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There May Be a Unique Coronavirus Immune Response

We’re starting to get a clearer picture of how the SARS-CoV-2 coronavirus works when it infects the body, and there are some surprises emerging. This new paper in Cell is an example (here’s a writeup on it at Stat).

We already know the RNA sequence of the virus very well, naturally, and that’s allowing us both to track mutations and to lay out exactly what proteins it forces a cell to make once it gets ahold of the machinery. That post has some background on some of these, and this earlier one mentions a number of them as well, with an eye to existing drugs that might interact with them. There aren’t very many in total – viruses in general are rather stripped-down. Recall that they start off by forcing the expression of a long polypeptide that (with the help of hijacked cellular proteins) starts cleaving itself into many of these necessary viral pieces, an alarmingly compact and efficient “autoloader” mechanism. The limited number of viral proteins means that you can usually assign a clear and necessary function (or more than one) to every one of them – it’s a lot like working at a small startup! There are no associate VPs in charge of facilitation of planning modalities in a viral genome; they are lean and mean.

And that means that they are stark naked examples of evolution in action as well. Recall that the guiding principle of evolution is “Whatever works”. That’s literally it, and nowhere more so than in something as small and as quickly reproducing as a virus. You know that old line about how an oak tree is just an acorn’s way of making more acorns? Viruses live it – the only thing they do is make more virus. There are no added complications for something like feeding behavior, because they don’t eat. There are thus no variations in metabolism, because they don’t have any metabolism. There are no crazy features driven by sexual selection, because they don’t mate. They infect cells and make more virus, and that’s it. And they do it very quickly, over and over. Any change that even slightly assists in infecting cells and making more viral particles that can make more viral particles will be amplified, any change that slightly decreases that efficiency will disappear.

This new paper is concerned with a vital part of that viral business: dealing with the immune defenses of the organisms that they infect. Recall that the human immune system has, broadly speaking, two branches. You have the adaptive part, the one that raises specific neutralizing antibodies and targets  T cells at an infection. That one takes a while to get going; there’s a lot to sort through and building up all those targeted weapons doesn’t happen overnight. And you have the innate immune system, which is the “always on” response that recognizes a number of general signs of infection and is ready to act immediately. If that by itself can clear an infection, it certainly will – otherwise it sort of holds the line until the adaptive immune system can range in the artillery and commence firing.

For viruses, the innate immune system is mostly recognizing weirdo RNA species as a sign of infection – these are things that shouldn’t be floating around, and when they show up it sets off the alarm. The receptors that pick these things up (such as the Toll-like receptors, TLRs) set off some serious transcription factor activity, namely NF-kappaB and various interferon regulator factors (IRFs). These head down to the DNA level and alter transcriptional activity, which has a lot of downstream sequels, too: for example, type I and type III interferon proteins (depending on the cell type) start being produced, which in turn set off a list of further interferon-stimulated genes. Over 300 of those are known, so you can see that listing all the effects is a task that gets out of hand really fast, which is a common problem in immunology. These interferons can be secreted to warn neighboring cells, and in addition, a whole list of chemokines are produced and excreted to recruit various types of circulating white blood cells.

Viruses that affect organisms (like us) with such defenses have had plenty of brutal selection pressure, and the pathogens we notice now are the ones that have assembled ways of infecting us anyway. The list of viral countermeasures is a long one – this battle has been going on for a while – and here’s an article that details ten of the most common ones. Many of these come down to hiding as much as possible from the cellular receptors as well as blocking them and their downstream partners with specific viral products. As the article says, this is a sort of arms race, and it has boundary conditions. An immune system varied and powerful enough to immediately wipe out every foreign pathogen could be hard to contain; we have enough problems with autoimmune disease as it stands. And a pathogen that ripped right through its host’s defenses and ran at full speed might well be quickly lethal, which could cut down on the opportunities for spreading. The successful pathogens (looking at the situation from their viewpoint) are the ones that spread in a way that leaves them constant opportunities for growth.

This new paper compares the transcriptional changes that kick in during infection with the current coronavirus to the past SARS and MERS cornaviruses as well as several other (non-corona) respiratory viruses. And it turns out that the SARS-CoV-2 is an unusual one: it manages to block the interfeon-I and III response quite thoroughly, while setting off a larger-than-normal cytokine secretion response. None of the other viruses studied have that profile. If you add IFN-I back to the infected cells in culture, they clear the virus very strongly – the machinery is working, but it’s just not being engaged. Likewise, the overall transcriptional profile of the virus in cells is unique. It’s not that it sets off more changes; in fact, it actually shows fewer transcriptional differences than the other viruses it’s being compared to. But the pattern of genes that are affected is a new one. There’s plenty of expression of a whole list of chemokines, that’s for sure: CCL20, CXCL1, IL-1B, IL-6, CXCL3, CXCL5, CXCL6, CXCL2, CXCL16, and TNF.

These cell culture results carried over quite well to animal models of infection (ferrets, in this case). Looking at nasal epithelial cells from the infected animals over time, the same lack of interferon response and strong cytokine secretion was observed, with what the authors describe as “a unique gene signature enriched for cell death and leukocyte activation“. Compared to influenza A virus infection in the same ferret model, the coronavirus transcriptional response was much less dramatic, but very distinctive. The team was even able to check transcription in human lung tissue (2 post-mortem samples compared to 2 different healthy patients). That’s a very small sample, necessarily, but it showed a very similar profile: no interferon upregulation and plenty of cytokine transcription. They were able to check circulating levels of these in a larger number of patients (24 infected cases versus 24 uninfected controls), and these results were also consistent: they tested negative for interferon, but showed elevation of CXCL9 (which attracts T cells) and CXCL16 (which attracts NK cells), CCL8 and CCL2 (recruiting monocytes and/or macrophages), and CXCL8 (which attracts neutrophils). A sudden oversupply of these cell types might be behind the pathology of the disease, which could be characterized, if these hypotheses are correct, as a uniquely imbalanced response: far too little interferon and far too many cytokines, too early.

