Expert Insight: The role of aberrant cytokine activity in the host immune response to COVID-19

Watch this webinar on demand to learn about the host immune response to COVID-19

19 Oct 2020



Kenneth Oh (top), Brad VanderWielen (bottom), and Kelly King (right)

In this webinar, Bio-Rad’s Kelly King, Brad VanderWielen, and Kenneth Oh will discuss the early research and nascent hypotheses regarding the pathophysiology of COVID-19 through evaluation of cytokine and chemokine profiles, the role of chronic inflammation in comorbidities, and the arc of immune resolution of historical virulent pathogens, such as SARS and MERS.

Read on for the highlights of the live Q&A session or register to watch the webinar at any time that suits you.

Q: What is the relationship between COVID-19 onset and the cytokine storm?

KO: In our observation, the relationship between COVID-19 onset and the cytokine storm is patient-dependent. Not all patients experience these severe symptoms and the cytokine storm is usually associated with hospitalized patients. It's characterized by high-levels of typically proinflammatory cytokines, but not all cytokine storms are the same. They can take place locally, as in the case of acute respiratory distress syndrome (ARDS), or distally, as observed with micro-thrombotic events in the heart, kidneys, or liver, for example.

Q: Can ACE inhibitors that are used to treat hypertension also be beneficial in treating inflammation due to COVID or other viruses?

BVW: First, I can’t comment on treatment efficacy as I am not a clinician and I can only approach this from an academic standpoint.  From my reading, there was controversy very early on in the pandemic about whether to continue or cease treatments with ACE inhibitors or ACE receptor blockers. All the data that I've seen up to this point suggests that if you are currently on ACE inhibitors or ACE receptor Blockers, you should remain on those treatments.  If you contract COVID-19 and you have comorbidities associated with high blood pressure, I saw one paper suggesting that you should start ACE inhibitors. 

But the main question is, how effective would inhibiting ACE, in the context of this virus and other viruses associated with inflammation, be in treating and avoiding inflammation due to viral infection?  I'm not sure how effective it would be, but I do think it is an interesting pathway to investigate. I think that there's probably other, more targeted mechanisms associated with the virus to investigate that are less prone to systemic side-effects.

Q: Can IP-10-blocking antibodies be a good therapy to target?

KK: As I am not a clinician either, I am unable to make any recommendations about therapeutics. From the research I have seen there have not been any early studies looking at IP-10 as a target for blocking antibodies against COVID-19. Although, I do think it would be an interesting study to look at how utilizing a blocking antibody would affect downstream signalling events. I have seen studies looking at IP-10 as a target for neutralizing antibodies for other infectious diseases and autoimmune processes so it would be interesting if someone did study and published that information, but as of right now, I have not seen any publications.

Q: What are the benefits of having a multiplex assay, if getting information on all other cytokines may just be clutter?

KO:  I think perhaps what you've seen in your own diligence as well as in the work that we presented today is that IL-6 is a strong indicator. However, our observation is that even in the case of severe symptoms and complications, the IL-6 levels vary greatly on a patient-by-patient basis. In addition to that, the onset of high levels of IL-6 typically occurs two or three weeks after the onset of COVID-19. Thus, part of the reason that we're advocating the continued use of multiplexing is to try to understand the complex pathophysiology/immune response in the early stages where more preventative measures can be taken before patients get severe symptoms.

Q: What is the relationship between cytokine synthesis and cytokine release? Are cytokines made and stored in advance, and then released due to an external stimulus? Or are they synthesized as needed?

BVW: Traditionally the cytokines aren't stored. They're essentially made on-demand after extracellular receptors are activated. 

KO: It's also tissue-dependent. For example, we know that IL-6 is stored in adipose tissue, and that's one of the leading hypotheses as to why more severe symptoms are associated with a high BMI. If one experiences fever-like symptoms that induces metabolism of adipose tissue, this can lead to additional release of IL-6 into circulation, resulting a positive feedback for potentially greater inflammation.

Q: Did you find any important cytokines that aren't currently included in the standard Bio-Rad Panel?

KO: We haven't found cytokines which aren't included, but we have found blood clotting factors that have been implicated, such as PROS1 protein and Bradykinin. These aren't formally cytokines, but there are functional similarities.

Bradykinin, for example, is a paracrine hormone that induces inflammation and can mediate clotting just as pro-inflammatory cytokines do. I think the issue with Bradykinin is that it is difficult to assay because it's enzymatically cleaved by ACE and it's not stable outside of the circulatory system. However, one can do PCR studies or one can investigate the relationship between Bradykinin mediation and the cytokines and chemokines, and thus form a proxy estimation of its effects.

DISCLAIMER: This webinar is a review of scientific publications related to COVID-19 and the role of cytokines in this disease. It is intended to be informational only; Bio-Rad does not make any suggestions for treatment of COVID-19 or related respiratory or inflammatory conditions.

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