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.