I expect we’ll see quite a few other papers in this area; we’ll see if this picture holds up. But it certainly seems consistent with what people have been seeing in the clinic, and it bodes well for the therapies that are aiming to dampen the cytokine response pathways. Does this mean that administration of IFN-I or IFN-III would also be beneficial?

118 comments on “There May Be a Unique Coronavirus Immune Response”

  1. Giannis says:

    Maybe giving IFN (inhaled maybe ?) as early as possible, even as prophylaxis, might tip the balance in our favor.

    1. Ben says:

      infect covid sufferers with something else that causes IFN-I immune response? Obviously something not very dangerous.

      1. Mark Brittingham says:

        That’s actually quite brilliant. I wonder how many asymptomatic cases come down to people who already had some mild infection?

        1. TMac says:

          And/or were already responding to it with an effective anti-viral?

        2. EugeneL says:

          There are supporting arguments for this idea, so far overlooked. Tight groups of people, such as prisoners or homeless in shelter homes often get the viruses together.
          Recent serosurveys showed that a large majority of prisoners or homeless appear to be asymptomatic (you can easily find these surveys yourself).
          Many people were puzzled by those results. But the explanation is simple: those groups have been exposed to some other (corona) virus that gave them partial immunity. Probably pretty recently.

          This theory is easy to test, just see if there is a correlation in asymptomatic cases within families.

          1. RA says:

            Really interesting idea. I wonder if there is any way we could/should test for antibody titers to other circulating coronaviruses (in addition to COVID-19) and see if there is any relationship between them and the risk of developing more severe covid 19 disease. Wouldn’t be ironic if all those crappy antibody tests with poor specificity because of cross-reaction with antibodies to other circulating coronaviruses actually told you something about your risk of severe disease?!?! I jest, because they are probably crappy at detecting the other circulating coronaviruses antibodies too…but the question is, do we have our paradigm on antibody testing wrong?

          2. Rory says:

            Interesting idea, perhaps I’m misunderstanding it but wouldn’t the similar genetics (and I suppose perhaps similar enviroment/diets etc…) of family members provide a lot of noise to see if there is a relationship as you describe?

          3. EugeneL says:

            A wife and a husband would not have similar genetics, would they? So they should be independently symptomatic or asymptomatic. This is easy to test by running through already collected serosurvey data.

            One doctor in NYC made a similar observation: family members are either all mild or not. He never tried to explain that.

          4. EugeneL says:

            The cowpox type vaccine may be around the corner. If a prior virus that turns covid into an asymptomatic form is descovered it can be a game changer.

      2. Philip says:

        @Ben, the idea that being infected by something else being protective is what is behind the idea that Oral poliovirus vaccines (OPV) and Bacille Calmette-Guérin (BCG) vaccine for tuberculosis are protective against SARS-CoV2. I don’t think ether of those vaccines are used in the US. FluMist is an attenuated virus vaccine that is used in the US. We will have to wait for studies to know if there is anything to this theory. There is enough information that if I was younger I would skip the flu jab and use FluMist.

        For more info:
        My other source for good SARS-CoV2 information.

        I am a computer programmer, not a health care professional, so don’t take my word for it.

        1. CJ says:

          The BCG vaccine was given to almost everyone in Quebec during the 1950s to the 1970s. It was rarely used elsewhere in Canada. Today Quebec has suffered 61% of the Covid-19 deaths in Canada, while having only 24% of the population. This is a contraindication to the notion that BCG vaccination gives protection.

          1. LdaQuirm says:

            You’ve missed the point. The point was not that the vaccine gives subsequent immunity to the virus, but rather that: on receiving the vaccine, an immune response occurs which contains factors missing from the normal CoV-2 immune response. I.E. Replication-deficient & detectable virus (vaccine) + infectious & non-detectable virus (Covid) = infectious & detectable virus

          2. Mike says:

            Excellent point.

          3. Aarti S says:

            On a bit of a far-fetched tangent to this, countries that have had a BCG policy in place for a long time, tend to be the ones with a high TB burden, with a significant fraction of the population exposed to and harbouring latent TB. If latent TB elicits the “missing pieces” of the immune response, countries which have a TB problem shouldn’t have a huge COVID problem? If true, BCG administration could indeed be protective.

        2. eub says:

          Ben is suggesting an active infection to raise IFN now against the CoV. Having had BCG as a child doesn’t give you raised IFN levels decades later, so if it’s doing anything (and BCG does a lot), it’s not by the mechanism proposed.

        3. Toni says:

          This report, which is linked in the Twiv604, is remarkable.
          1. The efficacy of the new approach to nonspecific emergency prevention of influenza and ARIs
          using live oral enterovirus vaccines as interferon inducers was evaluated.
          2. The use of live enterovirus vaccines in controlled trials reduced the incidence rate 3.2 fold
          allowing to recommended the use of LEVs for nonspecific emergency prevention of influenza
          and other ARIs within the initial phases of outbreaks.”

        4. Philip says:

          I was not clear. Sorry about that. The idea is NOT that an attenuated active vaccine provides protection against SARS-COV2 by training the adaptive immune system. The idea is that it primes the innate immune system for some short period of time. Perhaps a few months.

          If we had adequate testing and tracing and if the hypothesis is correct, attenuated active vaccines could be given in hot spots. To put out the fires.

          For the data mining folks, an interesting question would be if those who got the flu were less likely to got COVID-19.

          1. Ed says:

            Such as mandatory flu shots among medical personnel….

