Deficiency of peripheral serotonin caused by Tph1 abrogation attenuates cerebral malaria severity
In cerebral malaria (CM), the most severe neurological complication caused by Plasmodium falciparum infection, accumulating evidence suggests that tryptophan metabolism mediates disease severity by modulating inflammation and, consequently, blood-brain barrier disruption. Here, we have established an experimental CM mouse model to dissect the differential role of the host tryptophan-serotonin metabolic axis in regulating disease pathogenesis. Peripheral serotonin-deficient mice ( Tph1 −/− ) displayed reduced mortality and blood-brain barrier permeability defects. In addition, we found that in the absence of serotonin synthesis via the enzyme Tph1, mice develop inflammation characterized by a mixed type 1 and type 2 cytokine signature. Pharmacological depletion of peripheral serotonin through injection of the Tph1 inhibitor telotristat in wild-type mice significantly improved resistance against CM. Thus, we propose that targeting serotonin synthesis through Tph1 antagonism could have a therapeutic role in P. falciparum infection and may act as a potential treatment strategy for CM. Video abstract
Authors
- Vasileios Oikonomou (ORCID: https://orcid.org/0000-0002-7553-0159)
- Maria Teresa Antognoni (ORCID: https://orcid.org/0000-0002-5469-7996)
- Giulia Bicchieraro
- Antonella Turco
- Roberta Spaccapelo (ORCID: https://orcid.org/0000-0003-2100-6172)
- Giorgia Renga (ORCID: https://orcid.org/0000-0002-9762-6493)
- Marco Gargaro (ORCID: https://orcid.org/0000-0003-0645-9800)
- Carolina Colliva (ORCID: https://orcid.org/0000-0001-8360-9142)
- Max H. Lombardi (ORCID: https://orcid.org/0009-0009-7975-5046)
- Francesca Fallarino (ORCID: https://orcid.org/0000-0002-8501-2136)
- Angelo Sidoni (ORCID: https://orcid.org/0000-0002-8458-5901)
- Martina Mandarano (ORCID: https://orcid.org/0000-0001-5019-4825)
- Claudia Floridi
- Luigi Vaccaro (ORCID: https://orcid.org/0000-0003-4168-2303)
- Teresa Zelante (ORCID: https://orcid.org/0000-0002-7071-0302)
- Nicola Giacchè (ORCID: https://orcid.org/0000-0002-4810-3960)
- Arianna Miglio (ORCID: https://orcid.org/0000-0002-5459-6298)
- Gloria Iacomelli (ORCID: https://orcid.org/0009-0000-4130-4842)
- Gianluca Vascelli
- Alessia Sulla (ORCID: https://orcid.org/0009-0008-3864-8319)
- Aurora Barbetta (ORCID: https://orcid.org/0009-0009-0786-4534)
- Gabriele Rossini
- Alicia Y.W. Wong
Institutions
- University of Perugia (IT)
Publication Details
- Journal
- iScience
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1016/j.isci.2026.118002
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministero dell'Istruzione e del Merito