Virulence test using nematodes to prescreenNocardiaspecies capable of inducing neurodegeneration and behavioral disorders

Abstract

BackgroundParkinson’s disease (PD) is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain—some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin. Nocardia are Actinobacteria that can cause human diseases like nocardiosis. This illness can lead to lung infection or central nervous system (CNS) invasion in both immunocompromised and immunocompetent individuals. The main species involved in CNS are N. farcinica, N. nova, N. brasiliensis and N. cyriacigeorgica. Some studies have highlighted the ability of N. cyriacigeorgica to induce Parkinson’s disease-like symptoms in animals. Actinobacteria are known to produce a large variety of secondary metabolites, some of which can be neurotoxic. We hypothesized that neurotoxic secondary metabolite production and the onset of PD-like symptoms in animals could be linked.MethodsHere we used a method to screen bacteria that could induce dopaminergic neurodegeneration before performing mouse experiments.ResultsThe nematode Caenorhabditis elegans allowed us to demonstrate that Nocardia strains belonging to N. cyriacigeorgica and N. farcinica species can induce dopaminergic neurodegeneration. Strains of interest involved with the nematodes in neurodegenerative disorders were then injected in mice. Infected mice had behavioral disorders that may be related to neuronal damage, thus confirming the ability of Nocardia strains to induce neurodegeneration. These behavioral disorders were induced by N. cyriacigeorgica species (N. cyriacigeorgica GUH-2 and N. cyriacigeorgica 44484) and N. farcinica 10152.DiscussionWe conclude that C. elegans is a good model for detecting Nocardia strains involved in neurodegeneration. This model allowed us to detect bacteria with high neurodegenerative effects and which should be studied in mice to characterize the induced behavioral disorders and bacterial dissemination.

Comprehensive Analysis of the Nocardia cyriacigeorgica Complex Reveals Five Species-Level Clades with Different Evolutionary and Pathogenicity Characteristics

“…PCoA revealed that the virulence profiles of five clades were distinct, suggesting distinct genetic strategies for host adaptation in the NCC clades. Previous studies have shown virulence heterogeneity, like the higher virulence of clade A strains DSM 43208 and DSM 44484 T compared to clade D strain GUH-2 in challenged mice ( 43 , 44 ). A possible explanation for this might be the presence of additional toxin-coding genes ( mlsA1 and mlsB ) in clade A, and this hypothesis needs to be further explored.…”

Mce1C and Mce1D facilitate N. farcinica invasion of host cells and suppress immune responses by inhibiting innate signaling pathways

“…Nocardia is an intracellular gram-positive pathogenic bacteria that is partially acid-fast, aerobic, catalase positive, and ubiquitous in the environment 1 . There are more than 80 recognized Nocardia species, with 33 being responsible for human diseases 2 , 3 . Nocardiosis is mainly an opportunistic infection, and it affects immunocompromised hosts in up to 60% of cases, causing severe, life-threatening disseminated infections 4 , 5 .…”

The Heparin-Binding Hemagglutinin of Nocardia cyriacigeorgica GUH-2 Stimulates Inflammatory Cytokine Secretion Through Activation of Nuclear Factor κB and Mitogen-Activated Protein Kinase Pathways via TLR4

“…Nocardiosis is usually an opportunistic infection and may cause life-threatening disseminated infections, especially in immunosuppressed hosts (Ambrosioni et al, 2010). Currently, there are more than 90 Nocardia species that have been recognized, and ∼33 species can cause nocardiosis in humans (Bernardin Souibgui et al, 2017;Churgin et al, 2019). Nocardia infection mainly causes brain, lung, and/or skin abscesses, and by dissemination, it can also cause infection in almost all organs; however, the specific mechanism of dissemination remains unclear.…”