Nov 19, 2020
This month on Episode 18 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the October 23 and November 6 issues of Circulation Research. This episode features an in-depth conversation with Drs Eric Boilard from the Université Laval in Quebec, Canada, and Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco regarding their study titled Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19.
Article highlights:
Feng , et al. No Contribution of EMPs to Endothelium
Lin, et al. Step Count and Predicted CVD Risk
González-Hernández, et al; Sox17 in Developmental Coronary Arteriogenesis
Khawaja, et al; HIV Antiretrovirals Alter Endothelial Activation
Dr Cindy St. Hilaire: Hi, welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh and today, I'll be highlighting four articles selected from the late October and early November issues of Circ Res. Dr Milka Koupenova, who is a platelet expert at the University of Massachusetts Medical School, will join me to interview Drs. Eric Boilard from the Université Laval in Quebec, Canada, and Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco. They're here to discuss their study, Platelets Can Associate with SARS-CoV-2 RNA and are Hyperactivated in COVID-19.
Dr Cindy St. Hilaire: The first article I want to share is titled No Evidence for Erythro-Myeloid Progenitor-Derived Vascular Endothelial Cells in Multiple Organs. The first authors are Teng Feng and Zibei Gao, and the corresponding author is Hui Zhang from ShanghaiTech University in Shanghai, China.
Dr Cindy St. Hilaire: In the early stages of mammalian embryogenesis, a population of cells called mesoderm-derived angioblasts, gave rise to self-renewing intraembryonic endothelial cells, that go on to populate the entire vasculature of the growing fetus. Recent studies have suggested that there is an additional embryonic source of vascular endothelial cells that is derived from erythro-myeloid progenitor cells, also called EMPs, that are found in organs such as the liver, the lung, the heart, and the hindbrain.
Dr Cindy St. Hilaire: Evidence of an EMP cell source for vascular endothelial cells stemmed from the use of mirroring cell lineage tracking models. However, the authors of this study argue that these former conclusions were based on flawed genetic tools. To mark erythro-myeloid progenitor cells, the initial study had used a set of supposedly EMP-specific transgenes. However, transgenes are notoriously leaky, meaning, that cells other than EMPs may have been marked. To more accurately mark EMP derived cells, this study used a reporter that they integrated into the endogenous loci of a gene, CSFR1, which is specifically expressed in EMPs. Using this model, they failed to find any evidence of EMP derived vascular endothelial cells in any organ, thus they consider it unlikely that EMPs give rise to vascular endothelial cells. Knowing the true origin of vascular endothelial cells is essential, as it informs the design, development of treatments, and regenerative medicine approaches for vascular diseases.
Dr Cindy St. Hilaire: The second article I want to highlight is titled Association of Habitual Physical Activity with Cardiovascular Disease Risk. First author is Mayank Sardana and the corresponding author is Honghuang Lin, and they're at Boston University School of Medicine. Everybody knows that exercise is very good for overall cardiovascular health and current government guidelines suggest a minimum of 150 minutes of moderate to vigorous exercise per week is necessary to keep hearts healthy. There's an ever-growing interest in the use of smart watches and fitness trackers to assess an individual's activity, and many people believe that 10,000 steps a day is a good health goal. However, it's unknown whether the data obtained from smartwatches actually aligns with cardiovascular health prediction.
Dr Cindy St. Hilaire: To address this gap, this study recruited participants from the Framingham Heart Study to wear Apple smart watches for a month. The participants had also undergone a 10 year atherosclerotic cardiovascular disease risk assessment based on their age, sex, cholesterol levels, blood pressure, diabetes diagnosis, and smoking history. The step count and activity data from 903 participants found that for every 1,000 average daily step increases, there was an associated 0.18% reduction in predicted cardiovascular disease risk. This association was weaker but still significant after adjusting for body mass indices. The authors conclude that like other measures of activity, those recorded by smart watches are correlated with better cardiovascular health.
