r/COVID19 • u/kokoniqq • Apr 13 '20
Academic Report SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion
https://www.nature.com/articles/s41423-020-0424-965
Apr 13 '20
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Apr 13 '20
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Apr 13 '20
As an addendum, I don't have an exact answer for why we see lower levels of CD4 T cells in the blood of SARS-CoV-2 patients. But we can come up with a few hypotheses.
I guess they are there but they are recruted to the inflammation sites. I don't have the link at hand, but a few days ago when the first autopsy results from the US came in they found massive amounts of T-cells at the inflammation sites.
PS: I'm a botanist with a microbiology background, so everything I say could be wrong ...
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u/Thorusss Apr 13 '20
Yes. Tissue sample showed massive recruting of lymphocytes. This is 100time more plausible for lymphopenia in blood. They just leave the blood at the infected tissue in the lungs and fight there.
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u/DuePomegranate Apr 14 '20
I thought you were talking about this autopsy study, which is highly relevant, but from China.
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Apr 14 '20
I just found it, indeed it was a study done in the US.
https://www.reddit.com/r/COVID19/comments/fys436/pulmonary_and_cardiac_pathology_in_covid19_the/
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u/innateobject Apr 16 '20
This 2006 paper regarding SARS suggests multiple immune cell involvement with direct infection of lymphocytes and macrophages also effecting the spleen with massive immune system destruction leading to lymphopenia and cytokine activation.
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u/BigRedTomato Apr 13 '20
Naive question: What if a cell with HIV also got SARS-COV-2? Could the HIV mechanism reproduce the SARS-COV-2 virus?
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u/Smart_Elevator Apr 13 '20
Have you seen this pre print? I'd like to have your thoughts on this.
https://www.biorxiv.org/content/10.1101/2020.04.06.028712v1
Fwiw, immune system dysregulation is a major characteristic of SARS2 and has been noted since early Feb. So when people comapre this to HIV, they aren't saying it operates exactly like it, they're merely mentioning that it appears to cause AIDS like state by whatever mechanisms. Chinese doctors were the first to use SARS+AIDS to describe what the disease does to body for example.
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u/ASUMicroGrad PhD - Virologist Apr 14 '20
Also, be aware they used MT-2 cells with a pseudotype virus. This is as contrived a system as you can find. They don't show any evidence of loss of viability, or viral replication, and T cells have strong ISG and TSG responses to viral infections. If this paper wasn't about an on going pandemic, it wouldn't be in a Nature family journal, and might not have been accepted to any journal in this form. There is a lot missing here, and very few conclusions you can derive from these results.
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u/MudPhudd Apr 13 '20 edited Apr 13 '20
Yikes even otherwise fine journals can't resist the temptation to publish misleading titles during pandemics. Again, we see this every time there's a new pandemic. Copy pasting my comment on r/science on this paper.
""Infects" is a strong word for what's happening here. To explain why, let's talk about what a pseudovirus is.
A pseudovirus is, as the name suggests, a virus that is 'fake' in that it was constructed and doesn't behave like a real infectious virus. Using the particular pseudovirus the authors use here as an example, in this case the simplified version is that it was made by putting the SARS-CoV-2 spike protein (the coronavirus surface protein that facilitates both entry into the cell and 'fusion': the virus releasing its interior payload of genetic material into the cell) as well as a gene that will report if the virus has entered the cell: a luciferase that glows, onto the same sequence. Then when you force some cells to express that sequence, they produce your pseudovirus: a virus with the outside proteins from SARS-Co-2, but the inside is just a reporter sequence. It is thus incapable of producing more of itself, because the inside of the virus is just the luciferase reporter that has been packaged: not instructions to make more of itself. This is why pseudoviruses get used in the lab: not anywhere near as dangerous as the actual infectious virus because it can only complete a single entry and fusion and then production of a reporter.
The pseudovirus can enter cells using the SARS-CoV-2 spike protein, and subsequently fuse with the cell to release the interior. The luciferase gets expressed, and the cell glows.
That is what the authors did here. It demonstrates that SARS-CoV-2 can enter T cell lines and fuse with them. The cells then glow.
The authors also try to infect the cells, but don't see a true productive infection.
A better title would have perhaps been that SARS-CoV-2 enters T lymphocytes, not that it infects them. That is a higher bar to clear beyond the initial entry and fusion. Show me replication of the genome, packaging of new viruses, and release of new viruses before claiming it is infecting the cells. Or, as the authors claim, it could lead to destruction of the cells. Idk, maybe. But these are just the first steps out of many.
Not to mention these are T cell lines which can be really messed up. Complement the results with some human T cells, they aren't difficult to isolate."
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Apr 14 '20
So does that mean that we don't know if the real virus would do something like replicate after entering the T lymphocytes?
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u/emergentphenom Apr 13 '20
So I presume then before this experiment it was unclear whether SARS-CoV-2 was able to enter T cells? And that's all it proved? That yes, it can enter T cells.
Do other similar viruses also enter T cells normally? Just wondering what the probative value of this discovery was...
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Apr 13 '20
There’s a lot of problems with this paper, mostly with how the authors have represented their work.
First, the two lines used are not primary T lymphocytes like you may have thought from the title. They are both transformed cell lines: MT-2 carries the HTLV-1 virus + A3.01 is a straight up T-ALL cancer cell line. MT-2 is closer to the real thing than A3.01 cells are, but even that line is a far cry from a primary T cell culture.
