By David Tuller, DrPH

I have spent two weeks hammering the CFS/ME Research Collaborative about “Renal-gate”—that is, vice-chair Esther Crawley’s recent lecture at a conference of kidney disease experts, in which she falsely accused me of writing “libellous blogs.” The CMRC’s chair, Stephen Holgate, recently assured me that Dr. Crawley had the “full support” of the executive board—a statement I dutifully conveyed to Virology Blog readers.

To be clear, I don’t know what Dr. Crawley actually said in the lecture, or if she mentioned my name. The slide live-tweeted from her talk, which featured the phrase “libelous blogs” near a screen-shot of one of my Virology Blog posts, speaks for itself. (Esther, if I’ve misunderstood and you meant to highlight my post instead as an example of an accurate, non-libelous blog, let me know ASAP.)

Despite the claim that Dr. Crawley enjoyed “full support” from the board, one of the CMRC’s charity members, ME Research UK, announced a few days later that it was withdrawing from the collaborative, “with immediate effect.” ME Research UK’s announcement did not mention Dr. Crawley, but the meaning was clear given the timing and abruptness of the move. So it appeared that the “full support” of the board for Dr. Crawley was likely less than “full” even as Dr. Holgate made the claim.

I am now trying to ascertain what prompted Dr. Holgate to issue such a statement. I had assumed he canvassed every single member of the executive board to gauge whether there was in fact “full support” for Dr. Crawley. Perhaps he did—and perhaps ME Research UK affirmed support for Dr. Crawley yet decided to leave days later for unrelated reasons. But that just seems unlikely.

On the Phoenix Rising forum, Renal-gate has generated a huge amount of interest. The Renal-gate thread has received more than 31,000 views. One commenter suggested that Dr. Holgate was urged to make the statement by the Science Media Centre’s Edward Sykes, an observer on the CMRC executive board. I have no idea if this is true. I have written to both Dr. Holgate and Dr. Sykes to find out how this statement of “full support” arose. I have asked if in fact every member of the CMRC board was canvassed before Dr, Holgate spoke on their behalf. I don’t expect a response, but will provide an update if I hear from Dr. Holgate or Dr. Sykes or anyone who can shed light on what happened.


In other news, Action for ME also issued a statement last week. The statement came out of a board meeting that took place in April—that is, before these most recent events. So no one should expect it to have addressed the public relations nightmare that Dr. Crawley has since presented to all those within her circle, including Action for ME.

(I want to stress that conscientious organizations really do need to take time in responding to challenges. It is much easier for me to immediately blog and shoot darts than it is for those who run big groups to consult each other and address difficult issues in a responsible way.)

On the positive side, the Action for ME statement noted the ongoing controversy surrounding the PACE methodology and trial conduct, and stressed that the questions and concerns need to be addressed “as a matter of urgency.” The statement highlighted the recent reanalysis of the reported recovery findings from the 2013 Psychological Medicine paper, quoting the new study’s conclusion that “the claim that patients can recover as a result of CBT and GET is not justified by the data.”

The statement also urged NICE, which is re-visiting the issue of clinical guidelines for ME/CFS, to “take full account of emerging biomedical research, the views and experiences of people with ME, and clearly reflect nuances around findings and re-analysis related to the PACE trial.” And it included a strong endorsement of the need for sharing of research data. These are important messages that deserve to be widely disseminated.

But the statement falls short in rejecting the call to sign onto an open letter to Psychological Medicine, which was posted on Virology Blog in March. The open letter requested retraction of the reported recovery findings and was signed by more than 140 scientists, academics and other experts, as well as ME/CFS organizations. The open letter’s retraction request was based on the reanalysis of the recovery data, which documented how the PACE investigators weakened their recovery criteria in ways that jacked up their reported results. Although Action for ME was not informed of the open letter before it was originally posted, it was asked to add its name afterward. The organization declined.