Dr Cindy St. Hilaire: The third article I want to share is titled, SOX17 Controls Emergence and Remodeling of Nestin-Expressing Coronary Vessels. The first author is Sara González-Hernández and the corresponding author is Joan Isern, and they're from Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain. The exact signals and mechanisms that regulate coronary vascular development are not fully characterized, yet defining these pathways could provide valuable insights into both life threatening congenital coronary abnormalities as well as the neovascularization process that occurs after myocardial injury. To examine coronary vasculature development in more detail, this team created a transgenic reporter system, which used an enhancer region within the Nestin gene to specifically label mouse coronary artery endothelial cells.
Dr Cindy St. Hilaire: Cells were isolated from developing embryos at stages of vessel sprouting and vessel remodeling, embryonic days 13.5 and 17.5 respectively. And transcriptional differences were assessed between coronary and endocardial endothelial cells. They found that the transcription factor SOX17 was more highly expressed in these coronary endothelial cells compared with the endocardial endothelial cells, and that expression of SOX17 increased between these two time points that hearts were collected. Coronary specific deletion of SOX17 in genetically engineered mice lead to severe defects in arterial remodeling, confirming the transcription factor's role in coronary vessel development. The team suggested that perhaps SOX17 could be a future therapeutic target for conditions, where promoting coronary artery regeneration or remodeling might be of clinical benefit.
Dr Cindy St. Hilaire: The last article I want to share with you before we switch to our interview is titled, HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk. The first author is Akif Khawaja, and the corresponding author is Michael Emerson from the Imperial College, London. Infection with HIV is not the death sentence that it once was. With a regime of continuous anti-retroviral medications, the disease can be managed for the long term. Now that people with HIV are living longer, it is clear that they are at a greater risk of developing cardiovascular disease, possibly due to the off-target effects of these drugs. One HIV treatment, Abacavir Sulfate or ABC, was found to cause a 90% increase in the relative risk of myocardial infarction. ABC has been proposed to cause endothelial dysfunction, however a mechanism by which this may occur has not been established. To see if anti-retrovirals effect endothelial cell function, this group tested three drugs; ABC, as well as tenofovir alafenamide or tenofovir disoproxil fumarate, TAF and TDF respectively, on human endothelial cells in culture.
Dr Cindy St. Hilaire: They found that treatment with ABC, but not TDF or TAF, caused endothelial cells to produce more cell adhesion protein, ICAM-1, and also tissue factor, both of which promote blood clotting. Endothelial-derived microparticles, or EMPs, are a biomarker of vascular dysfunction, and these were produced in the ABC treated cells, not in the TDF or TAF treated cells. These EMPs also promoted the increase of ICAM-1 and tissue factor expression, as well as the activation of platelets which can induce blood clotting. These results suggest that altering HIV treatments to avoid or minimize endothelial damage could help to reduce the cardiovascular disease risk in HIV patients.
Dr Cindy St. Hilaire: Today, I'm excited to have with me Drs. Eric Boilard from Université Laval in Quebec, Canada, Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco, and they are here to discuss their study, Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Also, with me today is Dr Milka Koupenova from the University of Massachusetts Medical Center in Worcester Mass, and she's an expert on platelet virus interactions, and she also wrote the editorial that's accompanying this article in our November 6th issue. So thank you, everyone, for joining me today.
Dr Eric Boilard: Thank you for inviting us. I look forward to reading the editorial.
Dr Milka Koupenova: I hope you like it Eric.
Dr Cindy St. Hilaire: Yeah, we're spanning a lot of time zones and we're actually having a little bit of technical difficulties so hopefully Fadila is going to be able to pop in. We can certainly see her on our Zoom call right now. But with that, we're many months into this pandemic now and it is blatantly clear that COVID does not just present with pulmonary symptoms. Many organ systems can be affected, such as the circulatory and neurological systems, but one thing that connects all the parts of the body is the blood system, and before we get into the details of the study, I would love to hear how this collaboration between Quebec and Morocco happened. And then, could you summarize the major findings?
