Maria Mota Lab

Biology & Physiology of Malaria

Disease burden is disproportionally distributed around the globe. A direct contributor to such asymmetry is malaria – more than 200 million new infections and 400 thousand deaths still occur every year. Despite this unacceptably high health, economic and social burden, the factors that dictate the onset of severe disease and outcome of infection remain poorly understood, which significantly impairs the combat to this deadly disease.

Our overall goal has been and will continue to be towards the elucidation of the most fundamental and conceptually innovative questions of Host-Plasmodium interactions.

With previous work, we have challenged the widespread assumption that Plasmodium can infect and replicate inside hepatocytes undetected by showing that Plasmodium activates a type I IFN response in the liver (Liehl et al., 2014. Nature Medicine). Actually, work from our lab shows that liver stage Plasmodium requires active interactions with the host cellular machinery to prevent clearance. We identified two Plasmodium parasitophorous vacuole membrane (PVM) resident proteins that operate on ensuring parasite survival by: blocking infected cells autophagy (Real et al. 2018. Nature Microbiology) and through interaction with host cell actin affecting its polymerization and eluting the actin structures used as part of host cytosolic defenses (M’Bana et al. 2022. iScience).

We have also identified a host factor mediating the antagonistic effect of one of the parasite’s stage over the other (Portugal et al., 2011. Nature Medicine). That finding paved the way to elucidate how Plasmodium regulates iron levels in order to survive (Slavic et al., 2016. Nature Communications) and ushered the concept that nutrient availability and dietary habits strongly impact the establishment and course of a malaria infection by interfering with both host and parasite pathways during different stages of infection (Mancio-Silva et al., 2017. Nature; Zuzarte-Luis et al., 2017. Nature Microbiology; Marreiros et al, 2023. Communications Biology).

Our recent work indicates that the web of host-Plasmodium interactions is indeed densely woven, with liver stage and the blood stage interacting towards pathology and disease severity (Chora et al., 2023. Immunity). Moreover, we have identified a third party determining disease – host microbiota (Mukherjee et al., 2022. Nature Communications).

We are also continuing to pursue a lasting question – What is so special about the liver? Our recent work provided a comprehensive single-cell gene profiling of hepatocytes and parasites in infected livers over time (Afriat et al., 2022. Nature), enriching our understanding on liver stage malaria. Additionally, our current data shows that the liver special metabolism is the key to modulate the ability of Plasmodium species that infect mammals and achieve extraordinary rates of replication to generate tens of thousands of erythrocyte-infectious merozoites. These observations opened a new and exciting line of research aiming at revealing the consequences of the high replication rate and the impact in the outcome of infection and disease progression.

Research Team

Research Areas

• Host-Plasmodium interactions.
• Parasite nutrient sensing and adaptation.
• Liver Metabolism determining parasite replication.
• Liver parasite replication: molecular regulation and consequences.
• Liver and blood stages of infection cross-talking.

Ongoing Research Projects

2023/2024 Genetic variability in Plasmodium liver stage schizogony. Coordinator: Inês Bento. Funding Agency: Fundação para a Ciência e a Tecnologia.

2022/2023 Plasmodium exploitation of host immune complement system in malaria. Coordinator: Yvonne Azasi. Funding Agency: Fundação para a Ciência e a Tecnologia.

2022/2023 The enemy within: The unexpected role of red blood cell homeostasis in malarial Anemia. Coordinator: Cristina Arias. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018 Sanofi - Institut Pasteur Awards 2018. Coordinator: Maria Mota. Funding Agency: Institut Pasteur.

2018 L'Oréal Award. Coordinator: Inês Bento. Funding Agency: L'Oréal Paris.

Previous Research Projects

Awards

• International

2018 - Maria Mota, Sanofi Institut Pasteur Prize.

2016 - Maria Mota, EMBO Member, European Molecular Biology Organization.

2005 - Maria Mota, International Research Scholar, Howard Hughes Medical Institute, U.S.A.

2004 - Maria Mota, European Young Investigator Award, European Science Foundation.