    2. Grumpy Old Professpr says:

      I agree that this is interesting. Some time ago (Contoli et al PMID: 16906156) a study was published suggesting that IFN lambda was deficient in asthma. This sparked a flurry of activity and the results were unclear (just one of the complications of doing research in humans and not mice – haha – poke around pubmed here and here, if you’re interested).

      Anyway – a company was formed to deliver IFN-L and or IFN-B by inhalation, but it never quite got off the ground as far as I can tell, but I haven’t followed it closely. Suffice to say that, if one wanted to try this local delivery for COVID-19, then some of the problems are already solved.

      As far as giving IFN systemically, then (and there’s a good discussion below of the Eiger Pharma work) lambda would be the way to go, given the very restricted receptor expression.

      Thanks for the blog, Derek!

  2. Isaac Machado says:

    Because generation of reactive oxygen species (ROS) is an important characteristic of pro-inflammatory responses in phagocytes (BRANDES et al., 2014; KOZLOV et al., 2017), NRF2 is mainly an anti-inflammatory mediator, confining inflammatory responses (REDDY et al., 2011). One explanation for the anti-inflammatory effect of NRF2 is its ability to inhibit the expression of pro-inflammatory cytokines, like TNF- and IL-6, as well as inducible nitric oxide synthase (iNOS). NRF2-dependent induction of antioxidant target genes, such as heme-oxygenase-1 (HO-1), Nqo1, glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, blocks the activation of the classical pro-inflammatory transcription factor NF- B, thereby inhibiting the transcription of pro-inflammatory mediators (BELLEZZA et al., 2012; LEE et al., 2009).

  3. Paul Johnson says:

    Thanks for all your hard work assembling these blogs. They’re a great help to everyone.

    1. franko says:

      Please let me second this. I am in awe of the breadth of your knowledge and I deeply appreciate the time and effort you take to write these up.

      1. Mike says:

        I completely agree. Although I have a very limited understanding of what is discussed and debated in the posts I am nonetheless extremely grateful for the content. It gives me comfort knowing that such bright people are working tirelessly in an effort to neutralize and/or treat this pathogen.

  4. Adrian Bunk says:

    That IFN-I might be able to clear the virus is actually known from SARS.
    “During the SARS outbreak in 2003, an animal study revealed that recombinant human IFN-α2b spray can prevent SARS-CoV infection in Rhesus monkey model by inhibiting virus infection and replication.”

    That’s an article published February 5th citing a SARS article from 2005.

    1. Adrian Bunk says:

      And to answer your last question from the same source (written in January):
      “The Novel Coronavirus Infection Pneumonia Diagnosis and Treatment Standards (the fourth edition) and Diagnosis, treatment and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement also listed IFN-α atomization as a choice of treatment for 2019-nCoV pneumonia.”

      Data with Interferon in Wuhan in January also look promising:
      “IFN treatment accelerated viral clearance by ~7 days”

      This was an “uncontrolled, exploratory study”, but it looks more promising than some of the stuff that is being hyped.

      1. Ian Malone says:

        On a very rough skim, Table 1. Days from symptom onset to treatment, 9 days higher in the ARB + IFN group gives me pause. At the discretion of the attending physician (rather than randomised), so I suppose they decided to hit their more advance cases with the combination? On the other hand, their IFN only group is actually the one that shows fastest decrease in proportion positive and a quick find over the document doesn’t pick up fatality, death, omitted or excluded, so maybe something there.

      2. John Holst says:

        Yes, like Remdesivir, which I read they want several hundreds into thousands of $ for a weeks course.

        1. Derek Lowe says:

          Link for that cost estimate, please. Thanks.

  5. Alan Goldhammer says:

    Derek, the final hyperlink doesn’t link to anything.

    1. Derek Lowe says:

      Oy, so it does. Or doesn’t! Fixed now. . .

  6. psoun says:

    Would this be an appropriate trial in light of this?

    1. David Young MD says:

      Yes, I believe so.

      Here is another study of pegylated Interferon lambda:

      And another study with pegylated Interferon lambda:

  7. Trew says:

    Out of curiosity, does anyone know if RNA binding drugs such as the tetracyclines or aminoglycosides have been investigated in this “throw everything at the wall and see what sticks” approach to drug discovery and clinical trials.

    1. Alan Goldhammer says:

      Doxycycline is in a couple of clinical trials. I have not seen any aminoglycosides being tried out.

      1. psoun says:

        Different context, but a combination to test:

  8. Steve B says:

    At the higher end type-I interferons inhibit type-II interferons and other inflammatory cytokines. Thus, the severity the cytokine storm could be indirectly caused by the impairment of type-I interferon production. SARS1 has several factors that attenuate the production of type-I interferon and the signaling pathways downstream of the type-I interferon receptor. It seems plausible that SARS2 has simply gotten better at this skill set. I have no idea if the salient interactions have been structurally characterized, and, if so, whether they look ‘druggable’.

  9. Tom says:

    Naive non-immunologist question.. but… couldn’t you just make an attenuated virus that drops these proteins? Wouldn’t that be a quick path to a live virus vaccine? Or is there a problem with that approach? Sounds like it still infects, just poorly.

    1. Derek Lowe says:

      Not a crazy idea, but it’s probably best done by forcing some variation to occur, rather than trying to do it in a more targeted fashion. Here’s a paper bearing on just that:

  10. RA says:

    Thanks…very interesting! This seems to explain a bit more about the patients who suddenly crash with cytokine storms…I also wonder about what is happening in the immune systems of the patients who have prolonged symptoms…i.e. those who may never get hospitalized but feel miserable for months. Also, wonder about what is happening immunologically with the kids and young adults with the multisystem inflammatory syndrome that may occur long after initial infection…this virus is so bizarre in so many ways!

