenka J (2007). Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Alternative medicine review : a journal of clinical therapeutic, 12 (1), 25-48 PMID: 17397266