Katerina Akassoglou: Blood Clots, Brain Inflammation, and Covid

Superimposed on an impressive body of work on the blood-brain-barrier and immune system, Prof Akassoglou and her collaborators just published an elegant study in Nature that centered on the direct binding os the SARS-CoV-2 spike protein to fibrin with marked downstream pro-inflammatory effects. The findings and potential treatments have implications beyond Covid, Long Covid to other neurologic diseases.

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Transcript with links to audio and to relevant papers, graphics

Eric Topol (00:07):

Well, hello this is Eric Topol with Ground Truths, and with me today is Katerina Akassoglou. She is at the Gladstone Institute and she is a remarkable neuroimmunologist who has been doing extraordinary work for three decades to unravel the interactions between the brain, blood vessels and the role of inflammation. So Katerina, there's a lot to discuss, so welcome.

Katerina Akassoglou (00:40):

Thank you. Thank you so much. It's a great pleasure to join.

By Way of Background

Eric Topol (00:43):

It's really interesting going back in your career. First of all, we're thankful that you immigrated here from Greece, and you have become one of the leading scientists in this discipline of important discipline of neuroimmunology, which is not just about Covid that we're going to talk about, but Alzheimer's and neurodegenerative diseases. This is a really big hot area and you're definitely one of the leaders. And what I was impressed is that all these years that you've been working on the integrity of the blood-brain barrier, the importance of fibrinogen and fibrin, and then comes along the Covid story. So maybe what we can do is start with that, which is you've made your mark in understanding this whole interaction between what can get into the brain, through the blood-brain barrier and incite inflammation. So this has been something that you've really taken to the extreme knowledge base. So maybe we can start with your work there before we get into the important seminal Nature paper that you recently published.

Katerina Akassoglou (01:57):

Yes, of course. So since very early on, I was still a graduate student when we made the first discovery and at the time was like mid-90s, so it was really ahead of its time. That dysregulation of cytokine expression in the brain of mice was sufficient to induce the whole cascade of events, triggering neurodegeneration, demyelination in pathological alterations, very reminiscent of multiple sclerosis pathology. And it was really hard to publish that study at the time because it was not yet accepted that this regulation of the immune system modeling the brain can be linked to neurodegeneration. So that was 1995 when we made that discovery, and I became really interested, what are the pathogenic triggers that actually polarized the immune cells in the brain? So with this, of course, this transgenic animal was expressing TNF, it was an artificially made animal that we made, but naturally what were the triggers that would polarize the innate immune cells? So I looked really early on in this mice and what I found was that the very first event was leaks of blood-brain barrier. It was opening of the blood-brain barrier in this mouse before inflammation, before demyelination, before neuronal loss. And this is really what shaped the question that, is it possible that these blood leaks that happened very early in the pathology, could this be the instigators of pathogenic inflammation in the brain?

Eric Topol (03:34):

Yeah. So in a way, you got at this question because of the chicken-and-egg and what happens first, and you got to the temporal saying, which happened first as you said, the leak before you could see evidence of inflammation and being able to study this of course in the experimental model, which you couldn't really do in people. And what I love about the description of your career, which has been quite extraordinary contributions is connecting the dots between the blood, the inflammatory response and the brain. Perhaps no one has done that like you have. And before we get into the recent paper, a lot of people are not aware that a year ago, a group in the UK known as PHOSP-COVID, they published a really important paper in Nature Medicine of over 1,800 people who were hospitalized with Covid and they found that fibrinogen was the best marker for cognitive deficits at 6 and 12 months (Figure below)

(04:40):

So that's just one of many papers, but it's a particularly well done study that already before you got into this work that recently published had emphasized fibrinogen. And by the way, again, having spent a lot of years in clots in the arteries, for me, we have to just get it down to fibrinogen plus thrombin gets you to fibrin. Okay, so fibrin is a major player here when fibrinogen is cleaved. So here we have the basis that you established, which is the fibrinogen leakage into the brain, activating inflammation, activating microglia, which like the macrophages of the brain and inciting the whole process. And before we close, I want to not just talk about Covid, but Alzheimer's too. But now let's get into the study that you did, [Fibrin drives thromboinflammation and neuropathology in COVID-19] which is striking, I mean really striking. And can you kind of take us through, because you not only demonstrated the importance of fibrin in inciting neuroinflammation in this model, but also how you could reverse it or prevent it. So this, and you looked at it in many different ways, this was a systematic approach. Maybe you can take us through how you were able to make such compelling evidence.

The Multimodal Evidence

Katerina Akassoglou (06:09):

Yes, thank you. First of all, thank you for bringing up the human relevance because this was also our inspiration for the work that we did in the Covid study. S