  11. march21 says:

    Several articles on the internet says Cuba has been using Interferon Alpha 2B since March to fight covid19. And China has been using it from January. So why didn’t Western nations didn’t look into it earlier?

    1. David Young MD says:

      Why? I suppose because there were so many other entities that were claimed to be the cure-all for Covid19. It is hard to test everything at once. Having said that, I am a little critical of the lack of coordination among medical centers for not having an organized approach here. Interferon Beta, and perhaps Interferon Lambda should have been submitted to a randomized studies earlier. That said, I don’t trust anyone who claims success without a randomized, placebo controlled clinical study. I sure don’t trust the Cuban scientists or any one for that matter.

    2. Blaine C. White, M.D. says:

      When one looks at the viral proteins and our translation system (ribosomes), CoVs non-structural-protein-1 (Nsp1) is special trouble. It contains a RNAse, and that destruction is directed specifically at our mRNAs because CoVs RNAs have a 5′-leader with self-hybridizing hairpins recognized and spared by Nsp1. The results on RNA Northern blot and autoradiograph of 35S-amino-acid-labeled protein synthesis are that our mRNAs are destroyed and only viral proteins are made (Lokugamage et al. J Virol 2015). So – no interferons. When Nsp1 is deleted from SARS-CoV, the virus induces interferon production (Narayanan et al. J Virology 2008). Nsp1 requires cyclophilin cofactor(s) (Pfefferle et al. PLoS Pathog 2011). Cyclosporin binds cyclophilins tightly (see Ke et al. Structure 1994) and inhibits CoVs replication (De Wilde A et al. J Gen Virol 2011). Indeed, Remdesivir may also obstruct Nsp1 (Sharma et al. ChemRxiv 2020). Cyclosporin has been widely used to manage other examples of cytokine-release storm (CRS). Dr. Carl June (Richard W. Vague Professor in Immunotherapy at U Penn) has proposed a cyclosporine clinical trial. That seems a very good idea.

  12. Todd says:

    Just looking at this, this screams INTERFERON ADMINISTRATION!(tm) It’s well defined, and we know how to do it medically. Throw it in with remdesivir and generous amounts of anticoagulants (of which there are plenty in the marketplace), and we might be getting somewhere. That this holds up well on so many levels is a good thing.

  13. Trumpster says:

    shut up lowe, ye dont know what ur talking about. covid be curable, all yous need is inject yoself with some good old disinfectant

    1. Sirius says:

      So not helpful and childish. I wonder if any of the words in the article even registered for you.

      1. Derek Lowe says:

        Oh, this is someone having fun. The real fanatics sound different than that. . .

  14. Rob says:

    Wasn’t there a recent trial in Hong Kong where they used an interferon in combination with some antivirals? I remember it being small, but with quite promising results.

  15. steve says:

    Interferon, like all cytokines, is a double-edged sword. For one thing, SARS-CoV-2 uses interferon as a feed-forward signal because it up-regulates the expression of ACE2. Giving it systemically early on it could be helpful but people generally don’t know that they’re infected early on. Unlike what was stated earlier, IFN was NOT effective in SARS or MERS. With SARS-CoV-2 the issue in those who are sick is the cytokine storm and IFN is a big part of that storm. Adding more at that point is unlikely to be beneficial. The immune system is a highly complex interactive network of cells, cytokines and other signals. Just dumping in one of them is often a recipe for disaster.

    1. Derek Lowe says:

      Points well taken!

    2. AJ the Husky says:

      Actually, from the triple therapy paper, it seems that adding IFN is quite beneficial.

      This is not a suprise, since there are several papers arguing that the virus doesn’t induce IFNs. Since IFN-III (lambda) is a lot safer, but same (if not with higher antiviral effect) in prior studies, that’s the approach that should hold most promire.

      1. Rob says:

        Yes, this is the study I referred to above.

  16. Mark says:

    Please remember that all of us who are here are descended from humans, and pre-humans, that survived many pathogens. This process led to the immune system we have. Our immune system is the system of winners. It is very tempting to modulate it, but let’s be very careful about the way we go about changing something that actually works pretty darn well. I am not saying that interventions should not be done, but we need a sound scientific basis for action. A gee-whiz report in an unreviewed preliminary publication is not a call to action.

    1. You hit the nail on the head. COVID-19 severity is iatrogenic.

      Immunological mechanisms explaining the role of IgE, mast cells, histamine, elevating ferritin, IL-6, D-dimer, VEGF levels in COVID-19 and dengue, potential treatments such as mast cell stabilizers, antihistamines, Vitamin C, hydroxychloroquine, ivermectin and azithromycin

      1. William Meisheid says:

        I think you forgot to include vitamin D3, which is integral in stopping the cytokine storm, hence deals with the initial problem the virus creates.

        Dr. Russell Blaylock addressed this issue clearly in March of 2018 in his newsletter, available here.

        1. Agree that Vitamin D is important. And Vitamin A,C,D may prevent severe disease.

          It can explain why colored people have more severe disease and is one reason for seasonality.

  17. Dana says:

    In paragraph starting:

    “Viruses that affect organisms (like us) …”

    Link to article on countermeasures is broken.

  18. John Wayne says:

    I have never heard that line about the oak tree and the acorn. Thank you.

    1. EngProf says:

      I believe the usual version is “a chicken is just an egg’s way of making another egg.”

      1. Hap says:

        I thought someone wrote about humans being a way for corn to make more corn.

        1. Mammalian scale-up person says:

          Are you thinking of Michael Pollan? I remember that too.

        2. Simon Auclair the Great and Terrible says:

          People are shits way of making more shit

          1. matt says:

            Nobody does it better. Both ends, sometimes.
            Also, unique amongst the animal world, capable of producing bull, horse, chicken, and bat shit as well. Others available on request.

