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Review
. 2024 Jan;40(1):28-44.
doi: 10.1016/j.pt.2023.11.005. Epub 2023 Dec 8.

Unravelling mysteries at the perivascular space: a new rationale for cerebral malaria pathogenesis

Samuel C Wassmer  1 , Tania F de Koning-Ward  2 , Georges E R Grau  3 , Saparna Pai  4
Affiliations
Review

Unravelling mysteries at the perivascular space: a new rationale for cerebral malaria pathogenesis

Samuel C Wassmer et al. Trends Parasitol. 2024 Jan.

Abstract

Cerebral malaria (CM) is a severe neurological complication caused by Plasmodium falciparum parasites; it is characterized by the sequestration of infected red blood cells within the cerebral microvasculature. New findings, combined with a better understanding of the central nervous system (CNS) barriers, have provided greater insight into the players and events involved in CM, including site-specific T cell responses in the human brain. Here, we review the updated roles of innate and adaptive immune responses in CM, with a focus on the role of the perivascular macrophage-endothelium unit in antigen presentation, in the vascular and perivascular compartments. We suggest that these events may be pivotal in the development of CM.

Keywords: antigen presentation; blood–brain barrier disruption; cerebral malaria; pathogenesis; perivascular macrophages.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.
Schematic representation of the sequestration of Plasmodium falciparum-infected red blood cells (iRBCs) in cerebral malaria (CM). The expression of P. falciparum-infected erythrocyte membrane protein 1 (PfEMP1) on the iRBC surface leads to sequestration of the iRBC. In addition to the direct sequestration of iRBCs, additional mechanisms contribute to cerebral microvessel plugging and ischemic injury during CM. These include rosetting, the binding of uninfected erythrocytes to iRBCs to avoid immune clearance, and clumping of platelets and iRBCs. Platelets can also bridge CD36-binding PfEMP1 and tumour necrosis factor- (TNF)-activated endothelial cells (ECs); or iRBC and von Willebrand factor (vWF) multimers produced by histamine-activated endothelium. The PfEMP1 antigens are encoded by one of 60 var genes; one PfEMP1 variant is expressed by a single iRBC at any one time. The extracellular region of PfEMP1 is encoded by Duffy-binding-like domains (DBL) and cysteine-rich interdomain regions (CIDR); their particular combination in PfEMP1 variants has led to classification of domain cassettes (DCs) that enable binding to diverse receptors, including intercellular adhesion molecule 1 (ICAM-1), endothelial protein C receptor (EPCR), CD36 and oncofetal chondroitin sulfate A (CSA) expressed on ECs. ICAM-1 and EPCR are expressed in the brain, but there is either little or no constitutive CD36. EPCR binding occurs via the CIDRα1 domain, CD36 binding via the CIDRα2–6 domain, and ICAM binding may occur via DBLβ domains, while the binding phenotype of CIDRβ,γ,ε is unknown. PfEMP1 proteins are also classified as Group A, A/B, B or C according to their chromosomal location, upstream promoter sequence, and direction of var gene transcription. Group A and A/B are linked with severe disease, including CM, and they comprise subclasses of DBL and CIDR domains that bind EPCR or ICAM1. Group A EPCR or dual EPCR/ICAM-1 binders are most clearly associated with CM (adapted from [120]).
Figure 2.
Figure 2.
Immune response and pathogenetic mechanisms involved in blood–brain barrier (BBB) dysfunction during cerebral malaria (CM). After Plasmodium falciparum-infected red blood cells (iRBCs) or their antigen-carrying extracellular vesicles (EVs) are recognized and phagocytosed by dendritic cells (DCs) and macrophages (Mϕ), parasite antigens are presented to CD4+ T cells by their major histocompatibility class (MHC) II. Concomitantly, stimulated macrophages secrete high levels of tumour necrosis factor (TNF), lymphotoxin (LT), interleukin-6, and -1β, leading to the activation of endothelial cells (ECs) locally. Once activated by antigen-presenting cells (APCs), CD4+ T cells recruit CD8+ T cells through the release of CXCL9 and CXCL10, resulting in their activation by antigen-presenting cells via MHC I, the secretion of gamma interferon (IFN- γ) and the maturation of CD8+ T cells into cytotoxic T lymphocytes (CTLs). The latter then target brain endothelial cells, contributing to their destruction and BBB permeability. Pathogen-associated molecular