This system is widely used to study entry and the authors used it to look at nCoV2019 entry in a variety of cells expressing (or not) ACE2 and TMPRSS2. They also used a protease inhibitors, including a TMPRSS2 inhibitor, to investigate requirements for S priming
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The experiments are well-controlled and indicate that ACE2 can act as a receptor and TMPRSS2 for priming. The data are convincing. HOWEVER. There are caveats.
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1. VSV pseudotyping systems and other in vitro studies must be interpreted in context. These are artificial viruses used to study entry in cell lines. This is very different than physiologically relevant circumstances in which nCoV2019 infects a person
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2. Cell lines are almost always cancer cells or cells that have been immortalized by inserting genes that allow them to divide indefinitely. In this case, most experiments were done in HEK293T cells, which were transformed by 2 different viruses: an adenovirus & SV40 T antigen.
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293Ts are great for transfection and protein expression. But they are NOTHING like cells in the human airway. They came from a human embryonic kidney, but it's also unclear what kind of cells they even are. Fibroblast? Epithelial? Neuronal? Who knows, they were made in the 1970s.
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3. Receptor requirements are not the sole determinants of cellular tropism. These other factors include things like cellular antiviral responses (interferon signaling) or cell type-specific proteins or RNA that are required for virus genome replication or exit from the cell
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4. ACE2 and TMPRSS2 can function for nCoV2019 cell entry but that doesn't mean they are the only proteins that can. The idea of using ACE inhibitors or TMPRSS2 inhibitors as antivirals is intriguing, but that doesn't mean they are guaranteed to be effective in patients
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If the virus can use another protein as a receptor or another protease for S priming, then this doesn't matter. That doesn't mean it's a dumb idea, but we can't interpret studies done in vitro with tools for studying entry mechanism as promising preclinical data
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To be clear the authors aren't suggesting that. They only state that a TMPRSS2 inhibitor approved for human use in Japan should be considered. They also interpret the data well in the context of the study and do not overstate their results.
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In fact, the most interesting part of the study (to me) is their last experiment, showing that serum from a SARS patient can block entry. This suggests that maybe people with preexisting immunity to SARS might be more resistant or SARS antibodies could be used to treat nCoV2019.
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To their credit, the authors acknowledge the limitations of using serum from a single patient. They don't make wild assertions about the implications on tropism or what it might mean in terms of pathogenesis. I am impressed that the authors did a well-designed study so rapidly
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However, I wanted to illustrate that critical mechanistic entry work like this is distinct from determining mechanisms of pathogenesis. It is one piece of a larger puzzle. To understand how nCoV2019 causes disease, we need data from animal models & clinical samples from patients.
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The bottom line is that these in vitro studies are critical to establish mechanism of entry, but more detailed studies need to be done with authentic nCoV2019 in vitro and in vivo before we can conclude anything about the significance for disease, treatment, or diagnostics
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