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coronavirus Spike

Small animal models (mice, ferrets, hamsters) are essential for understanding how SARS-CoV-2 causes disease and for pre-clinical evaluation of vaccines and antiviral therapeutics. One promising model has been developed by modifying SARS-CoV-2 so that it binds to murine ACE2.

Laboratory mice cannot be infected with SARS-CoV-2 because the viral spike glycoprotein (illustrated) does not bind to murine ACE2, the orthlog of the human receptor. Mice transgenic for the human ACE2 gene, produced after the SARS-CoV outbreak, can be infected with SARS-CoV-2, but the pathogenesis does not resemble that observed in humans. For example, mortality in infected mice appears to be a consequence of replication in the central nervous system, not in the respiratory tract. The altered pathogenesis might be due to improper expression patterns of the ASCE2 gene.

In another approach to producing a mouse model for COVID-19, the spike glycoprotein of SARS-CoV-2 was modified so that it efficiently binds murine ACE2 protein. Only two amino acid changes in the S protein were required to allow infection of cells that produce murine ACE2 without affecting reproduction in human cells.

Upon intranasal infection of young mice, virus replication was detected in the upper and lower airways and was accompanied by mild to moderate disease. In contrast, after inoculation of older mice, viral replication was not only detected in the upper and lower tract but was associated with lung inflammation and loss of pulmonary function. The age-dependency of disease mimics what is observed in humans.

As a proof of principle, the mouse model was used to evaluate efficacy of a vaccine and antiviral. After vaccination of mice with a Venezuelan equine encephalitis vector carrying the SARS-CoV-2 spike protein gene, reduced virus replication in lung and upper respiratory tract was observed after challenge compared with control mice. Furthermore, prophylactic and therapeutic administration of IFN-lambda-1 reduced virus titers in the lung compared with untreated mice.

This mouse model is attractive because it does not require the development of genetically altered animals. However it is not a perfect model because there are likely differences in tissue distribution of ACE2 in mice and humans which could affect disease outcomes. Whether this difference has an impact of the usefulness of the mouse model remains to be seen. Meanwhile other mouse models are being developed which might have other advantages: for example the production of human ACE2 in mice by using adenovirus-associated virus vectors.

I have always made it clear that I pay attention when smart patients assess bad research. That’s how I stumbled into this whole mess in the first place–by reading what patients were writing about the PACE trial. (In that case, I at first dismissed the concerns when I read about how participants could get worse and still be counted as recovered. I figured patients must have it wrong. I knew no credible journal could have published such a study–much less failed to retract it when the problem had been pointed out.)

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I have recently written a few posts–herehere and here–about a study in BMJ Paediatrics Open that appears to be marred by multiple methodological and ethical problems. This is certainly not a one-time occurrence when it comes to BMJ journals. Last week, I sent a letter to the study’s senior author inviting him to send me his response for posting in full on Virology Blog. I have not heard back.

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Raul Rabadan joins TWiV to explain the use of computational biology to demonstrate how recombination and mutation led to emergence of SARS-CoV-2.

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Daniel Griffin provides a clinical update on COVID-19, then we review TETRIS by Paterson NJ, modeling the effects of intervention in the US on cases and deaths, mixing PCR and serology data, and much more, including listener email.

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By David Tuller, DrPH

In the past week, I have written three posts about a Norwegian study of cognitive behavior therapy plus music therapy for adolescents with chronic fatigue after acute Epstein-Barr virus infection–an illness known as mononucleosis in the US and glandular fever in the UK. The corresponding author of the study is Vegard Bruun Wyller, a professor at the University of Oslo’s Institute of Clinical Medicine.

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CoV2-cigaretteSome evidence suggests that cigarette smokers are more likely to develop severe COVID-19 disease than non-smokers. Chronic smoke exposure appears to trigger the expansion of cell types in the respiratory tract that produce ACE2, the receptor for SARS-CoV-2. This observation provides a plausible hypothesis to explain why cigarette smokers might experience more severe COVID-19.

A number of independent observations show that cigarette smoke increases expression of the ACE2 gene:

  • Mice exposed to cigarette smoke daily for 5 months had up to 80% more ACE2 expression in the lung compared with control mice
  • Human lung epithelial cells from the bronchi of smokers had 30-55% more ACE2 expression than cells from non-smokers
  • Lung samples from patients who smoked more than 80 pack-years had 100% more ACE2 expression than those who smoked less than 20 pack-years
  • Quitting smoking was associated with a 40% decrease in ACE2 expression
  • In murine and human lung, ACE2 is expressed at high levels in secretory and goblet cells and alveolar type 2 cells. Chronic smoke exposure leads to expansion of mucus-secreting goblet cells, and consequently higher levels of ACE2.

There are two caveats to this study. In the observations listed above, ACE2 expression was assessed by quantifying RNA, not protein. While the authors show a correlation between ACE2 RNA and protein in selected cell lines, the same correlation might not extend to tissues. In other words, increased ACE2 RNA might not lead to increased ACE2 protein.

An important question not considered by the authors is how increased levels of ACE2 would lead to more severe COVID-19. One explanation is that the effect is mediated by increased susceptibility of cells to infection: more ACE2, more virus produced. Whether this situation holds true is unknown, as experiments to address it have not been done. Another issue is that severe COVID-19 typically occurs after a few weeks of virus multiplication in the upper tract, and is accompanied by decreasing viral loads in the respiratory tract. Furthermore, how increased ACE2 might affect the immune imbalance that contributes to severe disease is not known.

These observations make it clear that cigarette smoke increases ACE2 expression; however they do not provide an explanation for how smoking might exacerbate COVID-19. Despite this uncertainty, there are many other good reasons not to smoke cigarettes.

Vincent, Kathy and Rich discuss COVID-19 research paper overload, Moderna’s mRNA vaccine Phase I results, increase of ACE2 RNA by cigarette smoke, and answer listener questions.

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Nels and Vincent continue their discussion of SARS-CoV-2 evolution, including understanding recurrent mutations in the viral genome, and the potential for re-emergence of the virus from an animal reservoir.

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By David Tuller, DrPH

Norway’s got a double whammy going on. First there’s the group of investigators that seems to have had trouble determining whether their newly published research on CBT and music therapy was an actual randomized trial or merely a feasibility study. (More on that below.) Then we have Dagbladet, a widely read tabloid, promoting a new study of the Lightning Process–with the same senior investigator as the music therapy research. Dagbladet has so far published two stories about the matter (here and here), with perhaps more on the way.

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