# Monocyte-derived dendritic cells in malaria

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $403,342

## Abstract

Project Summary
Cerebral malaria (CM) is a severe neurological manifestation of infection with Plasmodium species.
Mortality is high and neurocognitive deficits may persist in recovered patients. Evidences obtained from
humans and in a rodent malaria model indicate that sequestration of infected erythrocytes within cerebral
blood vessels and neuroinflammation are essential components of CM. Hence, to fulfill the promise of
immune-based therapeutic interventions, a better understanding of relevant mechanisms of CM
pathogenesis is needed. While a variety of immune cells, primarily CD8+ T cells, are involved, the
mechanisms that govern immune cell cooperation leading to this lethal pathology are poorly understood.
Using selective depletions recent studies have demonstrated the importance of CD11c+MHC-IIhi dendritic
cells (DCs) as well as CD11b+F4/80+Ly6c+CCR2+ inflammatory monocytes (iMOs), both in host resistance
to Plasmodium and pathogenesis of CM. Although these cell subsets have overlapping functions, DCs are
more specialized in antigen presentation and shaping T cell mediated immunity. However, the main DC
subset(s) that mediate CM development has not been defined. We found that infection with P. berghei
ANKA (Pba) promotes a massive differentiation of iMOs into splenic monocyte derived dendritic cells (MO-
DCs) at 5 days post-infection, and two days later they emerge in the CNS culminating in the development of
lethal CM. Thus, our main hypothesis is that MO-DCs are central players in promoting neuroinflammation in
PbA infected mice. Our goal is to interrogate what are the endogenous elements that promote differentiation
of iMOs into MO-DCs and the mechanism by which MO-DCs promote neuroinflammation in rodent malaria.
Our first aim is to fully characterize the malaria-induced splenic MO-DCs based on cell surface markers,
morphological properties, and unbiased analysis of gene expression. Our preliminary results indicate that
the highly purified MO-DCs (CD11c+MHC-IIhi CD11b+F4/80+DC-SIGN+Ly6c+) express high levels of
IFNγ-inducible chemokines, CXCL9 and CXCL10, as well as the chemokine receptor CCR5, thus we named
these cells CCR5+CXCL9/10+ MO-DCs. Furthermore, activation of nucleic acid sensing TLRs have been
shown to initiate cytokine response by both human and mouse macrophages and DCs exposed to
Plasmodium components. Hence, in the second aim we will investigate the importance of TLR activation as
well as IFNγ in promoting MO-DCs differentiation and function. Finally, in Aim 3 we will investigate the
emergence of MO-DCs in the CNS of PbA infected mice. Our preliminary data also suggest that CCR5 is a
key chemokine receptor that mediates MO-DC migration into inflamed brain. We hypothesize that once in
the CNS, MO-DCs are important source of CXCL9 and CXCL10, amplifying recruitment and activation of
pathogenic CD8+ T lymphocytes. Taken together, these studies will provide novel and significant insights
into the mechanisms that DCs mediate th...

## Key facts

- **NIH application ID:** 9870967
- **Project number:** 5R01NS098747-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** RICARDO TOSTES GAZZINELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,342
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870967

## Citation

> US National Institutes of Health, RePORTER application 9870967, Monocyte-derived dendritic cells in malaria (5R01NS098747-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870967. Licensed CC0.

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