Author(s):
Ramos, Susana ; Ademolue, Temitope W ; Jentho, Elisa ; Wu, Qian ; Guerra, Joel ; Martins, Rui ; Pires, Gil ; Weis, Sebastian ; Carlos, Ana Rita ; Mahú, Inês ; Seixas, Elsa ; Duarte, Denise ; Rajas, Fabienne ; Cardoso, Sílvia ; Sousa, António G G ; Lilue, Jingtao ; Paixão, Tiago ; Mithieux, Gilles ; Nogueira, Fátima ; Soares, Miguel P
Date: 2022
Persistent ID: http://hdl.handle.net/10362/142754
Origin: Repositório Institucional da UNL
Subject(s): evolutionary trade-off; heme; hypoglycemia; malaria; transmission; virulence; Physiology; Molecular Biology; Cell Biology; Infectious Diseases; Parasitology; SDG 3 - Good Health and Well-being
Description
Funding Information: We thank Dr. Silvia Portugal (Max Plank Institute, Berlin) and Dr. Jessica Thompson (Instituto Gulbenkian de Ciência; IGC) for their critical review of the manuscript; Dr. Joanne Thompson (University of Edinburgh) for PcAS-GFPML parasites; BEI Resources for P. falciparum parasites (MRA-1029, deposited by Andrew M. Talman and Robert E. Sinden); and excellent support from IGC's Advanced Imaging, Flow Cytometry & Antibody and Genomics facilities. S.R. was supported by Fundação Para a Ciência e Tecnologia (FCT; 5723/2014; FEDER029411); T.W.A. by the Gulbenkian foundation (IBB2017); E.J. by the Deutsche Forschungsgemeinschaft (DFG, EXC 2051; 390713860); A.R.C. by FCT (SFRH/BPD/101608/2014); S.W. and J.G. by the Center for Sepsis Control and Care (CSCC), Jena University Hospital (BMBF 01EO1502), and DFG (EXC 2051, 390713860, and WE 4971/6-1); and D.D. and F.N. by FCT (GHTM; UID/04413/2020). The M.P.S. laboratory is supported by the Gulbenkian, “La Caixa” (HR18-00502), and FCT (5723/2014; FEDER029411) foundations, as well as by the Oeiras-ERC Frontier Research Incentive Awards. M.P.S. is an associate member of the DFG Cluster of Excellence “Balance of the Microverse” (https://microverse-cluster.de/en). Support by Congento (LISBOA-01-0145-FEDER-022170) is acknowledged. Study design, experimental work, data analysis, and interpretation, S.R. and T.W.A.; Plasmodium scRNA data, E.J. (with S.R. and T.W.A.); in vitro experiments on heme regulation of gluconeogenesis, A.R.C. and Q.W.; indirect calorimetry measurements of heme-treated mice, J.G. and S.W.; flow cytometry experiments R.M. (with T.W.A.); Plasmodium virulence experiments, G.P. assisted S.R. and T.W.A.; experiments of induction of illness-induced anorexia in response to Plasmodium infection, I.M. and E.S. assisted S.R. and T.W.A.; maintenance and characterization of mouse strains; S.C.; bulk RNA and scRNA sequencing data analysis, A.G.G.S. and J.L. (with S.R. T.W.A. and E.J.); data interpretation, G.M. and F.R.; P. falciparum glucose tolerance in vitro experiments, F.N. (with S.R. and D.D.); formulation of the original hypothesis, study design, and writing of the manuscript, M.P.S. (with S.R. and T.W.A.). All authors read and approved the manuscript. The authors declare no competing interests. Funding Information: We thank Dr. Silvia Portugal (Max Plank Institute, Berlin) and Dr. Jessica Thompson (Instituto Gulbenkian de Ciência; IGC) for their critical review of the manuscript; Dr. Joanne Thompson (University of Edinburgh) for PcAS-GFP ML parasites; BEI Resources for P. falciparum parasites (MRA-1029, deposited by Andrew M. Talman and Robert E. Sinden); and excellent support from IGC’s Advanced Imaging, Flow Cytometry & Antibody and Genomics facilities. S.R. was supported by Fundação Para a Ciência e Tecnologia (FCT; 5723/2014 ; FEDER029411 ); T.W.A. by the Gulbenkian foundation ( IBB2017 ); E.J. by the Deutsche Forschungsgemeinschaft (DFG, EXC 2051 ; 390713860 ); A.R.C. by FCT ( SFRH/BPD/101608/2014 ); S.W. and J.G. by the Center for Sepsis Control and Care (CSCC), Jena University Hospital ( BMBF 01EO1502 ), and DFG ( EXC 2051 , 390713860 , and WE 4971/6-1 ); and D.D. and F.N. by FCT (GHTM; UID/04413/2020 ). The M.P.S. laboratory is supported by the Gulbenkian, “La Caixa” ( HR18-00502 ), and FCT ( 5723/2014 ; FEDER029411 ) foundations, as well as by the Oeiras-ERC Frontier Research Incentive Awards . M.P.S. is an associate member of the DFG Cluster of Excellence “Balance of the Microverse” ( https://microverse-cluster.de/en ). Support by Congento ( LISBOA-01-0145-FEDER-022170 ) is acknowledged. Publisher Copyright: © 2022 Elsevier Inc.
Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.