In last week’s statement, Action for ME explained that decision by noting that Psychological Medicine had already refused the retraction request. “Therefore signing now will have no impact,” the statement noted. This is fallacious reasoning. I doubt many of us who signed the open letter believed it would magically result in retraction—certainly I had no such delusion. The decision-makers at journals like Psychological Medicine and The Lancet have long shown themselves to be impervious to arguments based on logic, common sense and scientific integrity.

From my perspective, the function of the open letter was to demonstrate to the journal editors, the PACE authors and the UK medical establishment that the larger scientific world rejects the kind of upside-down evidence cited by members of the CBT/GET ideological brigade. Action for ME’s argument that it “will have no impact” at this point to support the call for retraction is just silly. The opposite is true. An endorsement of the open letter by Action for ME would be viewed as a turning point in the debate, and I assume the organization’s trustees understand that.

I hope Action for ME will rethink this decision. I also believe the organization, given its close association with Dr. Crawley and her work, should specifically address the concerns raised by her lecture, although that seems unlikely to happen. In fact, having been pressed by patients to take a stand on the issue, the organization has already stated the following: “Action for M.E. had no input into this presentation and none of our team were present at the talk, so we cannot comment on its content.”

Unfortunately for those who have allied themselves with Dr. Crawley, however, she has been caught leveraging her prestige and her public platform at a professional gathering to portray those seeking the truth about questionable research as “vexatious” and “anti-science.” She has been caught slandering me personally, along with my friend and colleague, Dr. Racaniello. I doubt she expected her slides to go viral. But they did.

Dr. Crawley has created a real mess for herself and for everyone around her, and she refuses to clean it up. Someone really needs to stage an intervention.

Freelance science journalist Tim Requarth joins the TWiVers to explain why scientists should stop thinking that explaining science will fix  information illiteracy.


You can find TWiV #442 at, or listen below.

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Virology 2017Every year I teach a virology course to undergraduates and masters students at Columbia University. I record video and audio of each of the twenty-five lectures and release them on YouTube – so that not only the students but the rest of the world can learn about the amazing field of virology.

With the spring semester behind us, this year’s lecture series is complete (link to the entire playlist at YouTube). The first 11 lectures cover the fundamentals of virus replication, including virus entry into cells, genome replication, protein synthesis, and assembly. In the remaining 14 lectures we focus on how viruses cause disease, how to prevent or resolve infections, and viral evolution and emergence.

All the lecture slides are also available as pdf files, as well as study questions for each lecture. You can find them at

I plan to use these videos to revise my Coursera virology course – which is no longer online – by the end of the summer.

By David Tuller, DrPH

For the last couple of weeks, I have been hammering the CFS/ME Research Collaborative to take a position on the actions of its deputy chair, Libelous Esther—better known as Dr. Esther Crawley. As I reported in several previous posts, Dr. Crawley falsely accused me of writing “libelous blogs” and Dr. Racaniello of posting them. To keep members of the CMRC board in the loop, I have sent them e-mails with links to these posts. In these e-mails, I have tried to be direct and pointed, but reasonably polite. I have mostly succeeded, although the recipients might have their own perspective.

At first, the CMRC refused to respond at all. Then the chair of the board, Stephen Holgate, sent me what could only be interpreted as a “f**k off” message. He told me that Dr. Crawley’s actions had nothing to do with the CMRC because it was just a “voluntary” group of colleagues with “no official standing.” Therefore, he wrote, I had to pursue my concerns through “other avenues.”

To me, “other avenues” meant more blogging about the false accusations of libel and the CMRC’s inadequate response, among other things. So I wrote yet another post about L’Affaire Crawley, noting the CMRC’s explanation that it could not possibly take a position because it was only a voluntary group with “no official standing.” I duly sent this post to the CMRC board.

And on Friday, I finally received from Dr. Holgate an enthusiastic endorsement of Dr. Crawley and her work. The statement made no mention of her recent multi-media spectacle, including her false libel accusation and her portrayal of legitimate requests for information as “vexatious.” In other words, the CMRC has sent me its second “f**k off” message. Happy International ME Awareness Day!

