IBD augmentation of CHIP and Platelet mTOR's impact on Cerebral Malaria

Summary

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Blood Podcast Summary

Episode: IBD Augmentation of CHIP and Platelet mTOR's Impact on Cerebral Malaria
Date: May 14, 2026
Host: Dr. Laurie Sen, Associate Editor
Podcast: American Society of Hematology – Conversations with Blood Authors

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Episode Overview

This episode features two leading-edge hematology discussions:

1. Dr. Ruben Kapoor on how Inflammatory Bowel Disease (IBD)–induced inflammation augments Clonal Hematopoiesis of Indeterminate Potential (CHIP) via Ref1—shedding light on novel mechanisms and potential therapeutic strategies.
2. Dr. Robert Campbell on how heme-induced ITAM signaling exacerbates malaria-associated neuropathogenesis via platelet mTOR activation—deepening understanding of platelet involvement in cerebral malaria and introducing new intervention avenues.

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Segment 1: IBD, CHIP, and Ref1 – With Dr. Ruben Kapoor

[00:35–10:54]

Background and Rationale

• Prior Knowledge: Very few studies have examined CHIP specifically in IBD; a small human sample study existed. Kapoor’s team leveraged two major biobank populations (UK Biobank and All of Us, together >600,000 individuals) for definitive large-scale analysis.

• Key Insight: CHIP is not only associated with IBD but appears causally linked based on Mendelian randomization.

  "We have identified some additional findings and strengthened the findings that have been previously published to very definitively demonstrate that CHIP is indeed not only associated with IBD but also causal in these cases"
  — Dr. Ruben Kapoor [01:14]

Biobank Analysis and Findings

• Collaboration: Worked with Broad Institute and Massachusetts General Hospital experts.

• Major Findings:

  • Sex and Age Associations:
    • CHIP strongly associated with women aged 60+ and with Crohn’s disease in those over 60.
    • Particular mutations (DNMT3A, ASXL1) had sex-based associations—more prevalent in males.
    • TET2 mutations strongly tied to ulcerative colitis in those ≤45 years.

• Implications: First evidence of nuanced relationships by sex, age, and specific IBD manifestations.

  "Clearly these studies for the first time suggested that not only is there distinction between CHIP and different forms of IBD manifestation, but also a fairly strong association between sexes..."
  — Dr. Ruben Kapoor [02:27]

Mouse Model Mechanistic Studies

• Design: Used mouse models with DNMT3A mutations, subjecting them to DSS (dextran sulfate sodium) to induce colitis.

• Findings:

  • DNMT3A mutant mice had more severe colitis—higher inflammation, T-cell and myeloid cell recruitment, and increased oxidative stress.
  • Ref1 (APE/Ref complex) significantly upregulated in colon and bone marrow post-inflammation.
  • Using a well-studied small molecule inhibitor of Ref1 (in phase 2 clinical trials for other indications) reduced Ref1 expression, dampened inflammation, and reversed IBD changes in mouse models.

  "If one treated these animals using a small molecule inhibitor... it substantially reduces the expression of Ref1 in these models and represses the inflammatory [response]..."
  — Dr. Ruben Kapoor [07:31]

Therapeutic Implications

• Potential Approaches:

  • Screen IBD patients for CHIP mutations—those unresponsive to standard care may benefit from Ref1 inhibitors as adjunct therapy.
  • High-risk individuals with high CHIP allele frequency could be targeted preemptively.

  "Perhaps those individuals can be treated with this inhibitor in conjunction with the existing therapies..."
  — Dr. Ruben Kapoor [08:40]

Commentary and Next Steps

• Peer Feedback: David Curtis and Jasmine Singh highlighted need for longitudinal CHIP-IBD studies to confirm human relevance.

• Future Directions: Kapoor’s group is initiating these essential human cohort studies.