2003 - Maria Mota, EMBO Young Investigator Award, European Molecular Biology Organization.

• National (a selection)

2017 - Maria Mota, Pfizer Award Basic Research, SCML & Pfizer Laboratories.

2017 - Inês Bento, “Medalhas de Honra L’Oréal Portugal para as Mulheres na Ciência”.

2013 - Maria Mota, Prémio Pessoa.

2005 - Maria Mota, Commander, Grã-Cruz Ordem do Infante D. Henrique, Portuguese Presidency.

Others:

2009 - Maria Mota, Prémio Rotary Investigação-Ciência, Rotary Club.

2009 - Maria Mota, Prémio Saúde, Correio da Manhã.

2008 - Maria Mota, Mello Award, Mello Foundation.

2008 - Maria Mota, Mulher Activa 2008 (2º prémio), Revista Activa.

2007 - Maria Mota, Seeds of Science, Ciência Hoje.

2007 - Maria Mota, CESPU Award, CESPU Foundation.

2005 - Maria Mota, AMI Health Prize, AMI Foundation.

2004 - Maria Mota, Prémio de Mérito e Talento, SIC.

Selected Publications

Marreiros IM, Marques S, Parreira A, Mastrodomenico V, Mounce BC, Harris CT, Kafsack BF, Billker O, Zuzarte-Luís V, Mota MM (2023). A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency. Communications Biology. 6(1):205.

Chora ÂF, Marques S, Gonçalves JL, Lima P, Gomes da Costa D, Fernandez-Ruiz D, Marreiros MI, Ruivo P, Carvalho T, Ribeiro RM, Serre K, Heath WR, Silva-Santos B, Tate AT, Mota MM (2023). Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis. Immunity. 56(3):592-605.e8.

Afriat A, Zuzarte-Luís V, Bahar Halpern K, Buchauer L, Marques S, Chora ÂF, Lahree A, Amit I, Mota MM, Itzkovitz S (2022). A spatiotemporally resolved single-cell atlas of the Plasmodium liver stage. Nature. 611(7936):563-569.

Mukherjee D, Chora ÂF, Lone JC, Ramiro RS, Blankenhaus B, Serre K, Ramirez M, Gordo I, Veldhoen M, Varga-Weisz P, Mota MM (2022). Host lung microbiota promotes malaria-associated acute respiratory distress syndrome. Nature Communications. 13(1):3747.

Lahree A, Baptista SJS, Marques S, Perschin V, Zuzarte-Luís V, Goel M, Choudhary HH, Mishra S, Stigloher C, Zerial M, Sundaramurthy V, Mota MM (2022). Active APPL1 sequestration by Plasmodium favors liver-stage development. Cell Reports. 39(9):110886.

M'Bana V, Lahree A, Marques S, Slavic K, Mota MM (2022). Plasmodium parasitophorous vacuole membrane-resident protein UIS4 manipulates host cell actin to avoid parasite elimination. iScience. 25(5):104281.

Mello-Vieira J, Enguita FJ, de Koning-Ward TF, Zuzarte-Luís V, Mota MM (2020). Plasmodium translocon component EXP2 facilitates hepatocyte invasion. Nature Communications 11(1):5654.

Real E, Rodrigues L, Cabal GG, Enguita FJ, Mancio-Silva L, Mello-Vieira J, Beatty W, Vera IM, Zuzarte-Luís V, Figueira TN, Mair GR, Mota MM (2018). Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes. Nature Microbiology. 3(1):17-25.

Zuzarte-Luis V, Mello-Vieira J, Marreiros IM, Liehl P, Chora AF, Carret C, Carvalho T and Mota MM (2017). Dietary alterations modulate susceptibility to Plasmodium infection. Nature Microbiology. 2(12):1600-1607.

Mancio-Silva L, Slavic K, Grilo Ruivo MT, Grosso AR, Modrzynska KK, Vera IM, Baena-Gonzalez E, Tewari R, Llinás M, Billker O, Mota MM (2017). Nutrient sensing modulates malaria parasite virulence. Nature. 547(7662):213-216. (evaluated in F1000 Biology).

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