NSP4–Lipoprotein Complexes and Developmental Lipid Transport in Neonatal Rotavirus Encephalopathy: A Mechanistic Hypothesis

Rotavirus-associated encephalopathy is a rare, severe complication in infants and young children, but its molecular basis remains unclear. Rotavirus nonstructural protein 4 (NSP4) is secreted from infected cells as a phospholipid-associated oligomer and can disrupt calcium homeostasis, yet its presence in circulation, interactions with the blood-brain barrier (BBB), and central nervous system access remain unproven. This hypothesis article integrates evidence on NSP4 structure and lipoprotein-like behavior, low-density lipoprotein receptor-related protein 1 (LRP1), caveolin-1, and developmental BBB transport. This article proposes that NSP4–lipid complexes could interact with glycosaminoglycans and, potentially, with LRP1- and caveolin-associated uptake in brain endothelial cells. If NSP4 crosses or is retained within the BBB, it might perturb calcium signaling and cellular homeostasis in endothelial and neural cells, including astrocytes, microglia, neurons, and oligodendrocyte precursor cells. These links are hypothesis-generating because NSP4–LRP1 binding, BBB transcytosis, and cell-specific effects in the developing brain remain unproven. This article outlines experiments to test or refute this developmental lipid-transport model.