  "Those are studies that are absolutely essential and we're now in the process of initiating those studies..."
  — Dr. Ruben Kapoor [09:56]

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Segment 2: Platelet mTOR and Cerebral Malaria – With Dr. Robert Campbell

[10:55–19:45]

Cerebral Malaria Clinical Context

• Disease Burden: P. falciparum is highly prevalent and deadly in children in Sub-Saharan Africa, often causing lifelong disability.

• Research Focus: Campbell’s lab investigates platelet roles in infection, specifically malaria.

  "Plasmodium falciparum, which is very common in Sub Saharan Africa... can lead to long term disability."
  — Dr. Robert Campbell [11:24]

Platelet Activation in Malaria

• Shifting Roles: Platelets may protect early but worsen disease later—timing crucial in pathogenesis.

• Motivation: Campbell wanted to uncover mechanisms for platelet activation and their harmful/beneficial roles in cerebral malaria.

  "...Early on in malaria, platelets play a protective role... whereas later... platelets played this more of a, a negative pathologic role..."
  — Dr. Robert Campbell [12:18]

Experimental Approaches & Mechanistic Insights

• Model: P. berghei ANKA mouse model for cerebral malaria.

• Genetic Manipulation: Selective knockout of mTOR in platelets to assess outcomes.

• Key Findings:

  • Platelet mTOR essential for pathologic platelet activation in malaria.
  • Heme (from lysed red blood cells) activates platelets via KLEC2 (a hemi-ITAM receptor).
  • Blocking KLEC2-heme interaction is protective in mice.

  "Our data suggests that it's more through this Cleck2 mechanism and blood blocking. This interaction with heme binding to cleck 2 was protective in our malaria model."
  — Dr. Robert Campbell [17:25]

Individual Susceptibility and Spectrum

• Genetic/Physiologic Variation: Platelet responses vary by individual—this could help explain why some patients progress to cerebral complications and others do not.

  "Platelet activation is definitely on a spectrum in terms of people where everybody's platelets sort of react differently, and there's many physiologic factors, genetic factors..."
  — Dr. Robert Campbell [15:56]

Therapeutic Implications

• Potential for Targeted Intervention:

  • Potential to use Cleck2 inhibitors or downstream signaling blockers (e.g., BTK inhibitors already in clinical use for cancer) to mitigate cerebral malaria.

• Challenges:

  • Timing, identification of at-risk patients, risk of bleeding, and translation from preclinical to clinical contexts.

  "...There is the potential out there and something that we're actively pursuing in our murine models."
  — Dr. Robert Campbell [17:25] "...When you target platelets potentially you also lead to potential bleeding consequences. So I feel like we have laid a foundation, a framework..."
  — Dr. Robert Campbell [18:43]

Commentary and Translation

• Peer Review: Dr. Martin Schlesinger lauded the novelty but questioned human translation.

• Next Steps: Further studies necessary to address dosing, timing, side effects, and validation in human infection.

  "Our work is very preclinical and with the hopes that we can get it over the hump and get it to be more translational..."
  — Dr. Robert Campbell [18:43]

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Key Takeaways and Memorable Quotes

• CHIP and IBD:
  • "CHIP both arises from and amplifies intestinal inflammation..." — Commentary cited by Dr. Sen [09:29]
  • Ref1 is a promising target for treating severe, mutation-driven IBD.
• Cerebral Malaria:
  • "Targeting KLEC2 or some of these downstream signaling molecules potentially... has the therapeutic benefit in patients that develop cerebral malaria." — Dr. Robert Campbell [17:25]
  • The interplay between genetic variation, heme, and platelet activation may determine individual cerebral malaria risk.