  19. Carl Pham says:

    It seems kind of iffy that IFN would help once the patient is showing obvious signs of inflammatory distress of the type that gets them tubed. You might need to do it very early on.

    Which means we need (1) a really sensitive and fast test, widely applied, or (2) really effective contact tracing, so you know even without widespread testing the exact people who might benefit from early therapy (and make it worth the risks).

  20. COVID-19 immune response may not be unique. It looks similar to dengue secondary infection response.

    Immunological mechanisms explaining the role of IgE, mast cells, histamine, elevating ferritin, IL-6, D-dimer, VEGF levels in COVID-19 and dengue, potential treatments such as mast cell stabilizers, antihistamines, Vitamin C, hydroxychloroquine, ivermectin and azithromycin

    BTW, IL-1B, IL-6, TNF are not chemokines.

  21. gippgig says:

    Poly rI:rC (anyone remember that one?) seems worth a try… and has anyone considered using SARS-CoV-2 in cancer immunotherapy?
    To totally change the subject, has losartan been tried?

    1. Rob says:

      It’s in trials, but I haven’t seen results reported.

      1. Rob says:

        Losartan, that is.

    2. Toni says:

      STING-Antagonists (as well as Agonists) are being tried in Immuno-Onco trials.

  22. James Tiberius Smirk says:

    How about those nicotine trials?

  23. Stephane says:

    Hello Derek,
    Thanks for this post and all others – I’m no biologist or chemist (graduated in maths and computer science, what feels like aeons ago) but your posts are unfailingly fascinating to read and give great insight into your area of expertise. You’re almost providing a public service here.
    If I have one wish, in these unsettling times, we need a couple of “things I won’t work with” to lighten the spirit.
    Thanks again and keep safe.

    1. David M. Snyderman says:

      Derek, I’m going to second that. Right now, the levity of one of your “things I won’t work with” would be great.

      1. Hg(FOOF)2 says:

        That would also have an added benefit of attracting more readers to this rare source of enlightenment. I came for that funny fluorine stuff and stayed ever since.

  24. Peter Jackson says:

    Hi Derek, I am interested to hear your thoughts on the R. Kip Guy paper published in Science just today. They seem to entertain the idea of the HCQ/Azrithromycin combo and cite Didiers paper. I always thought Kip Guy was a great, well respected researcher (more than can be said for Didier). Do you agree with his take? Has he missed the mark?

  25. A Nonny Mouse says:

    This study says lack of T-cells is a problem and IL-7 may help.

  26. idiotraptor says:


    An interesting read as always.

    “These interferons can be secreted to warn neighboring cells, and in addition, a whole list of chemokines are produced and excreted to recruit various types of circulating white blood cells.”

    secreted, not excreted

  27. CR says:

    I’m confused, because other reports have showed type I and III interferon induction in human cells infected with Cov2 virus, and in BAL fluid of COVID patients. In addition, single cell data from infected cells in BAL fluid had a population of IFNA+ monocytes, showing at least some induction – along with induction of targets of interferons (ISGs). So the data aren’t very consistent – who do we believe? The clinical data from that triple combination posted above seem suggestive that there’s not enough IFN induction, or room to improve by adding more. Maybe it’s because this new paper looked at cadavers, and either there’s a link between low IFN induction and mortality (so cadavers are biased towards a low-IFN population), or IFN goes down at late stages of infection? In the living patients they looked at blood for IFN, not BAL fluid, so it’s possible that the IFN response is too localized to the lung to be systemically detectable.

  28. permadoc says:

    Inject nCOVID 19 patients with IL-12/IL-18, get plenty of IFN-y from NK cells. Might kill you though. As I recall this kills mice if activation is too much.

    1. Mom in NC says:

      Interesting thought. I have psoriatic arthritis, which presents with high levels of IFN gamma, as well as IL-1β, IL-6, IL-17, IL-22, and IL-23. Usually, a common cold virus sends me straight to pneumonia… but I have been extremely healthy during Covid-19, even though I have been exposed to many opportunities to catch it. My husband and my daughter are both essential workers and I work on a college campus (where we had students test positive shortly after our “lockdown” began). I would be interested in having the antibody test…maybe my normally elevated interferon (albeit type II) have been blocking the cytokine storm.

  29. Former Merckoid says:

    Greetings Derek at al…

    You write: that the “innate immune system is mostly recognizing weirdo RNA species”.

    Not exactly on topic (not an immunologist) but if I understand the mRNA vaccines, the “immunized” cells translate the mRNA (SARS-CoV-2) spike protein and present it on the outer surface of host cells.

    What little I remember of immunology, immune cells will express these proteins in the context of self.

    If mRNA is translated by host cells, is there a risk that the rest of the immune response will see that spike protein as “self”?


    Former Merckoid

  30. Tom says:

    Is it possible to train a person’s immune system outside their body?

    For example, if you take blood with B cells and memory cells in it (I assume the blood makes up the immune system but please correct me if I’m wrong) out of the human body, incubate it to keep it alive, healthy and active, then put the COVID-19 virus into it, would it be able to fight off the virus outside the body and gain immunity? Then once it has completely neutralised the virus, put it back into the host person’s body giving the person active immunity?

    Also why can’t active immunity and memory cells from COVID survivers (or survivors of any other virus) be transferred from person to person to give the receiver with a compatible blood type active immunity instead of just passive immunity?

    Also could an extremely low viral load be put into a
    Petri dish containing your own cells and just before the virus is destroyed in the Petri dish, the virus sample with your immune that’s in the Petri dish is injected back into your body so that the viral load is much smaller and your immune system has had a massive head start.

    Sorry all if it’s a silly question or idea, I’m not a doctor and have no knowledge about this stuff.