Here’s Dr. Holgate’s e-mail:

Dear David,

Prof Esther Crawley has the full support of the CMRC Executive Board in her role as Vice-Chair. The CMRC exists to promote the highest quality of basic and applied evidenced-based and peer-reviewed research into CFS/ME and Prof Crawley helps us to do this. Prof Crawley’s science is tested through the demanding procedures that all scientists must face when seeking grant-funding and publication in leading journals. The high quality of her research is recognised by her peers and she is a Professor of Child Health at the University of Bristol and an NIHR Senior Research Fellow. She is the clinical lead for the specialist child CFS/ME service at the Royal United Hospital in Bath and, sadly, is one of very few scientists in the UK actively trying to find a way to help children affected by CFS/ME. Contrary to some claims this collaborative is not fixated on any one cause, therapy or branch of science – our only goals are to improve our understanding of this serious illness and help alleviate suffering. In the meantime, our work remains focused on increasing collaboration and funding for more research and we will continue to work with all key stakeholders to achieve this.


I wrote back to Stephen and other board members that I took his answer to be an endorsement of Dr. Crawley’s actions and her false libel accusation. I noted that PACE, like Dr. Crawley’s research, had also been “tested through the demanding procedures” required of scientists. Given that PACE was a disaster, I pointed out, I didn’t hold those “demanding procedures” in as high regard as he did. I again noted the serious flaws in Dr. Crawley’s research.

Finally, I let Stephen and the CMRC board members know that I would be discussing the PACE mess and the Crawley situation, including their own role, during my talk on June 1 at the Invest in ME conference dinner. I included a link to the dinner information, in case any of the CMRC board members wanted to attend.


On a related issue, a number of people have urged me to sue Dr. Crawley. I have made it clear I’m not going to do that. Not because she doesn’t deserve it, but because I don’t deserve it. Lawsuits are hell for everyone. The opportunity costs in time, money, and energy are incalculable. Except for Donald Trump and attorneys, no one who has ever been involved in a lawsuit would ever want to be involved in another one. (Of course, not filing a lawsuit does not mean I can’t file complaints with her university and medical regulators.)

There are other excellent reasons not to pursue that route. For one, by taking legal action off the table, I occupy the moral high ground. That allows me to slam Dr. Crawley and the CMRC for their awful behavior as much as I want.

For another, and here’s the real challenge, I would have to prove that Dr. Crawley’s false accusation has actually caused me harm. Dr. Crawley has had tremendous influence over the health and lives of people with ME/CFS, especially in the U.K., but she has no power over me. I cannot honestly argue that her behavior, however distasteful, has damaged my reputation, caused me anxiety or led to economic loss. On the contrary, she’s given me great material to blog and talk about, complete with an excellent slide-show that documents her unprofessional behavior. Going forward, this stunt of Dr. Crawley’s and the resulting visuals are likely to haunt her career and inflict permanent damage on her reputation.

Now If I were to suffer a renal emergency in the UK and no nephrologists would see me because they had heard Dr. Crawley’s false accusation of libel, then I might be able to argue that I had suffered actual damage. Until then, no. (I do have a history of kidney stones and I am coming to the U.K. soon, but I don’t think she‘s gotten to the urologists yet.)

The Beacons of Viral Education (aka the TWiVoners) reveal a cost of being a male mouse – the Y chromosome regulates their susceptibility to influenza virus infection.

You can find TWiV #441 at, or listen below.

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X and Y chromosomesDisease and death caused by influenza virus are greater in human females than in males. But disease is more common in males from birth through age 15, after which more females are affected. In mice, genetic variation in the Y chromosome controls susceptibility to influenza virus infection (link to paper). Increased susceptibility does not correlate with increased viral replication, but an expanded pathogenic immune response in the lungs.

A panel of mice (strain B6) with the Y chromosome from eleven different strains were used to determine the effect of infection. The mice fell into two groups with distinct high and low survival after intranasal infection with the mouse-adapted PR8 strain of influenza virus. These results show that variation in the Y chromosome influences survival after infection. Furthermore, the previously reported greater susceptibility of female B6 mice to influenza virus infection compared with male mice is due to the presence of the Y chromosome.

