Neuregulin-1/ErbB4 signaling modulates Plasmodium falciparum HRP2-induced damage to brain cortical organoids

Adriana Harbuzariu; Annette Nti; Keri Oxendine Harp; Juan C Cespedes; Adel Driss; Jonathan K Stiles

doi:10.1016/j.isci.2022.104407

Neuregulin-1/ErbB4 signaling modulates Plasmodium falciparum HRP2-induced damage to brain cortical organoids

iScience. 2022 May 14;25(6):104407. doi: 10.1016/j.isci.2022.104407. eCollection 2022 Jun 17.

Authors

Adriana Harbuzariu¹, Annette Nti¹, Keri Oxendine Harp¹, Juan C Cespedes¹, Adel Driss¹, Jonathan K Stiles¹

Affiliation

¹ Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.

Abstract

Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum (P.f.) infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB), perivascular cellular injury, and brain swelling. P.f.histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin-1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified toll-like receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous acute treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain.

Keywords: Cell biology; Molecular microbiology; Neuroscience; Parasitology.