    1. permadoc says:

      Good question: For your first question, I think that is something researchers would like to do, and it has not been done yet. Part of the problem is that antigen recognition and immune cell development occurs in specific tissues (like lymph nodes), and to develop active and specific B, T, and NK cells that recognize and neutralize viruses may require that additional tissue for this process to occur. These tissues are very complex and I don’t think they can easily be mimiced in a petri dish.

      What can be and is done is that you can take specific cells like T and NK out of the body, “juice them up” with cytokines like IL-2, IL-15, IL-12/IL-18 in a petri dish, and add them back to attack antigenic stuff you don’t want like cancer or viral infected cells, so I would imagine in principle this could be done for viral infections. The problem is you can juice them up too much and it could kill you.

      I think it would be difficult to take cells from covid survivors and put them into a different person, because the receiver would recognize them as foreign and would kill the cells (most transplants will not work unless the receiver is immunosupressed with something like cyclosporin, or the donor is a identical twin (!) with the exact same proteins as the receiver).

      My two cents, from a PhD in chemistry that does research in immunology.(please anybody correct me).

    2. Med(iocre) Chemist says:

      I’m no immunologist, but I think it’s way, way more complicated than “incubate B cells in blood with antigen”. The initial activation involves a cascade of events between many different cell types that would be hard to recapitulate, but even if you could, the response you’d get would be weak and fleeting. Multiple or sustained exposure to an antigen gives you better antibodies through a process called affinity maturation, but that all happens in actual organs like lymph nodes and the spleen. There’s probably some way of doing all that in a test tube, but it would be complicated, prohibitively expensive, and probably too slow to save someone who’s already at the hospital. If you’re thinking about this as a prophylactic measure, then what you’re describing is just vaccination, but with extra (and extremely expensive!) steps that are more likely to fail.

      Your second idea is called adoptive cell transfer, and it’s still in the experimental phase as far as I know, mostly for cancer treatment. The main drawback is safety (it’s hard to keep the transferred cells from attacking you or you from attacking the transferred cells). You would have the same shortage of raw material as with convalescent plasma.

  31. jz78817 says:

    I wish more people would read your blog posts instead of letting bots on Twitter and Facebook induce them into screaming at each other.

  32. Tony says:

    There was a recent paper in Lancet that suggests ribavirin and IFN were effective in COVID patients. No idea why it wasn’t big news.

    I think the issue is the IFN could be given to quickly diagnosed patients more often. However, late in the disease it will exacerbate the inflammation. The other issues are that it is expensive, and side effects include unpleasant flu like symptoms.

    1. jz78817 says:

      maybe- just maybe- we should give time for studies to actually produce some firmer evidence before blowing it up into “big news.” I know we collectively have the patience of a toddler, but going off half-cocked every time someone somewhere says “this might be effective” is doing us no good whatsoever.

  33. E P Pecanha says:

    What about a early cross immune/interferon response to a virus infecting 3.7 billion people, leading to mild/asymptomatic development ? HERPES SIMPLEX?
    Just another Immunonaive crazy idea.

  34. JJM says:

    Derek, could you do an analysis of:
    Does the research indicate that a certain, significant, portion of the population will have immunity to COVID-19 without antibodies post exposure?

    1. Nathan says:

      I was just about to post a reflection on this as well. I believe Derek mentioned this in his post a few days ago.

      “And here’s something to think about: in the unexposed patients, 40 to 60% had CD4+ cells that already respond to the new coronavirus. This doesn’t mean that people have already been exposed to it per se, of course – immune crossreactivity is very much a thing, and it would appear that many people have already raised a response to other antigens that could be partially protective against this new virus. What antigens those are, how protective this response is, and whether it helps to account for the different severity of the disease in various patients (and populations) are important questions that a lot of effort will be spent answering. As the paper notes, such cross-reactivity seems to have been a big factor in making the H1N1 flu epidemic less severe than had been initially feared – the population already had more of an immunological head start than thought.”

      I’ll be honest, I have been pretty baffled as to why, after initial infection surges and reopenings across the world, there haven’t been major spikes in infections and deaths, even though many of the “super spreader” events have been cancelled. And I think this finding goes a long, long way towards explaining it and is understated good news. It seems like this finding is essentially saying that, no, we don’t have “herd immunity” towards Covid-19, but amongst a huge segment of the population, there is significant quasi-para-crossreactive-immunity towards Covid-19.

      This might explain the massive variance in response to infection, and explain why those persistently exposed to large doses are much more likely to get severe disease; CD4+ cells cross-reactive to Covid-19 are able to fight off small doses of virus because they have imperfect/nontargeted activity, but if the virus is able to overcome the initial defenses of the CD4+ cells and proliferate, it can still wreak havoc in the body until a targeted adapted response is mounted by the body.

      It also might explain the lack of spikes after reopening (so far!) – after the initial pool of non-Covid-targeting-CD4+ carriers are infected and their 2nd, 3rd contacts (of vulnerable folks) are exposed, there is a much smaller pool of people available for “bad” infections with “bad” exposure times.

      1. RA says:

        I find this interesting too! Since it is not practical to test for these CD4+ cells in a large population, I wonder if there there is a correlation between having these cells and having (detectable) antibodies to other circulating “common cold” coronaviruses, which I imagine would be tested more readily.

      2. Erik Dienemann says:

        Yes, I had some of the same questions. One major question I have is that I hope that whatever non-exposed people they found the cross-reactivity in are being followed for whether or not they get the virus. No idea if there are enough of them to see some major difference vs. those without cross-reactivity, but if not, perhaps we could identify more of them through this type of analysis and try to establish, at least inferentially, whether they have any immunity (almost like a vaccine trial).

  35. “Does this mean that administration of IFN-I or IFN-III would also be beneficial?”

    One study suggests that COVID-19 is atypical of virus infection in that there is very little triggering of the innate immune response and subsequent IFN-I and III release. This may explain, in part, the weak adaptive response seen in some convalescent patients.