Viral replication in the lung does not differ between mouse strains with high and low mortality. Increased mortality is associated with an increase in a type of T lymphocyte called gamma-delta T cells which produce interleukin 17. The latter is known to provoke lung-damaging inflammation.

Differences in susceptibility of mice with different Y chromosomes has nothing to do with the immunosuppressive effects of testosterone. Exactly which genes on the Y chromosome affect influenza virus susceptibility are unknown. Analysis of RNA expression revealed differences in levels of small RNAs in mice of higher versus lower susceptibility. This observation raises the possibility that the Y chromosome might have global effects on gene expression from other chromosomes, which in turn influences susceptibility to infection.

Others have found that the Y chromosome regulates the speed of progression to AIDS in HIV-1 infected men. It seems likely that the Y chromosome has an important general role in modulating the pathogenesis of infectious diseases. A better understanding of how the Y chromosome regulates the expression of other genes will be needed to understand these effects.

by David Tuller, DrPH

Well, not in those words, of course. It was all very polite. But that was the message.

Here’s what happened. On Monday, I posted an open letter to the members of the board of the CFS/ME Research Collaborative. The letter involved the false accusation of libel that the CMRC’s deputy chair, Esther Crawley, disseminated against me at a conference of renal experts two weeks ago. Because the accusation involved a blog post I wrote for Virology Blog, the accusation of libel also extended to Dr. Racaniello, who hosts this site.

I sent a link to the open letter to Stephen Holgate, the CMRC’s chair, and other members of the collaborative’s board. Dr. Holgate is a public supporter of Dr. Crawley’s work—he appeared with her at a press conference organized by the Science Media Centre to promote her latest venture, FITNET-NHS, a trial of online cognitive behavior therapy for adolescents with ME/CFS. (I wrote about this flawed proposal in the purportedly libelous blog that Dr. Crawley displayed on screen during her infamous presentation to the British Renal Society. In that post, I criticized Dr. Holgate for supporting Dr. Crawley’s research, given that she has a tendency to conflate “chronic fatigue” and “chronic fatigue syndrome”).

I did not hear back after e-mailing the link to the open letter. However, Dr. Racaniello received a cryptic response from Dr. Holgate, apparently in error. It popped up in his in-box shortly after I sent my e-mail about the open letter to Dr. Holgate and other CMRC board members. After receiving my e-mail, Dr. Holgate sent the following message to the CMRC board members:

Friends, I hope you do not feel it necessary to respond to this.

Kindest Regards,


I had cc’d Dr. Racaniello on my original message; I presume that’s why he received a copy of Dr. Holgate’s e-mail. I wrote to Dr. Holgate, asking if he sent the e-mail to Dr. Racaniello in error, or if it was an indirect way of letting us know the CMRC would remain silent. I soon heard back from Dr. Holgate. He explained that the questions I have raised “are not the business” of the collaborative, which after all is a “voluntary” group and has “no official standing.” He told me I needed to pursue any concerns through “other avenues.”

So that is the CMRC chair’s response to the news that his deputy chair falsely accused two other academics of libel at a professional gathering, at which she also appeared to be advising medical professionals on effective ways of avoiding their legal obligations under the freedom of information law. Dr. Holgate apparently feels this has nothing to do with the CMRC itself because it is just a “voluntary” group with “no official standing.” (What does that mean? “Official standing” with whom? The CMRC has enough “official standing” to organize conferences, issue statements, and have a board, which includes a deputy chair who makes false libel accusations  and a chair who doesn’t think that’s a problem.)

Apart from her defamatory libel claim, Dr. Crawley also appears to think that the filing of freedom of information requests related to ME/CFS is tantamount to conducting a harassment campaign. And she continues to make this ridiculous argument, even though last year’s First-Tier tribunal decision on one such request dismissed this claim in harsh terms. With all due respect to Dr. Holgate’s assurance that Dr. Crawley’s actions have nothing to do with the CMRC, Dr. Crawley’s leadership role with the group has been well promoted. It is natural for observers to assume that she speaks for many if not most of the other board members, especially when she talks about research into ME/CFS.