Dr Eric Boilard: We both, in Morocco and in Quebec, we had pretty much the same working hypothesis that platelets may be contributing to the overwhelming inflammation in COVID-19 and why. As you know, in Morocco the pandemic hit before us in Canada, and they had a committee that studied patient samples and studies were going on. Whereas us in Quebec, in fact to be frank, in Quebec City, we didn't really have the first wave even. So we were very excited to evaluate our hypothesis but we had no clues other than the actual virus. We actually were working with the virus and human platelets from healthy individuals, but no samples from patients. Clinicians in Morocco were very willing to contribute and to perform working on patients so that's how Younes Zaid, the first author of the manuscript, and Fadila then contacted us given our past work on platelets and viruses and the collaboration was initiated.
Dr Cindy St. Hilaire: That's wonderful. I love hearing about these multi-institute collaborations. Team science is really the future. I think it really elevates everything.
Dr Eric Boilard: Despite the fact that the distance and I mean, it was through Zoom, but we've been doing weekly meetings with the two labs since March.
Dr Cindy St. Hilaire: So, can you maybe give us a quick summary of the major findings of your study? Then we'll dig into the details of it.
Dr Eric Boilard: Sure. When we actually started the work, what we knew about COVID-19 was that the severity was likely due to the overwhelming inflammation due maybe to a cytokine storm, so we knew that. It was reported that patients with COVID-19 had a lower platelet count and although thrombocytopenia in the patients was very mild or modest, and did not require transfusion, at that time, our hypothesis was that platelets could contribute to inflammation and therefore could release cytokines and other molecules from their granules in COVID-19. So it's only a couple of weeks after that became more of use that thrombosis and cardiovascular manifestations could also contribute to morbidity and mortality.
Dr Eric Boilard: Our design was to look at platelet activation in vitro. So there were studies where we performed aggregation assays with platelets from COVID-19 patients, some were severe and non-severe. There were assays where we actually evaluated a number of molecules and plasma from the patients. We looked at granular components, like PF4 and serotonin, that were greatly increased in COVID-19, both in non-severe and severe patients. We looked at vesicles, or microparticles, released from platelets that were also increased, and cytokines. We look at up to 42 cytokines, if I remember well, in the plasma of the patients and we also look at these cytokines in the platelets from the patients and we found less cytokines in the platelets when there was inflammations, which may suggest that platelets have released their cytokine cargo. I mentioned that platelets were hyperactivated so they bound better on collagen and they aggregated faster with suboptimal concentration of thrombin.
Dr Milka Koupenova: I find this dysregulation of cytokines in the platelets specifically very interesting and the fact perhaps that you see that certain cytokines are decreased in platelets and increased in plasma, basically can suggest that maybe platelets are the ones that are contributing to the overall cytokine storm, as you said. My question for you is, what do you think is the contribution of platelets to the dysregulated immune cell response in immune cell activation during this particular infection?
Dr Eric Boilard: That's a good question. There are studies that show that platelets could interact with leukocytes. The leukocytes migrate to organs through lungs in this case, so one possibility is that molecules derive from platelets and cytokines but also their interaction with leukocytes could further promote their migration to lungs or adhesion to vasculature. There are studies that suggest that NETs form in COVID-19 and could contribute thrombosis and NETs can implicate interaction between platelets and neutrophils. Or molecules derived from platelets that are neutrophils so these might be some of their contributions.
Dr Milka Koupenova: You are reporting changes of IL-7 in platelets which is particularly interesting because they're responsible for T and B cell development and activation. I was wondering if you could comment on that particular fact and how that may be practically responsible for these responses in these patients that come and present with symptoms.
Dr Eric Boilard: Yeah, it's a good question. If we look at the different cytokines that were in platelets, we found that many were reduced. That pointed to their release in COVID-19 and some we had expected, such as some broad factors and there was TGF, CD40 ligands inside the cytokine but we expect that its stored in platelets that was released. That made sense to us. IL7, like you said, it was not really reported in platelets and when we look at the 40... broad area of cytokines using the multiplex, that increased in platelets during COVID-19. So this one was increased. Does it mean that platelets translated but some of it is released but some remain in platelets? We have no explanation for this. Does it impact lymphocytes or B cells?
