A Metabolite-Based Resistance Mechanism Against Malaria

Figueiredo, A.; Trikha Rastogi, S.; Ramos, S.; Nogueira, F.; De Villiers, K.; Goncalves de Sousa, A. G.; Votborg-Novel, L.; von Wedel, C.; Tober-Lau, P.; Jentho, E.; Pagnotta, S.; Mesquita, M.; Cardoso, S.; Bortolussi, G.; Muro, A. F.; Tranfield, E. M.; Thibaud, J.; Duarte, D.; Sousa, A. L.; Pinto, S. N.; Kitoko, J.; Mombo-Ngoma, G.; Mischlinger, J.; Junttila, S.; Alenquer, M.; Amorim, M. J.; Vasavda, C.; Bosma, P. J.; Violante, S.; Drotleff, B.; Paixao, T.; Portugal, S.; Kurth, F.; Elo, L. L.; Paul, B. D.; Martins, R.; Soares, M. P.

doi:10.1101/2025.02.20.639306

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bioRxiv · 10.1101/2025.02.20.639306

A Metabolite-Based Resistance Mechanism Against Malaria

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Abstract

Whether jaundice, a common presentation of Plasmodium (P.) falciparum malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood (1-3). We found that asymptomatic P. falciparum infection was associated with a >10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (5), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasites food vacuole. In conclusion, jaundice represents a metabolic response to Plasmodium spp. infection that limits malaria severity.

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Figueiredo, A., Trikha Rastogi, S., Ramos, S., Nogueira, F., De Villiers, K., Goncalves de Sousa, A. G., Votborg-Novel, L., von Wedel, C., Tober-Lau, P., Jentho, E., Pagnotta, S., Mesquita, M., Cardoso, S., Bortolussi, G., Muro, A. F., Tranfield, E. M., Thibaud, J., Duarte, D., Sousa, A. L., Pinto, S. N., Kitoko, J., Mombo-Ngoma, G., Mischlinger, J., Junttila, S., Alenquer, M., Amorim, M. J., Vasavda, C., Bosma, P. J., Violante, S., Drotleff, B., Paixao, T., Portugal, S., Kurth, F., Elo, L. L., Paul, B. D., Martins, R., Soares, M. P.. 2025-02-26. A Metabolite-Based Resistance Mechanism Against Malaria. https://doi.org/10.1101/2025.02.20.639306

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