Innate immune responses to Plasmodium falciparum disrupt the blood-brain barrier
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Abstract
Plasmodium falciparum accumulation at the blood-brain barrier (BBB) is a hallmark of cerebral malaria, a life-threatening complication. Conversely, the contribution of the immune response to vascular injury has long been debated. Here, we studied the role of innate immune cells as potential effectors of vascular damage using a human in vitro 3D-BBB model. Parasite-stimulated immune cells from malaria-naïve donors increased adhesion to microvessels, at least partly through LFA-1. This caused barrier disruption and inflammatory activation of BBB cells. Secretion of TNF-α, IFN-γ, and granzyme B by monocytes, NK and γδ T cells correlated with vascular injury, and accumulation of immune cells was required for local barrier damage. Our computational analysis disentangled pathogenic mechanisms driven specifically by either P. falciparum parasite or immune cells, as well as shared pathways. These findings demonstrate how vascular-immune interactions may contribute to vascular injury in cerebral malaria and point towards the potential of immunomodulatory therapeutics.
Article activity feed
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Dibyadyuti Datta
Review 3: "Innate Immune Responses to Plasmodium falciparum Disrupt the Blood–Brain Barrier"
Reviewers find that the manuscript provides reliable evidence that Plasmodium falciparum–activated immune cells can directly disrupt the blood–brain barrier through inflammatory activation and leukocyte adhesion, even without sequestration of infected red blood cells.
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Ying Zheng
Review 2: "Innate Immune Responses to Plasmodium falciparum Disrupt the Blood–Brain Barrier"
Reviewers find that the manuscript provides reliable evidence that Plasmodium falciparum–activated immune cells can directly disrupt the blood–brain barrier through inflammatory activation and leukocyte adhesion, even without sequestration of infected red blood cells.
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Cressida Madigan
Review 1: "Innate Immune Responses to Plasmodium falciparum Disrupt the Blood–Brain Barrier"
Reviewers find that the manuscript provides reliable evidence that Plasmodium falciparum–activated immune cells can directly disrupt the blood–brain barrier through inflammatory activation and leukocyte adhesion, even without sequestration of infected red blood cells.
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Strength of evidence
Reviewers: C Madigan (UC San Diego) | 📗📗📗📗◻️
Y Zheng (University of Washington) | 📗📗📗📗◻️
D Datta (Indiana University) | 📗📗📗📗◻️ -