Dr Fadila Guessous: If we go further and in terms of seeing the front they know what was downstream, IL7 production in general does not look like for psychometry, what happens to B cells and T cells in our complex. So we just look at the panel of the 48 cytokines, but we didn't go really further.
Dr Cindy St. Hilaire: I kind of have a little bit of a more basic question regarding cytokines and where they're coming from. I'm going to guess it's definitely not known for COVID but in maybe any viral infection that can lead to a cytokine storm, is it known what the relative contributions of cytokines are from the platelets, from the leukocytes, and from inflammatory cells? Is there any evidence of which is the bigger player? I mean I know all the different camps have ideas, but has anyone looked at that?
Dr Fadila Guessous: We were talking about this actually with Eric. If I had to rephrase your question, like what's the starting point, right in terms of cytokine storms?
Dr Fadila Guessous: We don't know. We don't know because when it started in China, everyone was talking about the big cytokine storm. Everyone was talking about monocytes, about neutrophils, so on and so forth but the platelets we were just saying there was thromboembolism in the lungs, right? But no one was talking about cytokine production by the platelets. I think we were the first ones, Eric please correct me if I'm mistaken, we were the first ones to show, when we started, to show that there was the cytokine release by platelets. How big of the extent of the contribution of platelets to the cytokine storm, we don't know, but we have to figure out first what's the key player? The first one to respond, right?
Dr Cindy St. Hilaire: Lots of projects.
Dr Fadila Guessous: Well the big question, actually we have this big contribution in terms of the cytokine release and activation of platelets, but is it the starting point? We don't know.
Dr Cindy St. Hilaire: I guess related to that, you noted that you saw very little ACE2 expression in the platelets which most people appreciate is the entry mechanism of the virus into the platelets. Can you discuss that a little bit more, maybe explain it a little bit more and what that might mean? Your findings versus what other people have seen versus potential other means of entry?
Dr Eric Boilard: Yeah sure. As you mentioned, ACE2 is the putative receptor for the virus so that made sense to us to examine whether the receptor may be expressed by platelets. I don't think we mentioned it but we found that there were some... at least for some patients there were SARS-CoV-2 RNA associated with platelets and that's why in part we look at ACE2 RNA expression by platelets. It seems simple but it wasn't that simple. We were actually using through PCR and different approaches and primers we got different answers using intron-spanning and non-intron-spanning primers from that, the receptor was presented so that in fact we ended up concluding that there was little or no ACE2 RNA in platelets of COVID-19 individuals that we examined but that there was some DNA that could be contaminating, potentially due to extracellular DNA maybe provided by extracellular vesicles[inaudible 00:19:30] or something but either way we're speculating.
Dr Eric Boilard: One intriguing aspect of the study is that the SARS-CoV-2 RNA was not found on platelets from every patient, it was only in 20% of them and we unfortunately were not able to look at the RNA of these positive patients to determine whether these patients were positive for ACE2 RNA and potentially in some donor cells in some patients, there might be some levels of expression and we are not excluding this.
Dr Eric Boilard: So yeah, you ask whether it was consistent with other studies? There was the study by Manny that was published, in Blood where they also could not find the receptor but our studies contrast with the one that was more recently reported by Zhang in Journal Of Hematology & Oncology. In this study they found in fact that a robust expression of ACE2, both protein and RNA, and it was both in humans and mouse so clearly there's still work to do to determine whether ACE2 is present or not, but there could be other means of interaction between the SARS-CoV-2 and platelets if there is indeed an interaction. We speculated that maybe in some patients there could be antibodies against other coronaviruses, you know the cold, the viruses that give the minor cold symptoms and that in some of the patients these cross-reacting antibodies could promote the interaction with platelets through their receptor for IgG , that could be a means.
Dr Eric Boilard: There are other receptors that are expressed by platelets, there's probably several. I'm sure we have a list, but one could be the CD147. It's a receptor that is known to be expressed by platelets and that was suggested to interact with SARS-CoV-2, at least it does interact with SARS-CoV, the first one, CoV-1. So these are potential candidates. So there's work to do.
