On episode #33 of the science show This Week in Microbiology, Vincent, Michael, and Ivo review the requirement for segmented, filamentous bacteria for the induction of a specific type of helper T cell in the gut.
You can find TWiM #33 at microbeworld.org/twim.
On episode #32 of the science show This Week in Microbiology, Vincent, Elio and Michael speak with Rosie Redfield about her evidence that a bacterium cannot grow on arsenic instead of phosphorus.
If you only listen to one episode of TWiM all year, make it this one – Rosie is terrific!
You can find TWiM #32 at microbeworld.org/twim.
One of two papers on avian influenza H5N1 virus that caused such a furor in the past six months was published today in the journal Nature. I have read it, and I can assure you that the results do not enable the construction of a deadly biological weapon. Instead, they illuminate important requirements for the airborne transmission of influenza viruses among ferrets. Failure to publish this work would have compromised our understanding of influenza viral transmission.
The paper from Kawaoka’s group focuses on the viral hemagglutinin (HA) protein, an important determinant of whether influenza viruses can infect birds or mammals. In the image, the HA is shown as blue ‘spikes’ on the virion surface; a single HA molecule is shown at right. Avian influenza viruses prefer to attach to cells via a specific form of sialic acid that differs from the form bound by mammalian influenza viruses. This difference in receptor preference is one reason why avian influenza viruses do not transmit among mammals.
Kawaoka’s group used a random mutagenesis and selection approach to identify amino acid changes in the avian H5 HA protein that allow it to bind human receptors. These changes are located around the sialic acid binding pocket in the HA head (figure). Some of the amino acid changes were previously known, but there are also some new ones reported, expanding our understanding of how the HA binds sialic acids. Some of the HA amino acid changes allow virus binding to ciliated epithelial cells of the human respiratory tract (wild type H5 HA cannot). All of this is important new information.
The H5 HA genes with these amino acid changes were then substituted for the HA gene in a 2009 H1N1 pandemic virus, and this reassortant virus was inoculated intranasally into ferrets. The viruses did not replicate well in the ferret trachea, but viruses recovered from the animals contained a new change in the HA protein that improves replication. This change (asparagine to aspartic acid at amino acid 158) is known to prevent attachment of a sugar group to the HA and enhance binding to human receptors. Viruses with this change probably have a replicative advantage in ferrets.
A reassortant virus with HA amino acid changes N158D/N224K/Q226L transmitted through the air to 2 of 6 ferrets. Viruses recovered from one of the animals contained a new change in the HA protein, T318I. A virus with four amino acid changes in the H5 HA (N158D/N224K/Q226L/T318I) replicates well in ferrets and transmits efficiently, although the infection is not lethal.
Even more interesting are the results of experiments to understand how these HA amino acid changes affect viral transmission. The N224K/Q226L amino acid changes that shift the HA from avian to human receptor specificity reduce the stability of the HA protein. The N158D and T318I changes, which were selected in ferrets, restore stability of the HA.
There are three key questions concerning this work that must be answered.
Would an H5N1 virus with the changes N158D/N224K/Q226L/T318I transmit among humans? Probably not. The virus tested by the authors derived 7 of 8 RNA segments from a human H1N1 strain, which is well adapted for human transmission. It is likely that changes in other avian influenza viral proteins would be needed for human transmission. It might also be that entirely different changes in the H5 HA are required for transmission in humans compared with ferrets.
Is this information useful for the surveillance of circulating H5N1 strains; specifically, would the emergence of these HA changes signify a virus with pandemic potential? I don’t believe so. These are mutations that enhance the transmission of H5 viruses in ferrets, and their effect in humans is unknown. Ferret transmission experiments are not meant to be predictive of what might occur in humans.
If these results are not predictive of what might happen in humans, why were these experiments done? (to paraphrase Laurie Garret at the New York Academy of Sciences Meeting on Dual Use Research). A substantial portion of this work goes far beyond surveillance of H5N1 strains: it provides a mechanistic framework for understanding what regulates airborne transmission of avian H5 influenza viruses. In the Kawaoka study, amino acid changes that improve the stability of the HA protein were selected for during replication and transmission of the H5 viruses in ferrets. In other words, stability of the HA protein is an important property that allows efficient airborne transmission among ferrets. Additional experiments can now be designed to extend this idea. If such stabilizing changes can be shown to be important for transmission of human strains, then they might be a valuable marker of influenza transmission.
The Kawaoka paper is a significant piece of work that substantially advances our understanding of what viral properties control airborne transmission of influenza viruses. To view it as enabling construction of a bioweapon is highly speculative and fundamentally incorrect.
M. Imai, T. Watanabe, M. Hatta, S.C. Das, M. Ozawa, K. Shinya, G. Zhone, A. Hanson, H. Katsura, S. Watanabe, C. Li, E. Kawakami, S. Yamada, M. Kiso, Y. Suzuki, E.A. Maher, G. Neumann, Y. Kawaoka. 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. doi: 10.1038/nature10831.