patterns (PAMPs) released from bursting iRBCs during the intraerythrocytic cycle, and damage-associated molecular patterns (DAMPs) from injured endothelial cells, stimulate monocytes (Mo), triggering a cytokine storm and the endothelial upregulation of intercellular adhesion molecule 1 (ICAM-1), a receptor for the DC4 variant of P. falciparum-infected erythrocyte membrane protein 1 (PfEMP-1) that mediates sequestration. DC8/13 variants mediate the binding of iRBCs onto endothelial protein C receptor (EPCR) in the brain, abrogating the cytoprotective EPCR/activated protein C (APC) pathway. In parallel, neutrophils activated by iRBC-derived haeme and EVs release neutrophil elastase (NE), metallopeptidase-8 (MMP-8) and proteinase 3 (PRTN3), all contributing to endothelial damage. Neutrophil extracellular traps (NETs) consisting of decondensed chromatin laced with granular proteins and histones also fragilize the BBB. Parasite factors such as haem, histones, histidine-rich protein 2, and uric acid released by bursting sequestrated iRBCs can also directly increase endothelial permeability locally. The tipping of circulating angiopoietin-1/-2 (Ang-1/2) balance in favour of Ang-2 leads to the abrogation of endothelial quiescence promoted by the Ang-1-Tie-2 engagement. Lastly, platelets activated by contact with iRBCs release TGFβ1 after degranulation, which acts in synergy with TNF to induce endothelial apoptosis and alter the BBB.
Figure 3.
Figure 3.
Perivascular myeloid cells create a niche for immune cell recruitment, activation, and effector function. A hypothetical model illustrating the role of perivascular macrophage (PVM) and CD8+ T cells in the development of experimental cerebral malaria (ECM). (A) Following Plasmodium infection, circulating immune cells produce proinflammatory cytokines interferon-gamma (IFN-γ) and tumour necrosis factor (TNF), which upregulate intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and MHC-I on the surface of endothelial cells. (B,C) Leucocyte function-associated antigen-1 (LFA-1) and very-late antigen-4 (VLA-4) promote, and CXC-chemokine ligand 9/10 stabilize, CD8+ T cell adherence to the endothelium. (D) Adherence of infected red blood cells (iRBC), platelets, and endothelial vesicles lead to permeability of tight junctions. (E) T cells extravasate and crawl along the abluminal wall. (F) iRBC/parasites leak into the perivascular space. (G) PVMs lie under the basement membrane directly adjoining the endothelium alongside pericytes. PVMs phagocytose iRBCs directly from the vessel lumen. They produce chemokines for the recruitment of CD8+ T cells and monocytes. (H) PVMs create inflammation hotspots characterized by clustering, amoeboid appearance, phagocytosis of iRBCs in the perivascular space and MHC-I antigen presentation to CD8+ T cells. (I) Cytotoxic T cells release granzyme B, leading to clinical disease. Abbreviations: CSF, Cerebrospinal fluid; ISF, Interstitial fluid; NK, Natural killer cell; TCR, T cell receptor.
Figure 4.
Figure 4.
Proposed role for the immune targeting of antigen-presenting cells (APCs) in the blood–brain barrier (BBB) breakdown during cerebral malaria (CM). (A) P. falciparum-infected red blood cells (iRBCs) can transfer parasite antigens to the surface of endothelial cells (ECs) through either direct membrane contact or release of antigen upon schizont rupture. (B) iRBCs produce antigen-carrying extracellular vesicles (EVs) that bind to and/or fuse with the endothelial surface, thereby transferring parasite antigens to ECs. Erythrophagocytosis of iRBCs by ECs contribute to this antigen-presentation pathway (lower dash gray arrow, ‘?’). (C) Antigens are presented by ECs through their MHC-I. (D) Cytotoxic T lymphocytes (CTLs) engage with ECs and perivascular macrophages (PVMs) via their T cell receptor (TCR), leading to the release of granzyme B, targeting of ECs, and BBB permeability, ultimately resulting in vasogenic edema. Antigen-carrying EVs shed by iRBCs may contribute to CTL activation (upper dash gray arrow, ‘?’). (E) Parasite antigens are presented by endothelial EVs. (F) The physical proximity between ECs, PVMs, and iRBCs at sites of dense sequestration may increase their interactions, further exacerbating antigen transfer and presentation, leading to foci of BBB disruption and cerebral microhaemorrhage reported both in experimental and human CM. Abbreviation: P. pericyte.
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