    1. Doh! Read last sentence of the blog, which set off a memory twitch (I’ve posted on this particular study elsewhere)….dug out link to paper in attempt to be helpful. Which is the same paper as Derek uses for the blog article….

      Memo to self: read the whole chuffing piece before jumping in….

    2. JonRick says:

      Double blinded placebo trial with inhaled interferon beta, results due in next 2 to 4 weeks
      Not long to wait!!

  36. MariaE says:

    I don’t understand much. I just have a question, so how it affect those of us that have autoimmune diseases?

    1. Errorreport says:

      Auto-immune disease are problems of the adaptive immune system generally. This is talking about innate immune system responses which are generally referred to as Auto-inflammatory disease when they malfunction.

  37. fajensen says:

    This could explain (some of) why children gets over Covid-19 much easier:

    They normally sponge up every germ there is to sponge, especially when in daycare which is a plague-pit at all times (as every parent knows), så they are already running IL-1 and IL-2.

    When Covid-19 gets in, it meets a more hostile environment and doesn’t multiply well.

  38. Toni says:

    Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19:

    This mechanism of blood vessel formation and inflammation in Covid-19, which has been described for the first time, is believed to be responsible for the severity of the disease and demonstrates that lung failure in Covid-19 is largely due to vascular damage.
    Is this pathology due to the immune reactions or are we just learning about a new virus with still completely unknown virulence factors?

  39. NotADoc says:

    O/T, but asking here due to the unusually professional crowd:

    Is it worth using an inactivated whole virus to develop a vaccine?

    This type should (umm, with a handful of glib assumptions 😉 provoke a pretty good natural immunity, while having some element of risk. But since a) most people under 65 shrug off the virus with no lasting consequences (it appears) and b) treatments for those who catch it are steadily being found, doesn’t the risk/benefit look pretty good? Yeah, trial lawyers…. we could exile them to Wuhan for the duration.

    Another advantage of this type is it would, in theory, be easy to keep up with mutations.

  40. gentlemutt says:

    Naive question: would smoking tend to activate the innate immune system more often than experienced by non-smokers? If so, would the presumed locality (ie, the lungs) also play a role in beneficially ‘priming the innate pump’ before the virus can disable it?

    I ask because some early reports suggested that , IIRC, like prisoners and homeless people, smokers were surprisingly under-represented in serious cases.

    1. RA says:

      In addition to that, it is striking that some reports show patients with asthma are under-represented among those with severe covid disease. What to make of that? Are there changes in the lungs/immune system of people with asthma that provide some extra protection? And/or does this highlight that severe covid disease has more to do with blood vessel involvement? Or are the data thus far not good enough to say asthmatics are under-represented?

      1. Adrian says:

        To everyones surprise people with many pre-existing lung conditions are often not high risk groups for severe COVID-19.

        Note that even “under-represented” would not imply “changes in the lungs/immune system”, the “extra protection” could be something as simple as that people with asthma were already hiding at home when many other people were still partying because “COVID-19 is not worse than the flu” – for people with asthma the seasonal flu is a serious threat.

        1. RA says:

          Yes, that is a good point…the hospitalization mix could be confounded by the degree to which various groups are avoiding exposure. I also wonder about that particularly with children…so far the operating line is that MIS-C is “rare” in kids, but how many have yet to be exposed to COVID with schools out and many staying home and the fact that there appears to be a long lag time between exposure and disease onset? We are operating in the dark and decisions about reopening schools in the fall will need to be made in the not so distant future

          To me, this says that we need a much better strategy with population-level seroprevalence surveillance…it would be great if we could use a widespread strategy to determine whether asthmatics (or kids…or other subgroups of interest) have a different seroprevalence than the general public to help us tease out the relative contribution of biology vs social distancing in the observed differences in severe disease burden… and thus inform better policy and research prioritization.

          1. Adrian says:

            If COVID-19 is still a worry in the fall, I would call this a strategic fiasco.
            There is no further research needed.

            Thailand has 70 million people, Bangkok has the same population as New York City.
            Thailand managed to contain COVID-19, and is now down to around 10 new infections per week in the whole country.

            You can choose to still live with COVID-19 in the fall, or you can choose to follow the example of Thailand and get rid of COVID-19 before the fall.

            And it is not just Thailand, it is nearly all countries in East Asia and Southeast Asia and Oceania that have succeeded with that.

          2. Some idiot says:

            @RA, Adrian: Interesting points… Disclaimer: I am not a biochemist, medical profession, or directly involved in the clinic (I am a process chemist). Plus, I have not looked into statistics regarding asthmatics and COVID19, so I don’t know which way that one hops.

            However, I am an asthmatic, and I have been a guinea pig in many trials whilst I was doing my PhD in the dim distant past. Which means that I have a very good feeling for my own asthma, plus have _heaps_ of background information…

            When the inhaled steroids came on the market some decades ago, it really changed my life for the better (and was one of the reasons I got into Pharma; to try and help others as I have been helped!). Really made a big difference. The main downside (for me) is that it reduces inflammation in the lungs by moderation the immune system in the lungs, which means that I am more or less assured of getting any airborne virus going around (think flashing neon sign above my head saying “Kick Me!!!). However, given the problem with cytokine storms with COVID19, it _may_ be that the steroid helps to calm down the immune system…

            However, this is speculation, and I have no idea whether or not this is backed up by data…

    2. EugeneL says:

      As I noted in another comment, there is a nice explanation why prisons or homeless shelters sometimes have high incidence of mild/asymptomatic cases. Because these tight groups have been through a previous (corona) virus together, which gave all of them some a form of immunity – turning covid into a mild form. This has happened probably pretty recently, so the groups did not have much chance to shuffle.