Unlike Dr. Crawley, the rest of the scientific world is moving fast in the direction of open access to data. Although Dr. Holgate believes the CMRC has nothing to say about Dr. Crawley’s recent performance, other board members should certainly speak up if they don’t agree with the deputy chair’s view that freedom of information requests constitute harassment. And if they don’t think Dr. Crawley should disseminate false accusations of libel against those raising legitimate and still-unanswered questions, they should speak up about that as well.

It is hard to understand why Dr. Holgate and the CMRC board think the public or funders should support a research collaborative whose co-leader falsely accuses critics of libel and publicly advocates shielding trial data from scrutiny. I do hope Dr. Holgate and his colleagues find a way to improve on their current non-response going forward.

by David Tuller, DrPH

To Members of the Board of the CMRC:

Not long ago, at the annual conference of the British Renal Society, your deputy chair disseminated the false accusation that I had libeled her. As a corollary to that, she also disseminated the false accusation that Dr. Racaniello, the Columbia University microbiologist who hosts Virology Blog, had libeled her by publishing my work. I provided Dr. Crawley with a reasonable opportunity to offer either an explanation, evidence to support her serious charge, or an apology. Dr. Crawley has done none of these things.

I interpret that as Dr. Crawley’s admission that there is nothing in my blogs that needs correcting, and therefore nothing libelous. Yet her claim, which goes to the heart of my integrity and professional reputation, remains floating around out there in the ether. Slides that go viral live online forever. (Dr. Crawley’s lecture, of course, raises other concerns as well. For the moment, I am focusing on the one that involves me.)

I have no reason to believe this is the first time Dr. Crawley has made these reckless charges against Dr. Racaniello and me. She has probably stirred many audiences with her tales of courage in confronting “anti-science” zealots. However, I have no evidence of that, so I will pretend to believe this was an isolated episode. But I would be very, very unhappy to learn that Dr. Crawley has continued making such unsupported allegations. (Why was Dr. Crawley invited to talk to a group of kidney specialists, anyway? Can cognitive behavior therapy and graded exercise therapy now cure kidney disease just like they can cure ME/CFS?)

Although Dr. Crawley’s accusation is libelous and possibly actionable, I have no intention of suing her, as I have already indicated. But I do believe in moral closure. Dr. Crawley has so far failed her moral, ethical and professional obligation to rectify the situation. Given that she is the CMRC deputy chair, her unwillingness to clean up her mess also reflects poorly on the collaborative. Although I have conveyed my concern to you, I have heard nothing from the board. Perhaps I’ll hear something at some point in the future. But in not disavowing Dr. Crawley’s accusations in a timely manner, the CMRC is effectively endorsing and enabling her behavior, as well as allowing these falsehoods to continue to percolate among medical professionals. Your silence, like Dr. Crawley’s, is not acceptable to me. Nor is it acceptable to Dr. Racaniello.

On June 1st, I am honored to be giving the keynote presentation at the dinner before this year’s Invest in ME conference. I was planning to talk about PACE, and why it is–in my opinion—an incoherent pile of nonsense. I had not planned on talking about Dr. Crawley or the CMRC. Thanks to Dr. Crawley’s attention-getting performance, my plans have now obviously changed. I will of course still discuss PACE’s failings. But I’ve never been accused of libel before, so I’m eager to share the experience with colleagues.

Plus, Dr. Crawley herself has provided fantastic visuals: There she is on stage, and behind her looms an enormous slide that features, among other items, the phrase “libellous blogs” and a screen shot of one of my Virology Blog posts, along with my name. Slam dunk! Here I am, about to give a high-profile talk in front of top scientists and ME/CFS experts from around the world, and the cosmos gifts me with a slide that captures a researcher in the very act of slandering me! Even better, she happens to be a researcher very well-known to many if not all in the audience, by reputation if not in person! How cool is that? Small world!

