Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance to Plasmodium infection
Summary TNF has a dual effect in Plasmodium infection, bolstering the host’s immune defense while also triggering disease. Here, we show that TNF signaling hampers physical activity, food intake, and energy expenditure while enhancing glucose uptake by the liver and spleen as well as controlling parasitemia in P. chabaudi (Pc)-infected mice. We also demonstrate that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of HIF-1α, expression of glucose transporter GLUT1 and enhanced glycolysis in monocytic cells from Pc-infected mice. Importantly, Pc- infected iNOS-/-, TNFRΔLyz2 and HIF-1αΔLyz2 mice show impaired release of TNF and glycolysis in monocytes, together with increased parasitemia and disease tolerance. Together, our findings reveal that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior in Pc-infected mice.
Authors
- Juliana E. Toller-Kawahisa (ORCID: https://orcid.org/0000-0001-7323-5036)
- Leonardo Gomes Vaz (ORCID: https://orcid.org/0000-0001-7217-1325)
- Diego L. Costa (ORCID: https://orcid.org/0000-0002-9440-2814)
- Ogooluwa Ojelabi
- Ricardo T. Gazzinelli (ORCID: https://orcid.org/0000-0003-2427-7699)
- Kely Catarine Matteucci (ORCID: https://orcid.org/0000-0002-2474-1837)
- Isabella C. Hirako (ORCID: https://orcid.org/0000-0002-4390-6043)
- João S. Silva (ORCID: https://orcid.org/0000-0002-3410-3927)
- Nathalia PS Leite
- Franciele Pioto
- José C Alves-Filho
- Patricia A Assis
Institutions
- Universidade de Ribeirão Preto (BR)
- Instituto Federal de Educação, Ciência e Tecnologia de Minas Gerais (BR)
- University of Massachusetts Chan Medical School (US)
- Universidade de São Paulo (BR)
- University of Michigan (US)
- Microsoft (Brazil) (BR)
- Hospital Universitário da Universidade de São Paulo (BR)
- Clinics Hospital of Ribeirão Preto (BR)
- Institute of Biomedical Science (GB)
- Fundação Oswaldo Cruz (BR)
Publication Details
- Journal
- eLife
- Published
- 2026-07-27
- DOI
- https://doi.org/10.7554/elife.97759.4
- Citations
- 2
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais
- National Institute of Allergy and Infectious Diseases