Nearly four months ago I stood at the front of a crowded classroom at Columbia University and began teaching the third year of my undergraduate virology course. Twice a week we discussed the basic principles of virology, including how virions are built, how they replicate, and how they cause disease. Yesterday was the 26th and last lecture in the course, entitled “H5N1″. In this lecture we covered the recent controversy over the publication of results on adapting avian influenza H5N1 viruses to transmit by the airborne route among ferrets. Fittingly, one of the two papers in question will be published tomorrow.
Each lecture in my virology course has been recorded as a videocast and is available at the course website, at iTunes University, or on Vimeo. Eighty-seven Columbia University undergraduates registered for the course in 2012, but over 14,000 individuals have subscribed to virology W3310 through iTunes University. I believe that it is important that the general public understand as much as possible about viruses, so they can participate in the debate about issues that impact them, such as XMRV or H5N1. It is my goal to be Earth’s virology professor.
I am sure that the students were perplexed when I took their photo before the first lecture. Little did they know that they were about to take a very different science course, one taught by a professor who uses social media (blogs, podcasts, twitter) to teach the subject both in and out of the classroom. As one student wrote to me yesterday:
I wish that every professor I had had such passion and energy and a TWiV-like blog/show so I could be updated on all the big science gossip/news to complement my in-class knowledge! I can’t recount how many times I told my non-science friends about TWiV as an exhibit to prove that science is cool and important. Thank you for being passionate scientists that made me want to study science (and be super nerdy but connected to the world) in the first place.
I would like to thank all the students of virology in and out of the classroom for their enthusiasm and their willingness to learn a complex subject. Virology will be offered again in the spring of 2013, and you can be reassured that it will be different. My course, like viruses, is continually evolving.
A dairy cow in California is the fourth known American case of mad cow disease, which is caused by prions, infectious agents composed only of protein (the story hit the press the day after my lecture on this type of illness). Unlike viruses, prions have no nucleic acid and no protective coat. But virologists know all about them because, as Stanley Prusiner once said, there was a time when only virologists believed that they existed.
Prions are found in mammals and in fungi, but only in mammals are they infectious and pathogenic. All mammals make normal forms of the prion protein (PrPc) which is found in many tissues including the nervous system. The pathogenic form, called PrPSc, is a structurally altered form of PrPc. The PrPSc protein, named after the first prion disease studied, scrapie in sheep, causes PrPc to undergo a structural transformation to the pathogenic form. The PrPSc protein becomes deposited in amyloid fibrils in the brain, leading to neurodegenerative diseases known as transmissible spongiform encephalopathies (TSE), after the sponge-like appearance of the brain observed in afflicted animals (image).
There are three different ways to acquire a TSE. One is by infection: a human consumes meat that contains PrPSc, or receives a corneal transplant from a donor with an undiagnosed TSE . The PrPSc proteins make their way to the brain where they cause the host’s PrPc to misfold and become the pathogenic PrPSc. The more PrPSc that is made, the more the normal PrPc is converted to the pathogenic form. After an incubation period of many years, the host develops an invariably fatal neurodegenerative disease characterized by dementia in humans. There is also a familial form, in which mutations in the gene encoding PrPc are inherited; these cause the PrPc protein to misfold to form the pathogenic form. In the sporadic form PrPc spontaneously converts to PrPSc without any known mutation or infection.
TSEs occur in different forms with varied symptoms and pathology. There are TSEs of humans (Creutzfeld-Jacob disease, fatal familial insomnia, Gerstmann-Sträussler syndrome, Kuru) cows (bovine spongiform encephalopathy or mad cow disease), sheep and goats (scrapie), deer, elk, and moose (chronic wasting disease), and of a variety of other mammals.
This brings us back to the mad American cow, the first in the US since 2006. It died on a dairy farm and was tested for BSE as are 40,00o other cows each year in this country. The reason why this is big news is that back in the 1990s there was an outbreak of human TSE in the United Kingdom caused by consuming beef from animals with BSE. The cows acquired BSE by being fed processed animal byproducts as protein supplements, which unknowingly contained pathogenic prions. Bt the time the disease was detected in cows, contaminated meat had already entered the human food chain. Cows are routinely tested for BSE precisely to avoid a similar outbreak of human TSE.
The dead cow apparently had atypical BSE – that is, it was not a consequence of eating contaminated meat and it was not an inherited disease. Atypical BSE is caused by strains of prions distinct from other forms. This is good news because it means that the feed that the cow was receiving was not contaminated with pathogenic prions. Furthermore, the cow was not destined for meat production; it was a dairy cow that had died and was selected for random sampling.
Could the milk produced by this cow and consumed by humans pose a risk for transmission of a TSE to humans? It is known that ewes with scrapie shed infectious and pathogenic prions in their milk. However cows with BSE have much less PrPSc accumulation in peripheral tissues, and in particular lymphoid tissues which include the mammary glands. It seems unlikely that cow milk contains prions, but it is a question worth revisiting. Pathogenic prions are highly resistant to heat, ultraviolet irradiation and other extreme conditions, so would certainly survive the pasteurization process.
