Inflammatory response of 3D brain microvessels to TNF and Plasmodium falciparum
Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation is a hallmark of cerebral malaria (CM), leading to endothelial activation, microvascular occlusion, brain swelling, and death. The inflammatory pathogenesis is however poorly understood, partly due to the lack of suitable in vitro platforms to study CM biology. Here, we used 3D perfusable brain microvessels to investigate combinatorial pathogen and host inflammatory stimuli over the in situ parasite maturation and IE rupture. Whereas tumor necros factor (TNF) potently upregulated adhesion molecules and inflammatory pathways, and uniformly recruited leukocytes throughout the microvessels, P. falciparum-IEs upregulated unique stress response pathways, induced minor junctional disturbances and low levels of endothelial apoptosis, and preferentially recruited leukocytes at IE binding regions. Furthermore, parasites delayed recovery from TNF stimulation and enhanced inflammatory responses. Our findings offer insights into CM biology, and suggest that multiple events intersect to promote brain barrier inflammation in CM. Overall design: Comparative gene expression analysis from RNA seq data for 3D brain microvessels fabricated using primary human brain microvascular endothelial cells (HBMECs) treated with either TNF or control and perfused with either normal or Plasmodium falciparum-infected human red blood cells