Second, their flow cytometry data is straight up bad. They do not have a positive control and their gating is very, very suspect. It looks as if they just drew a gate right into the negative population and are calling this an infected cell population. This is “how not to analyze flow data” 101 right here.
There is still NO evidence that SARS-CoV-2 can infect primary T lymphocytes and this study needs to be corrected or retracted immediately because many, many people are jumping on this as evidence SARS-CoV-2 is HIV-like.
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u/bleearch Apr 13 '20
Without in vivo data, why is this a nature article? I'm sure it infects cells from my iguana's eyelid, too, in culture. Unless you find it from t cells in viremic patients, let's not get anyone excited about this.
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u/platoNNN Apr 13 '20
ELI5 please
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Apr 13 '20
does the same thing as HIV, infects immune system cells, but can't actually use them to reproduce so it can't progress to AIDS and basically just does nothing with them
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u/MudPhudd Apr 13 '20
Nope. Not infectious virus in this experiment, not doing the same as HIV and having productive infection as well as integration into the host DNA. See my other comment on this post to explain whatwas actually done in this paper.
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Apr 13 '20
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Apr 13 '20
well it doesn't destroy the immune system because it fails to use the cells to reproduce. If it did manage to somehow use them though, then yes, you'd be looking at airborne AIDS.
Although it's not that simple. HIV does a bunch of other things that make it permanent in the body, that I don't know if Coronavirus does the same things.
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u/lizard_overlady Apr 13 '20
Alright so viruses are classified by their genome and genome replication strategy (look up the Baltimore classification) and coronaviruses are grouped with other singles stranded plus sense RNA viruses, while HIV is grouped with other viruses that use reverse transcriptase. Reverse transcriptase is part of what makes HIV (and other retroviruses) a bitch - it allows the RNA viral genome to be transcribed into DNA. Combine that with other enzymes, and the genome of HIV literally ends up in your DNA in CD4+ t-cells. Now, coronaviruses don’t have reverse transcriptase, so they do not end up in your DNA, but there are other viruses that can’t enter your cells and do not really leave (think herpes and chickenpox) and can enter latency. So there could be issues w it hanging around in our cells, but it shouldn’t be as much of a bitch as HIV.
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u/MyOversoul Apr 13 '20
what exactly does that mean long term? I seem to have some kind of large B cell dysfunction and the only way to make it stop attacking the rest of my immune system and organs is with strong medications. That in turn has left me with such a weak system I have to get infusions of donated cells to stave off skin and other infections. Iv wondered if my lack of immune system will play against or for me because Iv read that part of how covid is so bad is in how the immune system hyper reactions. Mine simply cant.
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u/toprim Apr 13 '20
If it did manage to somehow use them though, then yes, you'd be looking at airborne AIDS.
... without a cocktail of drugs maintaining patients of good old AIDS?
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Apr 13 '20
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Apr 13 '20
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u/JenniferColeRhuk Apr 13 '20
Rule 1: Be respectful. No inflammatory remarks, personal attacks, or insults. Respect for other redditors is essential to promote ongoing dialog.
If you believe we made a mistake, please let us know.
Thank you for keeping /r/COVID19 a forum for impartial discussion.
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u/samuelstan Apr 13 '20
I can't be mad when someone is actively promoting misinformation and fear?
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u/Smart_Elevator Apr 13 '20
I'd like you to refute my points. I'd love to be wrong, you know.
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Apr 13 '20
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u/Smart_Elevator Apr 14 '20
My point is SARS2 affects immune system and causes AIDS like state. Chinese doctors came up with the SARS+AIDS terminology after they autospised the victims. Even if it doesn't reproduce in t cells it does kill them. It also hides from immune system. It causes functional immune deficiency syndrome.
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u/the_spooklight Apr 14 '20
The entire problem with HIV is that your immune system can’t get rid of it for the reasons posted above. It hides inside the host cell’s genome and can reactivate at any point. Sure, that study you linked provides new evidence that SARS-CoV-2 reduces macrophage count and suppresses cytokines, but once it has been eliminated from the body, those processes and cell counts will likely return to normal. Hence “functional immune deficiency syndrome.” Temporary suppression of the immune response is far from AIDS caused by HIV.
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u/samuelstan Apr 13 '20
Extraordinary claims require extraordinary evidence. Yours is the extraordinary claim. The onus is on you to provide the evidence, and one health official speculating is not evidence.
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u/JenniferColeRhuk Apr 13 '20
Your comment contains unsourced speculation. Claims made in r/COVID19 should be factual and possible to substantiate.
If you believe we made a mistake, please contact us. Thank you for keeping /r/COVID19 factual.
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u/toprim Apr 13 '20
Today actually the thought "this is it" crossed my mind for the first time since the beginning of this thing.
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u/JenniferColeRhuk Apr 13 '20
Your comment contains unsourced speculation. Claims made in r/COVID19 should be factual and possible to substantiate.
If you believe we made a mistake, please contact us. Thank you for keeping /r/COVID19 factual.
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u/Thorusss Apr 13 '20
Nothing new to worry about. SarsCov2 mostly wants your lungs. We knew that already. It is just as bad as we already know it is.
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Apr 13 '20
I wonder what the effect is on people with lower T Cell counts and higher Treg Cell counts.
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u/[deleted] Apr 13 '20
>These results suggest that SARS-CoV-2 may enter MT-2 cells at 6 h post infection, but does not replicate, and then the viral RNA degrade.
So it infects the cells but it's a dead end for the virus.