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Timestamps for Key Segments

• Introduction to IBD & CHIP research: [00:35–01:14]
• Major biobank findings: [02:27–04:25]
• Mouse model mechanistic study: [04:33–08:36]
• Therapeutic implications & commentary: [08:36–10:15]
• Introduction to cerebral malaria: [10:55–11:24]
• Platelet activation mechanisms & findings: [11:24–15:45]
• Therapeutic implications & translation: [17:20–19:45]

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Conclusion

This episode highlights the power of modern biobank analysis, translational mouse models, and molecular targeting in unraveling the interplay of genetics, inflammation, and infection in hematologic diseases. Both articles expand frameworks for future therapies—by targeting Ref1 in IBD-CHIP syndromes, and KLEC2/platelet mTOR pathways in cerebral malaria—while underscoring the need for careful clinical translation.

For access to the referenced studies, visit bloodjournal.org.

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Transcript

[Podcast Host]

Welcome to the American Society of Hematology Conversations with Blood Authors Podcast. This episode is hosted by Associate Editor Dr. Laurie Sen. She discusses Inflammatory Bowel Disease induced Inflammation augments Clonal Hematopoiesis of indeterminate potential through Ref 1 with Dr. Ruben Kapoor and she talks with Dr. Robert Campbell about his article Heme Induced ITAM Signaling exacerbates Malaria Associated Neuropathogenesis through Activation of Platele

[Dr. Laurie Sen]

hi, I'm Laurie Sen, podcast editor at Blood, and I'm joined today by Dr. Reuben Kapoor from the Herman B. Wells center for Pediatric Research at Indiana University School of Medicine. He's the senior author of a New Blood Journal article entitled Inflammatory Bowel Disease Induced Inflammation Augments Clonal Hematopoiesis of indeterminate potential through Ref1. Thanks for joining us today.

[Dr. Ruben Kapoor]

Thank you.

[Dr. Laurie Sen]

Perhaps you can start by providing some background on what was previously known about the relationship of CHIP and inflammatory conditions.

[Dr. Ruben Kapoor]

There have been very few studies that have looked at clonal hematopoiesis in the context of ibd. There was one study that was published a couple of years ago with few human samples and patient samples. However, we undertook a very extensive study involving two separate population databases, one the UK Biobank and the second one, all of Us, which involved over 600,000 individuals. In doing so we have identified some additional findings and strengthened the findings that have been previously published to very definitively demonstrate that CHIP is indeed not only associated with IBD but also causal in these cases based on random Mendelian random analysis.

[Dr. Laurie Sen]

It's quite impressive that you are able to access these large scale population based biobanks. Can you talk a little bit about your approach and essentially the major findings that did emerge from that analysis?

[Dr. Ruben Kapoor]

This study was done in collaboration with Dr. Z. Yu at Broad Institute and also Dr. Pradeep Natarajan at MGH and both of them are experts in looking at very large databases. In doing these analysis they were able to show a very strong association between CHIP and women, especially those women that were 60 years and above in age. They also showed a very strong association between CHIP and Crohn's disease, especially in individuals over 60 years of age. And thirdly, they showed a very strong association between ChIP and DNMP3Amutations, followed by ASLXL mutations that were more strongly associated in males as opposed to females. Interestingly, when we did this analysis we also found that tattoo mutations were strongly associated with ulcerative colitis, but in individuals who were 45 years and younger. Clearly these studies for the first time suggested that not Only is there distinction between a CHIP and different forms of IBD manifestation, but also a fairly strong association between sexes and also a pretty unique association with regards to what types of chick mutations are associated with males and females. Now, the exact rationale and reasoning behind why this is the case is unknown at this point, and these are some of the studies that we're currently pursuing in more detail to understand why the sex differences exist and why do chip mutations, especially ASL XL and DNMT3A in males are more prevalent than in females.

[Dr. Laurie Sen]

You subsequently used mouse models to then explore the mechanism of some of these relationships and what insights did this provide?