In my talk, I will portray Dr. Crawley’s accusation as an example of the scare tactics employed by scientists unable to provide satisfactory and adequate explanations for their methodological choices. In Dr. Crawley’s case, as I reported in the purportedly libelous blog captured immortally on screen, these troubling choices include the routine conflation of “chronic fatigue” and “chronic fatigue syndrome.” That conflation dramatically inflates the reported prevalence of the illness and leads to all kinds of problems.

Dr. Crawley and other PACE cheerleaders, not to mention the PACE investigators themselves, are similarly unable to provide logical answers to key questions like: “How was it possible that 13% of the PACE participants were already ‘recovered’ on one or both primary outcomes at baseline, before any treatment at all? Why was this key information not included in the published papers? Why were these participants even in the trial in the first place?” It is easier to accuse me of libel than to answer these prickly questions.

Dr. Crawley also showed a slide of the patient petition campaign against the MEGA project. Perhaps she believes that the Wellcome reviewers were negatively influenced by this organized opposition when they rejected her preliminary application. That could easily be the case, although it is also possible, as I noted earlier, that the MEGA proposal was simply not up to Wellcome’s exacting standards. Unfortunately for Dr. Crawley going forward, this most recent incident and the viral photos of her “anti-science” lecture are likely to stick to her and her professional reputation like glue. Through an easy google search, prospective colleagues, collaborators, grant reviewers and major funders will likely learn that she has accused other researchers of libel without explaining herself, providing any evidence, or apologizing.

It is also troubling that Dr. Crawley has, once again, positioned the filing of requests under the U.K.’s freedom of information (FOI) law as part of the “anti-science” playbook. Her slides on “vexatious requests” and other FOI exemptions suggest she was schooling the nephrologists in the most effective ways to sidestep the law’s requirements and avoid legal obligations to provide documents and information. I wonder if the University of Bristol believes it is appropriate for Dr. Crawley to be disseminating such advice. I doubt very much she informed the nephrologists that the most high-profile decision on a FOI request related to PACE, from the First-Tier Tribunal last summer, demolished the argument that the request was “vexatious.”

In ordering the liberation of the raw, anonymized trial data, the First-Tier Tribunal also noted widespread concern in the scientific world about the PACE trial’s irregularities. In particular, the decision cited an open letter to The Lancet and its editor, Richard Horton, that I organized last year. That letter, posted on Virology Blog, was signed by dozens of leading scientists and clinicians, who wrote that the PACE trial’s flaws “have no place in published research.” An open letter to Psychological Medicine, posted in March and demanding retraction of the PACE “recovery” paper, was signed by more than 100 experts. In other words, any suggestion from PACE defenders that only “anti-science” patients are challenging this body of deficient research is demonstrably untrue.

The First-Tier Tribunal also found no evidence supporting the PACE investigators’ hyperbolic claims of being the victims of a campaign of harassment, although the ruling acknowledged that Trudie Chalder had been heckled somewhere. Let me reiterate this critical point: The expensive lawyers for Queen Mary University of London, representing the interests of the PACE team to the best of their august abilities, presented NO CONVINCING EVIDENCE that the investigators were subject to abuse and death threats. (Having said that, I have no doubt that Dr. Crawley and other researchers have received many distasteful, hostile e-mails. While that is deeply unfortunate, it is no excuse for the persistent refusal to acknowledge flaws in the research.)

Moreover, as a result of the court order demanding release of the data, everyone can now see what was obvious to patients long ago: The PACE investigators changed their endpoints mid-stream in ways that jacked-up their reported rates of “improvement” and “recovery.” Then, when patients wanted to see the results per the methodology promised in the protocol, the PACE investigators stonewalled and called those requesting the data “vexatious.”

At first, the “vexatious” meme worked for the PACE team. But not anymore. The First-Tier Tribunal saw right through it. The scientific case against PACE has now been documented in peer-reviewed journals, and more publications are on the way. Dr. Crawley might not have liked the First-Tier Tribunal decision. She can misrepresent the results of the reanalyses of the PACE trial data, as she did in an interview several months ago, and continue to hail PACE as a “great, great” trial. But invoking “vexatiousness” at this stage, after the tribunal ruling and publication of the reanalyses, is not a viable strategy.