  41. Rob says:

    A naive question, and maybe I have this muddled up. I can see why blocking interferon production is in the virus’s evolutionary interest; let’s hope giving one of the interferons early will have a substantial impact. The virus also seems to up-regulate cytokine production. How is this in its evolutionary interest?

    1. Adrian says:

      For an established disease this is true, but this is the result of adaption to the host.

      COVID-19 is only starting to adapt to us as new host.

  42. Grumpy Old Professor says:

    Hi Derek, I’m once again fighting with your spam filter. I suppose that should be telling me something!

    It is very intriguing to me that there appears to be a CoV-2 Orf that encodes an IFN-silencing transcription factor (ORF3b: It’s even more interesting that there are additional cryptic variants that when artificially ‘released’, have enhanced inhibition.

    I’m curious to see whether these are functional directly on the alpha or lambda promoters – alpha is influenced by back-signaling from beta of course, so there may be indirect effects there, but lambda generally is not.

    This all drew my attention because a recent review on cGAS and STING suggested that IFN induction via TBK1 and IRF3, which is the aspect of STING that most people pay attention to, may occur later then the oft-ignored NFkB-driven pro-inflammatory one (Fig 2 of: This perhaps comes into a COVID-19 context when one considers the STING-driven clotting phenomenon recently described by Zhang et al (, which is STING-dependent, but independent of TBK1 or IRF3, or Type-I IFN.

    While triggering enhanced inflammation and clotting may be incidental to the virus relative to blocking IFN production, it may nonetheless represent an important pathway to clinical outcome in some patients.

    Many thanks again for the blog!

    Oh yes, and thank you very much for the link to the viral evasion paper!

    1. Toni says:

      this is really exciting. I have mentioned Sting agonists here in the context of possible adjuvants against respiratory viruses, because the current literature is very interesting.
      But the possibility that coagulopathies could be related to STING was not yet known to me.

  43. Erik Dienemann says:

    This was just published as a preprint from a group in Singapore. They found that people who had been exposed to SARS had memory T-cells reactive to SARS-CoV-2 proteins and furthermore that 9 of 18 people never exposed to SARS or SARS-CoV-2 had memory T-cells reactive to SARS-CoV-2 proteins and they think that resulted from previous infections with animal betacoronaviruses. I think I have that correct, but this is not my area of expertise, so feel free to clarify if needed.

    Obviously, as per the Cell paper and the Berlin paper, which Derek has discussed, and per this one, lots to think about with regard to whether and to what extent these findings mean some % of the population may either be immune to or only mildly affected by the novel coronavirus. I assume this is going to explode as an area of research. Link and abstract are below

    “Memory T cells induced by previous infections can influence the course of new
    viral infections. Little is known about the pattern of SARS-CoV-2 specific preexisting memory T cells in human. Here, we first studied T cell responses to
    structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of
    ORF1) regions of SARS-CoV-2 in convalescent from COVID-19 (n=24). In all
    of them we demonstrated the presence of CD4 and CD8 T cells recognizing
    multiple regions of the NP protein. We then show that SARS-recovered patients
    (n=23), 17 years after the 2003 outbreak, still possess long-lasting memory T
    cells reactive to SARS-NP, which displayed robust cross-reactivity to SARSCoV-2 NP. Surprisingly, we observed a differential pattern of SARS-CoV-2
    specific T cell immunodominance in individuals with no history of SARS,
    COVID-19 or contact with SARS/COVID-19 patients (n=18). Half of them (9/18)
    possess T cells targeting the ORF-1 coded proteins NSP7 and 13, which were
    rarely detected in COVID-19- and SARS-recovered patients. Epitope
    characterization of NSP7-specific T cells showed recognition of protein
    fragments with low homology to “common cold” human coronaviruses but
    conserved among animal betacoranaviruses.
    Thus, infection with betacoronaviruses induces strong and long-lasting T cell
    immunity to the structural protein NP. Understanding how pre-existing ORF-1-
    specific T cells present in the general population impact susceptibility and
    pathogenesis of SARS-CoV-2 infection is of paramount importance for the
    management of the current COVID-19 pandemic.”

  44. Eugenie says:

    I’ve been taking Interferon Lamba since March and did not get infected. Meanwhile my boyfriend Had the virus and tested positive while with me along with numerous people around me. I got tested negative for COVID and negative for antibodies.

    1. Grumpy Old Professor says:

      Lambda? Interesting – how is it being delivered? Are you part of a trial?

      Many thanks

  45. SARS 1 and 2 are both nitric oxide sensitive. Nitric oxide via immuno-stimulant (BCG), inhalation (gas), oral (via dietary reduction of inorganic nitric) may be an attractive prophylactic and therapeutic. Thoughts to consider:

    As to Covid draggable targets, again, nitric oxide becomes an intriguing candidate:

  46. Zara Lee says:

    Could someone with say an underlying latent TB infection, potentially fight this off faster then, then someone whose immune system is not that active? Sorry for the base simplicity of this question.

  47. Grumpy Old Professor says:

    Just how much of what we have been discovering about SARS-CoV-2 is new?

  48. james moran says:

    In a recent study of a nursing home in Massachusetts roughly half of the elderly residents tested for covid-19 that tested positive were asymptomatic. This begs the question – why do some of the weakest of the weak get the cytokine storms and others do not? Could it be that the roughly 45% of the population that have an MTHFR mutation and are poor methylators have inherent predisposition to inflammatory dysregulation and thus to cytokine storms? Could something of this nature be an indicator?

    1. Barry says:

      It was thought at one time that the peculiar mortality distribution of the “Spanish flu” was because the elderly were just not competent to mount the (lethal) cytokine storm that killed so many between 20ys and 50yrs. I think that theory is dead; Covid19 has shown that (many of) the elderly are quite capable of a lethal cytokine storm.

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