# Host Ciracadian Clock and Malaria

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $209,375

## Abstract

SUMMARY: Malaria, along with AIDS and tuberculosis, is one of the most devastating infectious
diseases in the world. A cyclic paroxysm, characterized by sharp peaks of high fever, chills and rigors,
is a pathognomonic sign of Plasmodium infection. The periodicity of malaria paroxysm is attributed to
the simultaneous burst of millions of infected red blood cells (RBCs) carrying synchronous schizonts
and relates to the intensity of malaria-induced cytokine storm. The underlying hypothesis is that
parasite and host components expelled from bursting RBCs trigger various pattern recognition
receptors and release of pyrogenic cytokines (e.g., IL-1β and TNFα). However, the mechanism that
regulates parasite synchronization remains a major knowledge gap on Plasmodium biology. The
scientific premise of this proposal is based on findings indicating that Pc synchronization
follows the host circadian cycle; glucose is the immediate energy source for proliferation of
Plasmodium blood stages; and systemic inflammation lead to a rhythmic hypoglycemia. Our
experiments indicate that parasite arrest into non-replicative stages associates with hypoglycemia,
whereas parasite proliferation occurs at the time of food intake. In addition, we found that the cyclic
hypoglycemia is attenuated and parasite synchronization disrupted in TNF receptor (TNFR)-/- as well
as clock genes (Clock-/-/Npas2-/- and Bmal1-/-) deficient mice. Bmal1 plays a key role as one of the
positive elements in the mammalian autoregulatory transcription translation negative feedback loop,
which is responsible for generating molecular circadian rhythms. Bmal1 becomes activate only in
association with either Clock or Npas2. We hypothesize that by influencing inflammatory
response and glucose metabolism, the host clock genes regulate synchronization of Pc blood
stages. This proposal will make substantial contributions to the understanding of the process by
which malaria blood stages synchronize with the vertebrate host circadian cycle. We propose to
investigate two main topics that are either unresolved or completely novel: (i) the mechanism
by which TNFα controls glycemia and synchrony of Plasmodium cell cycle; and (ii) the
importance of clock genes that control central and peripheral circadian cycle, on inflammation,
glycemia and parasite synchronization in Pc-infected mice. We expect that these findings have
important applications for future development of immune- and metabolic-based interventions in
malaria patients.

## Key facts

- **NIH application ID:** 10102199
- **Project number:** 5R21AI150546-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** RICARDO TOSTES GAZZINELLI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102199

## Citation

> US National Institutes of Health, RePORTER application 10102199, Host Ciracadian Clock and Malaria (5R21AI150546-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102199. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*