Dr. Crawley has failed to notice that the situation has shifted dramatically in the past two years. Top scientists outside the bubble-think of CBT/GET adherents have scrutinized the PACE study, found themselves shocked at its deficiencies, and confirmed that the reported results are bogus. They have made their views public to demonstrate the depth of their convictions about the study’s flaws. Does Dr. Crawley consider all of them “vexatious”?

It is understandable the CMRC board would prefer to hunker down and ignore the growing public relations disaster that Dr. Crawley has created. But your group has already stumbled multiple times in its efforts to gain credibility with the patient community, not to mention with funding bodies like Wellcome. You don’t have many chances left, if any. Dr. Crawley’s viral cri de coeur against patients (and others) seeking the truth about PACE represents another black mark for the organization.

Ignoring Dr. Crawley’s behavior or letting the matter drag on for weeks and months is not a recommended strategy. With no explanation or apology for your deputy chair’s actions anywhere in sight, the CMRC’s reputation is sustaining serious ongoing damage. My best advice is to behave like responsible scientists and address the matter of Dr. Crawley’s unjustified public accusations against Dr. Racaniello and me. Enough is enough.


David Tuller, DrPH
School of Public Health
Graduate School of Journalism
University of California, Berkeley

No problem not being nice to Dickson in this episode, because he’s absent for a discussion of a new giant virus that replicates in the cytoplasm yet transiently accesses the nucleus to bootstrap infection.

You can find TWiV #440 at, or listen below.

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nucleusAmong the multitudes of eukaryotic viruses with DNA genomes, some replicate in the cell nucleus, while others avoid the nuclear bureaucracy and remain in the cytoplasm. But biology is not always so rigid: a new giant virus has been found that replicates in the cytoplasm, where it seems to recruit components of the nuclear transcription machinery (link to paper).

Noumeavirus was isolated from a pond near – where else? – Noumea airport in New Caledonia. The 200 nanometer icosahedral particles infect the amoeba Acanthamoeba castellani and have a double-stranded DNA genome of 376,207 base pairs encoding 452 proteins. Sequence comparisons revealed Noumeavirus to be a new member of the family Marseilleviridae, which  includes other previously discovered giant viruses.

Other members of the Marseilleviridae replicate in the cytoplasm of the host cell, so it was assumed that the related Noumeavirus would do the same. However an analysis of the proteins in purified virus particles revealed an absence of components of the transcriptional machinery – which is needed for ths synthesis of mRNA. RNA polymerase, for example, is readily detected in other cytoplasmic viruses such as Mimivirus and poxviruses.

If proteins involved in transcription are not present in the Noumeavirus particle, and the virus does not enter the nucleus, how are viral mRNAs produced?  It appears that early in infection, the required proteins are moved from the nucleus to sites of viral replication in the cytoplasm. When nuclear proteins were labled with green fluorescent protein, within one hour after infection they can be seen moving out of the nucleus into the cytoplasm to sites of viral replication. The nuclear integrity remains intact, as host DNA does not leave the organelle. This recruitment of nuclear proteins is transient:  after 2-4 hours proteins are no longer leaving the nucleus.

This series of events suggests that nuclear proteins needed to initiate viral mRNA synthesis are recruited from the nucleus to sites of viral replication in the cytoplasm. Once viral mRNAs are made, the viral transcriptional machinery can be assembled and the nuclear proteins are no longer needed. The authors call this ‘remote control of the host nucleus.’

Confirmation of this hypothesis will require the demonstration that nuclear proteins involved in viral mRNA synthesis are recruited to early sites of viral replication in the cytoplasm. It will also be essential to identify the mechanism by which these nuclear proteins are extracted. Perhaps one or more virion proteins, such as an abundant 150 amino acid protein of unknown function, is involved.

Other giant viruses, such as Mimivirus, package the viral transcriptional machinery in the virus particle and are independent of the cell nucleus. At the other extreme are viruses that undergo transcription and DNA synthesis entirely in the nucleus (e.g., herpesviruses). Perhaps Noumeavirus is a relic of an evolutionary transition between the two replication strategies.

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