[Dr. Ruben Kapoor]

Great question. After observing these differences between CHIP and the presence of DNFD3Amutation and the strong association, we wanted to better understand how does this happen for these types of studies. We utilize some of the mouse models that have been described in the literature already and we utilize both DNMT3A heterozygous loss of function allele as well as homozygous loss of function allele mouse models and subjected these animals to sort of a severe or acute form of colitis and this can be manifested by administering dextrin sulfate sodium to animals. So by subjecting animals to this type of treatment you see quite a few manifestations that recapitulate some of the aspects of human colitis and in doing so we identified that this type of treatment to DNMT3A animals induces a lot more inflammatory changes and a very robust increase in pro inflammatory cytokines, recruitment of T cells, myeloid cells to the damaged colon. The damage to the colon is a lot more severe compared to control animals which have no CHIP mutation and that this also manifests in strong oxidative stress, stronger than what is normally seen in normal animals. Given the observation of extremely robust oxidative stress associated with the presence of CHIP mutations in the context of DSS treatment, we turned our attention to this pathway a little bit more in detail to see if we can inhibit some of the oxidative stress that is being manifested in these animals by utilizing inhibitor a small molecule inhibitor that regulates oxidative stress induced activation of some of the pro inflammatory soda compound and this molecule is called ref, a pyrimidic molecule that's a complex of APE and ref. The APE aspect of the molecule regulates the DNA repair function of the enzyme, whereas the REF is involved in regulating the redox function of multiple transcription factors that have been implicated in regulating inflammation including NF kappa B, stat 3, ape 1 as well as HIF1 alpha. The first study that we did was we wanted to see if the APE levels and REF levels are upregulated in both the colon as well as systemically in bone marrow cells of chipmuntant animals and we consistently found that in both those separate tissues APE REF expression was substantially elevated in response to DSS treatment and that if one treated these animals using a small molecule inhibitor that we've been working on for close to two decades now, which have just undergone phase 2 clinical trials for some of the other indications, substantially reduces the expression of Ref1 in these models and represses the inflammatory, including all of the known targets of REF and additional targets that have not been previously identified, thus down regulating the inflammatory responses, completely reversing IBD induced changes that were manifested as a result of DSS treatment in these animals.

[Dr. Laurie Sen]

What do you think the potential therapeutic implications of these findings are?

[Dr. Ruben Kapoor]

We've been looking to see whether there are patients or within the given patient population that don't respond to classical therapies that are standard of care to see if that may be as a result of presence of CHIP mutations in these individuals and perhaps those individuals can be treated with this inhibitor in conjunction with the existing therapies. And also moving forward, should we screen for individuals who have CHIP mutations with high variable allele frequency to see if we can inhibit some of the manifestations of IBD in high risk individuals that may not respond to the standard of care that is currently available?

[Dr. Laurie Sen]

In their commentary, David Curtis and Jasmine Singh from Monash University and the Fiona Center Stanley Hospital in Australia recognize that your study nicely demonstrates that CHIP both arises from and amplifies intestinal inflammation. But they do suggest that longitudinal studies of CHIP and IBD cohorts will be required to establish the human relevance. Can you comment on this?

[Dr. Ruben Kapoor]

That is an excellent comment and we completely acknowledge that those are studies that are absolutely essential and we're now in the process of initiating those studies and we hope that we will be able to share the data in the near future with the general audience.

[Dr. Laurie Sen]

I certainly look forward to seeing how this evolves. In the meantime, I hope you've enjoyed the conversation today. I've been speaking with Ruben Kapoor who has been discussing the newly published article Inflammatory Bowel disease induced inflammation augments clonal hematopoiesis of indeterminate potential through REF1. This study nicely establishes a bidirectional relationship between CHIP and IBD and identifies Ref1 as a key mediator raising the possibility of novel targeted approaches. This article is now available on bloodjournal.org.

[Dr. Ruben Kapoor]

thank you.

[Dr. Laurie Sen]

I'm also joined today by Dr. Robert Campbell from Washington University in St. Louis. He's the senior author of a New Blood Journal article entitled Heme Induced ITAM Signaling exacerbates Malaria Associated Neuropathogenesis through Activation of Platelet mtor. Thanks for joining us today.

