# Role of RBC-TLR9 in Acute Inflammatory Anemia

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $243,750

## Abstract

Project Abstract/Summary: The global burden of anemia is high, with a worldwide prevalence of 25%. Anemia
is a hallmark of infectious diseases, including parasite infection, and is often lethal in developing countries, with
life-threatening malarial anemia affecting predominantly babies and toddlers. In other parts of the world, anemia
is highly prevalent in critically ill patients, with almost all patients developing anemia during their ICU stay. In this
population, RBC transfusions are associated with increased morbidity and mortality. A mechanistic
understanding of the acute anemia characterizing infection and critical illness is urgently needed given the high
morbidity and mortality and potential harm of transfusions in select populations. One fundamental and critical
knowledge gap is a lack of understanding of how red blood cells (RBCs) contribute to the innate immune
response and inflammatory anemia. Whether RBCs are passive bystanders or actively contribute to the
development of acute inflammatory anemia is unknown. DNA-sensing is an essential component of the innate
immune response to infection and sterile injury, and nucleic acid sensing-TLRs in phagocytes are implicated in
developing inflammatory anemia, which is frequently observed during bacterial sepsis and parasitic infections.
We have recently found that RBCs express the nucleic acid receptor TLR9 and bind cell-free CpG-containing
DNA. During inflammatory states, RBCs capture DNA from the circulation and undergo morphologic changes
and accelerated senescence. Our preliminary data demonstrate that RBC, not phagocyte, TLR9 drives
accelerated erythrophagocytosis. Because elevated cell-free CpG-DNA and acute anemia are features common
to sepsis, parasite infection, and sterile inflammation, we hypothesize that nucleic acid capture by RBC-TLR9
and consequent erythrophagocytosis represents a universal mechanism of acute inflammatory anemia. Based
upon this hypothesis, we will address two aims using human erythroid-derived progenitor cells, genetically
deficient mice, and in vivo models of parasite infection, sepsis, anemia, and sterile inflammation. In aim 1, we
will determine if CpG-induced RBC senescence is dependent on RBC-TLR9. In aim 2, we will evaluate the
erythroid-specific role of TLR9 in driving inflammatory anemia in vivo. We will ask if RBC-DNA binding is sufficient
to cause anemia and whether RBC clearance is dependent on erythrocyte TLR9. We will also determine the
lineage-specific functions of RBC-TLR9 in the development of anemia during infection and sterile inflammation
using a combination of genetically deficient mice and RBC transfer models. While exploratory in nature,
discovering a universal nucleic acid-sensing mechanism by red cells may elucidate critical determinants of
inflammatory anemia, and completion of the proposed aims may provide insight into novel therapeutics for this
highly prevalent disease.

## Key facts

- **NIH application ID:** 10352593
- **Project number:** 1R21AI166813-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nilam S. Mangalmurti
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,750
- **Award type:** 1
- **Project period:** 2022-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352593

## Citation

> US National Institutes of Health, RePORTER application 10352593, Role of RBC-TLR9 in Acute Inflammatory Anemia (1R21AI166813-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10352593. Licensed CC0.

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