Dr Fadila Guessous: What we found was that in Eric's lab, that you have this 20% of aged people that have this SARS-CoV RNA in place, in 20% of aged people. So should we look only at aged people for this ACE2? If they have the receptor for ACE2, maybe? It's like 20%, only aged. And this 20% of people we investigated, they were only aged. Not other people. So do we... probably, we have to go further and investigate more of this age group for ACE2.
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Dr Milka Koupenova: So if I can make a comment, despite the fact if ACE2 was expressed or not, right? Could it explain the profound thrombotic response that you see? What's your take on it?
Dr Eric Boilard: Personally, I doubt it. I think the disease starts in the lungs and this is where the damages are made, and that it may expand to blood vessels and then multiple players can then from a place of activation damages themself, the lack of O2 in some patients that are in ICU. And then of course the activation of the other cells, the cytokines themselves. So there are numerous ways I will say that can be to play for activation. In fact, the study by us, the one in Blood, they use plasma from the COVID-19 patient and I would assume there was no actual virus particle in this plasma. And they incubated it with platelets, and platelets were then activated. So there are molecules in COVID-19 that circulate in blood that can activate platelets, and that adds to the vasculature damage trauma. I would think that that could come from principle factors.
Dr Milka Koupenova: Which would explain why is it so dysregulated, which brings it to the next question now with a favorite question in the literature. Should we be using antiplatelet drugs? Your opinion, Eric and Fadila?
Dr Fadila Guessous: Well with my collaborator, Younes Zaid you know, and first author on this paper, actually they are going for that. They are having small trial giving antiplatelets treatment to a few patients in our lab. You will hear the story. I don't know if Eric will allow me to disclose this? I don't know because Younes is not here, but they are using heparin for now and for the treatment, but now they are trying antiplatelet treatment as a small trial.
Dr Milka Koupenova: So when do they give antiplatelet drugs? At what stage of the disease?
Dr Cindy St. Hilaire: I think maybe the way to ask the question is: If you were going to use antiplatelet therapy for changing the course of the disease, where do you think is the best time point within the disease, from the day you get infected to symptom presentation and well after that, what time point do you think it's most critical, the platelet function?
Dr Fadila Guessous: It's a good question. It's a good question because the trial is done in in our lab and I didn't have insight. What time is the time point. Honestly, I don't have an answer for that in time point. Because I have a... they started the trial-
Dr Cindy St. Hilaire: No, but I guess, based on what we know and what you've found in your study, where would you think it's more critical, if we even can speculate on that?
Dr Fadila Guessous: Yeah, the symptoms. I would give them from the beginning of the symptoms for me. Because otherwise, when you are in the cytokine storm and you have all this [thromboembolism in the lungs and everything, it's too late.
Dr Eric Boilard: And if I can add something. When we think of immune cells or B cells, D cells, we don't say anti-lymphocytes or anti-neutrophil therapy. But when we come to platelets, we think that the molecules that are known to impact some of the platelet activities, we think of aspirin, clopidogrel, coagulation, and we call it anti-platelets but. But platelets, I mean, they can do a lot independently of from vaccine, independently of EDP, and sometimes we forget that they are more than just these poor thrombotic cells and that there are different studies that has been published by different groups and us that found that you can use, for example, COX-1-deficient platelets. So they won't make thromboxane yet, they can make lot of IL1 and be pro inflammatory, although they will not make thromboxane. So we actually use mice where were we use a variety of anti-platelet therapies but yet their platelets were able to come out inflammation so there's no one drug that can get all the platelet functions at once, so it's important to remember that.
Dr Cindy St. Hilaire: It sounds like maybe some of them could possibly make things like a cytokine storm almost worse, if we're targeting the wrong anti-activity?
Dr Eric Boilard: All depends on how platelets are activated. Whether we are activating a GP pathway, or a nighttime pathway or both at the same time, and the environment where platelets are localized and activated so that they all back the response to this.
Dr Cindy St. Hilaire: So you're saying it's complicated.
Dr Eric Boilard: Yeah, I think it's not simple.