[Dr. Robert Campbell]

Thanks for having me.

[Dr. Laurie Sen]

Perhaps you can start by providing some background on, on the clinical relevance of cerebral malaria.

[Dr. Robert Campbell]

I think that's a very important question, especially for those outside the United States where malaria is not very common. There are different strains of malaria that affect individuals worldwide and the specific malaria type that we've been interested in is P. Falciparum or Plasmodium falciparum, which is very common in Sub Saharan Africa and infects millions of children each year and it's fairly lethal in many of these patients and can lead to long term disability. And our lab is interested in platelet biology and understanding how platelets play a role in infection. And a lot of our work previously has been done in bacterial and viral infections. And we began to become interested in how parasites, which is the malaria model, how platelets may interact with different malaria models to understand how they play a role in the pathogenesis of the disease.

[Dr. Laurie Sen]

What motivated you to investigate the role of platelet activation with within the context of cerebral malaria?

[Dr. Robert Campbell]

The role of platelets in malaria is an interesting journey in the literature. There have been recent reports that platelets play a role in actively killing the parasite, and that is something that is still ongoing and something that we weren't directly interested in because our lab is very interested in how platelets become activated and then how they interact with immune cells and the vasculature to cause either thrombotic complications or bleeding complications. And we were really interested in understanding how platelets become activated in the context of malaria and then what happens in that context and how they contribute to this pathophysiology. There was work several years ago that suggested that early on in malaria, platelets play a protective role because when you remove platelets from the disease process, animals succumb to the disease more quickly, whereas later in the disease process, platelets played this more of a, a negative pathologic role because if you inhibited platelet function later on the disease, the animals were protected from the disease. So we really were trying to figure out how platelets were becoming activated and then why they seem to be more detrimental later on in the disease and the pathophysiology behind that.

[Dr. Laurie Sen]

Could you summarize the approach that you took to evaluate this along with some

[Dr. Robert Campbell]

of your key findings in terms of mirroring models of malaria. The one that we use and the one that represents cerebral malaria the most Is a model called P. Burgue onca. And in this model, mice become infected early on, and then over a course of six to seven days, the parasite develops, you get red blood cell lysis, you get more red blood cells infected, and eventually the animals begin to develop neurological symptoms and ultimately succumb to the disease. Our lab uses genetic models to understand how platelets interact with disease models. And in this model, we used a model where we removed mtor specifically from platelets to understand when platelet mtor is removed from the model, how that affects the outcomes of malaria. Platelet activation is very complicated, and there are many different ways a platelet can get active, activated, either through receptors on their surface and then downstream signaling pathways. And our lab has begun to understand one of these master regulators that when platelets get activated from different signals, they sort of descend or coalesce around this molecule called mtor, which is the mammalian target of rapamycin. This is a well studied molecule in a lot of different cells, and it was discovered almost 20, 30 years ago when platelets play a role in platelet clot retraction deposits play a role in platelet activation. The role of platelet mtor in terms of regulating platelet activation in disease situations has been less studied. We've shown that platelet mtor plays a role in aging, Plays a role in sepsis, and plays a role in something called immunothrombosis, where it interacts with neutrophils and platelets to cause thrombotic complications. Based on this body of knowledge, we began to really think about, well, how could MTOR be regulating platelet activation in the setting of malaria? In doing so, we realized early on that platelet mtor in the parent cell, the megakaryocyte of the platelet mtor was activated in the context of cerebral malaria and our mirroring model. And knowing that that gave us more confidence that maybe there was something mtor was doing pathologically to propagate the disease in our mirroring model.

[Dr. Laurie Sen]

Given this mechanistic insight, gentlemen, do you think this might explain why some patients are more prone to developing cerebral malaria and others don't manifest it?

