Transcriptomic profiling of “brain-eating amoeba” Naegleria fowleri infection in mice: the host and the protozoa perspectives

Guerlais, V., Allouch, N., Moseman, E. A., Wojciechowska, A. W., Wojciechowski, J. W., Marcelino, I

The free-living amoeba Naegleria fowleri (NF) causes a rare but deadly parasitic meningoencephalitis (PAM) in humans, with no effective treatments available. The molecular mechanisms behind NF pathogenesis and the host brain response remain unclear. To investigate natural virulence variation, two new environmental NF isolates (NF45 and NF1) were purified and tested for in vivo virulence in mice. NF45 exhibited high virulence (NF45_HV) compared to the lower virulence NF1 (NF1_LV), based on amoeba growth and mouse survival rates. RNA-seq analysis of infected mouse brains revealed differential gene expression patterns: NF1_LV upregulated genes related to translational proteins and protein modification, while NF45_HV modulated genes associated with DNA metabolism and cytoskeletal proteins. The virulence factor Cathepsin B was upregulated in NF1_LV but downregulated in NF45_HV. Host response analysis indicated stronger immune activation in NF1_LV infections, including blood-brain barrier leakage, immune cell recruitment, cytokine release (IL-6, IFN-Ɣ, TNFα), and neuronal damage. Neuromotor-related genes (Adam22, Cacnb4, Zic1 for NF1_LV and ChAt for NF45_HV) were linked to PAM symptoms like muscle weakness and seizures. The study highlights the varying virulence of environmental NF strains and their distinct effects on gene expression during infection, providing the first comprehensive insight into the molecular mechanisms of PAM pathogenesis. Targeting both the parasite and the host could be a promising approach for future PAM therapies.

DOI: https://doi.org/10.3389/fcimb.2024.1490280

Keywords: Naegleria fowleri, virulence phenotypes, mouse brain infection, RNA-seq analysis, neuroinflammation, host-parasite interaction, neurodegeneration, differentially expressed genes (DEGs)