Dr Milka Koupenova: Anything complicated, it's platelets. So in a way I think that perhaps what we need to acknowledge is targeting platelets for whatever response. I completely agree that platelets should be targeted at one point but what drugs should be used, is the question? What specific receptor or what specific response? And if we manage to figure some form of controlling the inflammatory response, that specific, what you see, that huge amount of cytokine dysregulation that will be great. But if you're targeting platelet-specific function when it comes to thrombosis, I'm a bit concerned that there has to be an exact time in which that's important. And the reason why is because if you have this damage in the endothelium, as you see reproducing the virus in the endothelial cells, and if platelets are not doing their own function then perhaps a lot more virus is leaking into the circulation. And that could be why you see some patients that have it, some patients that don't have it, which is a question that I want to ask.
Dr Milka Koupenova: Why do you think some patients have it and some patients don't have it? And do you think that perhaps as the virus gets processed into a platelet and digested, we are missing a time point? Because we're not taking platelets from patients at the same time after infection. We have no way of doing that. So what is your take on the fact that you have virus in some platelets? And from your study, perhaps, if we rely on the numbers, the people who have more severe symptoms seem to have a little bit more. Correct me if I'm wrong.
Dr Eric Boilard: Actually, the older people have more chance of having it but it was not in the more severe people. In fact, even among the non-severe patients, there was 20% of them that had platelets with positive RNA. So that didn't correlate with severity or any outcomes. The only correlation we could identify was age.
Dr Milka Koupenova: So do you think that perhaps in older individuals there are problems would be degradation of the virus, and hence they are not initiating the proper response?
Dr Eric Boilard: Yeah, potentially. Maybe there's somehow an indication of the virus from the organs and it's a destination or it's not captured fast enough on the first varrier of the immune cells in the lungs. Right now we don't have the evidence that it's actually the virus that is in platelets, right? The RNA and there's still work to determine if the virus is there.
Dr Milka Koupenova: So practically, in summary, we don't know what it is. Although, I mean, with a bias, me probably like you, and you're very nice, you're cautious, but I also believe that the virus... and it's a belief. That the virus gets inside of platelets.
Dr Fadila Guessous: How, Milka? How?
Dr Milka Koupenova: There could be some issue that we don't see, and as Eric says, it's some form of an age factor. There could be other receptors. Platelets are tricky, they don't act like every regular cell so they may have evolved to have other receptors that maybe they are not as functional in the ither cells but they're platelet specific. There is the process that from all these cytokines perhaps, platelets are just sucking in things by micropinocytosis, which has happened. The thing that's important to think and mention is that if a virus is not going into a platelet by receptor-specific mechanism, perhaps it's locating to the wrong compartment, and then not introducing the proper immune response. Perhaps that's the reason of why you're catching it only in 20%. This is all very, very speculative.
Dr Eric Boilard: Yeah. And are you putting in a contribution of megakaryocytes] in the lungs where they will burst …
Dr Milka Koupenova: Yes. That it. Absolutely, it's quite possible. That's a collaboration then you should perhaps consider with Dr Craig Morrell. Which is very interesting, right? We don't know. We were never able to figure, even with our full studies, we also saw, what is it, four out of 18? So it's like 25% of the platelets had RNA for a flu but when you look what the antibody of the virus you find that a lot more platelets have it. So is it that we're missing some form of a process that the virus quickly gets digested and it initiates a response? I don't know until we get the right tools. But currently we are struggling with tools, practically, to assess that question.
Dr Eric Boilard: Yet it's impressive what's been done since March with the Covid.
Dr Milka Koupenova: Oh, some of them is good. Some of them is really important science and some of them is questionable that raises more questions.
Dr Eric Boilard: Absolutely, yeah.
Dr Milka Koupenova I personally think it's very important what your study is showing because it gives a base of truly thinking about how platelets maybe truly acting as an immune cell at the beginning. I know that Eric and I might be a little bit biased when it comes to that, but when does the thrombotic response stop? And when does the immune response stop of a platelet? And is it necessary to stop and to be all together? How do we push one and doesn't stop the other? These are the questions that we in the field truly need to assess and that's what I really like about your study, is that it raises these important questions.
