RESEARCH ARTICLE Trypanosoma brucei infection protects mice against malaria Margarida Sanches-Vaz ID , Adriana TemporãoID , Rafael Luis ID , Helena Nunes-Cabac ¸oID , Anto ´ nio M. Mendes ID , Sarah Goellner ¤ , Ta ˆ nia Carvalho, Luisa M. FigueiredoID *, Miguel PrudêncioID * Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal ¤ Current address: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany * [email protected] (LMF); [email protected] (MP) Abstract Sleeping sickness and malaria are parasitic diseases with overlapping geographical distri- butions in sub-Saharan Africa. We hypothesized that the immune response elicited by an infection with Trypanosoma brucei, the etiological agent of sleeping sickness, would inhibit a subsequent infection by Plasmodium, the malaria parasite, decreasing the severity of its associated pathology. To investigate this, we established a new co-infection model in which mice were initially infected with T. brucei, followed by administration of P. berghei sporozo- ites. We observed that a primary infection by T. brucei significantly attenuates a subsequent infection by the malaria parasite, protecting mice from experimental cerebral malaria and prolonging host survival. We further observed that an ongoing T. brucei infection leads to an accumulation of lymphocyte-derived IFN-γ in the liver, limiting the establishment of a subse- quent hepatic infection by P. berghei sporozoites. Thus, we identified a novel host-mediated interaction between two parasitic infections, which may be epidemiologically relevant in regions of Trypanosoma/Plasmodium co-endemicity. Author summary Despite the geographical overlap between the parasites that cause sleeping sickness and malaria, the reciprocal impact of a co-infection by T. brucei and Plasmodium had hitherto not been assessed. We hypothesized that the strong immune response elicited by a T. bru- cei infection could potentially limit the ability of Plasmodium parasites to infect the same host. In this study, we showed that a primary infection by T. brucei significantly attenuates a subsequent infection by the malaria parasite. Importantly, a significant proportion of the co-infected mice do not develop Plasmodium parasitemia, and those few that do, do not display symptoms of severe malaria and survive longer than their singly infected counterparts. We further showed that the prevention or delay in appearance of malaria parasites in the blood results from a dramatic impairment of the preceding liver infection by Plasmodium, which is mediated by the strong immune response mounted against the PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1008145 November 8, 2019 1 / 27 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Sanches-Vaz M, Temporão A, Luis R, Nunes-Cabac ¸o H, Mendes AM, Goellner S, et al. (2019) Trypanosoma brucei infection protects mice against malaria. PLoS Pathog 15(11): e1008145. https://doi.org/10.1371/journal. ppat.1008145 Editor: Christian R. Engwerda, Queensland Institute of Medical Research, AUSTRALIA Received: May 14, 2019 Accepted: October 11, 2019 Published: November 8, 2019 Copyright: © 2019 Sanches-Vaz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. Funding: This study was supported by Fundac ¸ão para a Ciência e Tecnologia, Portugal (FCT) grants UID/BIM/50005/2019 (Ministe ´rio da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orc ¸amento de Estado) and PTDC-SAU- INF-29550-2017 to M.P. M.S.-V. was supported by a FCT fellowship PD/BD/105838/2014. A.T. was supported by a FCT fellowship PD/BD/138891/
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