Abstract Number: PB0763
Meeting: ISTH 2022 Congress
Theme: Hemostatic Systems in Cancer, Inflammation and Immunity » Platelets and Infection
Background: Cerebral malaria remains a major public health concern in Sub-Saharan Africa. The pathogenesis arises from damaged vascular endothelium and a maladaptive immune response. However, growing evidence suggests a crucial role for platelets in malaria.
Aims: Determine if the mammalian target of rapamycin (mTOR) in platelets contributes to the pathogenesis of malaria.
Methods: Platelet-specific mTOR knock out mice (KO; mTORfl/fl-Pf4-cre) and littermate controls (WT; mTORfl/fl) were subjected to a well-established model of experimental cerebral malaria (ECM) using Plasmodium berghei ANKA (PbA).
Results: The mTOR pathway was activated in platelets from PbA-infected C57Bl/6J mice, based on phosphorylation of mTOR and its downstream effector, 4E-BP1. Consistent with mTOR activation, we also observed increased protein translation in platelets from PbA-infected mice compared to uninfected controls. To study the role of platelet mTOR during ECM, KO mice and WT controls were infected with PbA. Platelet mTOR-deficient mice had significantly increased survival compared to WT mice (p=0.004). Increased survival was independent of parasitemia, thrombocytopenia and platelet turnover. Furthermore, KO mice had significantly reduced brain vascular permeability (p=0.007), which was associated with improved neurological outcomes. Interestingly, platelet adhesion to the brain vasculature was reduced in KO mice during late-stage ECM. As platelet adhesion to the vasculature is often accompanied by monocyte recruitment, we next assessed the number of monocytes in the brain. Interestingly, the number of inflammatory monocytes was significantly reduced in the brains (p=0.04) of platelet-deficient mTOR mice during ECM. Taken together, these results suggest that platelets assist in the recruitment of leukocytes to the brain vasculature during ECM, which is impaired when mTOR is ablated.
Conclusion(s): Our data demonstrates that the mTOR pathway in platelets plays a significant role in malaria pathogenesis. Deletion of platelet mTOR reduces vascular permeability and prolongs survival during ECM. We hypothesize that altered platelet-inflammatory monocyte interactions drive this phenotype.
To cite this abstract in AMA style:
Portier I, Denorme F, Queisser K, Kosaka Y, Petrey A, Zimmerman G, Morrell C, Campbell R, Rondina M. The mTOR Pathway in Platelets Contributes to the Pathophysiology of Experimental Cerebral Malaria [abstract]. https://abstracts.isth.org/abstract/the-mtor-pathway-in-platelets-contributes-to-the-pathophysiology-of-experimental-cerebral-malaria/. Accessed April 18, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-mtor-pathway-in-platelets-contributes-to-the-pathophysiology-of-experimental-cerebral-malaria/