Dr Fadila Guessous: Before the call, I was looking at the paper from University of Verona. I mean, I was hoping they will find more answers to the same question that is a favorite from University of Verona, and actually they are also more speculative. They didn't answer the question, the same questions we are asking.
Dr Milka Koupenova: Well, until we have the virus on hand, the actual virus, it's a little hard for us. And then the other point is even if you have the virus on hands, you're doing all of these in vitro studies, how do you assess the entire immune response? Can we think of platelets just as platelets without being in cells, right? What is your take on that, Eric or Fadila? Can you think of platelets just as platelets when it comes to mediating a response to a viral infection? Because we think okay we do this particular thing with platelets and then they mediate this and they mediate that, but perhaps the interaction between platelets and all the immune cells at the beginning of the response is super important. And I do struggle sometimes with the assessment of what amount is just platelets and what is the communication between each immune cell and platelet. It's very hypothetical.
Dr Eric Boilard: I agree that I see platelets as communicators to other cells. I mean, they're so numerous and there are bags with cytokines and other molecules and RNA and micro RNAs and it can impact for different organs, tissues, cells. The fact that they were activated, even in the non-severe patients, all the non-severe patients we analyzed, platelets were there, they were activated. So there was something going on, although thrombosis was not of use in these patients, so they made plates front row and the front part of the disease and the pathogen as a cell.
Dr Milka Koupenova: So is there a way of somehow, as you perceive in your future studies, to get platelets from people who get the virus but don't have any symptoms, and compare their cytokine profile of platelets to what you see? Because we focus so much on the people who get infected, logically, right? But truly to assess what is the difference, if we can figure why those patients are not having this profound response, right?
Dr Eric Boilard: Something that we dream of. The fact that collecting platelet from someone who has no symptoms is…Because we, if they have no symptoms, then they don't come to us. They don't stop-
Dr Fadila Guessous: They don't show up at the hospital.
Dr Milka Koupenova: And so you have to recruit them by tests, right? Because we screen, for instance, our institution screens. But it's hard, right? No one wants to take blood from a…
Dr Fadila Guessous: You get this kind of calls, people are asymptomatic, they don't have any symptom, they won't show up at the hospital. We used whatever we had in our recruitment from the hospital.
Dr Eric Boilard: In fact, you can maybe go through the transfusion work, the studies on transfusion where they actually collect blood from people and people sign that they have no symptoms when they do give blood. And there are studies from China and more recent ones in France where they then went back to this bags of... these were plasma, but maybe one could do it with platelet concentrates. And then go back to these bags where people had signed they had no symptoms when they gave blood, and screened platelets for RNA and then... but you have dozens of dozens of samples to test, but they are available. And maybe someone could find that many were positive but they were asymptomatic, using transfusion studies, maybe. But recruiting people from outside, asking we want people with no symptoms for…
Dr Cindy St. Hilaire: I know we're doing sentinal testing of our students, so. Somehow the group doing that needs to couple with platelets studies.
But that was wonderful. Thank you Dr Boilard, Geussous, and Koupenova for joining me today. This has been an amazing interview. It's a wonderful study. Good luck on the future research and thank you for moving the field forward on this.
Dr Eric Boilard: Thank you very much for inviting us. It was great and we are pleased to interact with you. Thank you.
Dr Milka Koupenova: Very nice to meet you Fadila, Eric.
Dr Fadila Guessous: Thank you so much for having us. It's really it's a pleasure to have this interview with you and of course I have to say that really it has been a wonderful collaboration with Eric and Younes in our lab. I am from Casablanca so we had really many people involved in this project and everyone, we worked really, really hard to get this very... I mean, you can see the time, it's from March to now, to get this paper out it was really a big effort. A big effort from the Moroccan side and from Eric's team in Quebec City and so we are really very pleased to have this wonderful collaboration. Thank you so much for having us.
Dr Cindy St. Hilaire: That's it for the highlights from the late October and early November issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Drs. Eric Boilard and Fadila Guessous, as well as Dr Milka Koupenova for co-hosting the interview with me.
Dr Cindy St. Hilaire: This podcast is produced by Rebecca McTavish and Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.