[Dr. Robert Campbell]

I think it's something that we're interested in understanding because platelet activation is definitely on a spectrum in terms of people where everybody's platelets sort of react differently, and there's many physiologic factors, genetic factors that we're still beginning to understand. Our mechanism and our understanding of how it works in this mirroring model system became apparent when we saw recruitment of inflammatory cells that were similarly across our wild type and knockout mice. And we saw that platelet deposition really was something that was correlating to neurologic dysfunction. We thought that there must be something about the malaria itself and potentially the bursting of the red blood cells that causes this downstream platelet activation. What we determined was it was a heme induced mechanism where heme was activating receptors on the platelet. Now, going specifically to your question, is there potentially a spectrum of how heme interacts with different individuals platelets to induce this? It is possible, and that's something that, again, we're interested in studying. It's a little bit harder for us to study malaria here in Missouri compared to studying in malaria, where it's, you know, more commonly found in sub Saharan Africa. But it is something that our understanding of the ability for platelets and heme and other inflammatory mediators that are released. Is there a spectrum? Yes. It is very possible that that may be why some people are prone to developing the robotic consequences of malaria and why some people may be more protected or less likely to develop these consequences.

[Dr. Laurie Sen]

And what do you think the potential therapeutic implications of your findings might be?

[Dr. Robert Campbell]

As I mentioned, we really began to study this role of heme, which gets released from red blood cells upon parasite rupture. And we think that heme activates ITAM receptors specifically on platelets. There are two different types of itams on platelets. Glycoprotein 6, which is generally thought to bind collagen along with fibrin, and then Cleck 2, which is a hemi itam that is normally thought to bind rotasetin. There's been reports in the literature that both of these receptors combine heme and activate platelets. Our data suggests that it's more through this Cleck2 mechanism and blood blocking. This interaction with heme binding to cleck 2 was protective in our malaria model. So one thought is if we could develop inhibitors or antibodies against Cleck2 or the downstream signaling pathways have the potential. And there are inhibitors out there clinically right now, BTK inhibitors, which are in cancer and other downstream signaling molecules. So there is the potential out there and something that we're actively pursuing in our murine models.

[Dr. Laurie Sen]

In his commentary, Dr. Martin Schlesinger from the Federal Institute for Drugs and and Medical Devices in Germany recognizes the novelty of your results and the potential for therapeutic targeting but he questions whether these findings can be directly translated to malaria infections in humans. Can you comment on this?

[Dr. Robert Campbell]

I think that's a very valid point. Our work is very preclinical and with the hopes that we can get it over the hump and get it to be more translational. I think there's a lot of promise in what we were able to show that potentially targeting KLEC 2 or some of these downstream signaling molecules potentially, potentially has the therapeutic benefit in patients that develop cerebral malaria. However, there are many things that still need to be done. Malaria is a very complicated disease. When would you give these inhibitors? How soon into the disease process that you identify children and adults that have cerebral malaria off target effects of these signaling pathways. When you target platelets potentially you also lead to potential bleeding consequences. So I feel like we have laid a foundation, a framework that for people who I feel are smarter than me to develop these therapeutic pathways that could drug target either platelets specifically or target the signaling pathways specifically in platelets. But I do feel like we have identified a new novel target that may be beneficial in cerebral malaria and ongoing studies are needed to really figure out timing, doses and off target effects.

[Dr. Laurie Sen]

I truly look forward to seeing how this moves forward. In the meantime, I hope you've enjoyed the conversation today and been speaking with Robert Campbell who has discussed the newly published article Heme induced ITAM signaling exacerbates Malaria associated neuropathogenesis through activation of platelet MtOR. This study elucidates the role of platelet activation through MTOR in the pathogenesis of cerebral malaria, raising the possibility of platelet targeted therapeutic strategies. This article is now available on bloodjournal.org

[Podcast Host]

thank you for listening to this episode of Conversations with Blood Authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.