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Toxocara canis- and Toxocara cati-Induced Neurotoxocarosis Is Associated with Comprehensive Brain Transcriptomic Alterations.

ABSTRACT: Toxocara canis and Toxocara cati are globally occurring zoonotic roundworms of dogs and cats. Migration and persistence of Toxocara larvae in the central nervous system of paratenic hosts including humans may cause clinical signs of neurotoxocarosis (NT). As pathomechanisms of NT and host responses against Toxocara larvae are mostly unknown, whole-genome microarray transcription analysis was performed in cerebra and cerebella of experimentally infected C57Bl/6J mice as paratenic host model at days 14, 28, 70, 98, and 120 post-infection. Neuroinvasion of T. cati evoked 220 cerebral and 215 cerebellar differentially transcribed genes (DTGs), but no particular PANTHER (Protein ANalysis THrough Evolutionary Relationships) pathway was affected. In T. canis-infected mice, 1039 cerebral and 2073 cerebellar DTGs were identified. Statistically significant dysregulations occurred in various pathways, including cholesterol biosynthesis, apoptosis signaling, and the Slit/Robo mediated axon guidance as well as different pathways associated with the immune and defense response. Observed dysregulations of the cholesterol biosynthesis, as well as the Alzheimer disease-amyloid secretase pathway in conjunction with previous histopathological neurodegenerative findings, may promote the discussion of T. canis as a causative agent for dementia and/or Alzheimer's disease. Furthermore, results contribute to a deeper understanding of the largely unknown pathogenesis and host-parasite interactions during NT, and may provide the basis for prospective investigations evaluating pathogenic mechanisms or designing novel diagnostic and therapeutic approaches.

SUBMITTER: Waindok P

PROVIDER: S-EPMC8779660 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Somatic migration of Toxocara canis- and T. cati-larvae in humans may cause neurotoxocarosis (NT) when larvae accumulate and persist in the central nervous system (CNS). Host- or parasite-induced immunoregulatory processes contribute to the pathogenesis; however, detailed data on involvement of bioactive lipid mediators, e.g. oxylipins or eico-/docosanoids, which are involved in the complex molecular signalling network during infection and inflammation, are lacking. METHODOLOGY/PRINCIPAL FINDINGS:To elucidate if T. canis- and T. cati-induced NT affects the homeostasis of oxylipins during the course of infection, a comprehensive lipidomic profiling in brains (cerebra and cerebella) of experimentally infected C57BL/6J mice was conducted at six different time points post infection (pi) by liquid-chromatography coupled to electrospray tandem mass spectrometry (LC-ESI-MS/MS). Only minor changes were detected regarding pro-inflammatory prostaglandins (cyclooxygenase pathway). In contrast, a significant increase of metabolites resulting from lipoxygenase pathways was observed for both infection groups and brain regions, implicating a predominantly anti-inflammatory driven immune response. This observation was supported by a significantly increased 13-hydroxyoctadecadienoic acid (HODE)/9-HODE ratio during the subacute phase of infection, indicating an anti-inflammatory response to neuroinfection. Except for the specialised pro-resolving mediator (SPM) neuroprotectin D1 (NPD1), which was detected in mice infected with both pathogens during the subacute phase of infection, no other SPMs were detected. CONCLUSIONS/SIGNIFICANCE:The obtained results demonstrate the influence of Toxocara spp. on oxylipins as part of the immune response of the paratenic hosts. Furthermore, this study shows differences in the alteration of the oxylipin composition between T. canis- and T. cati-brain infection. Results contribute to a further understanding of the largely unknown pathogenesis and mechanisms of host-parasite interactions during NT.

Project description:BackgroundNeuroinvasive larvae of the worldwide occurring zoonotic roundworms Toxocara canis and T. cati may induce neurotoxocarosis (NT) in humans, provoking a variety of symptoms including cognitive deficits as well as neurological dysfunctions. An association with neuropsychological disorders has been discussed. Similar symptoms have been described in T. canis-infected mice, whereas data on T. cati-induced NT are rare. Therefore, it was aimed to obtain insights into the impact on neurobehaviour as well as progression of neurological symptoms and behavioural alterations during the course of NT directly comparing T. canis- and T. cati-infected mice as models for human NT.Methodology/principal findingsC57BL/6 mice were orally infected with 2000 embryonated T. canis or T. cati eggs, respectively, the control group received tap water. Mice were screened weekly for neurobehavioural alterations and memory function starting one day prior infection until 97 days post infection (pi; T. canis-infection) and day 118 pi (T. cati-infection, uninfected control). Mostly motoric and neurological parameters were affected in T. canis-infected mice starting day 20 pi with severe progression accompanied by stereotypical circling. In contrast, T. cati-infected mice mostly showed reduced response to sudden sound stimulus (indicator for excitability) and flight behaviour starting day 6 pi. Interestingly, enhanced grooming behaviour was observed exclusively in T. cati-infected mice, indicating a possible role of neurotransmitter dysregulation. Reduced exploratory behaviour and memory impairment was observed in both infection groups with delayed onset and less severe progression in T. cati- compared to T. canis-infected mice.Conclusions/significanceResults highlight the need to consider T. cati beside T. canis as causative agent of human NT. Findings provide valuable hints towards differences in key regulatory mechanisms during T. canis- and T. cati-induced NT, contributing to a comprehensive picture and consequently a broader understanding of NT, which will aid in developing strategies towards prevention in addition to novel diagnostic and therapeutic approaches.

Project description:BackgroundNeurotoxocarosis (NT) is induced by larvae of the dog or cat roundworm (Toxocara canis or T. cati) migrating and persisting in the central nervous system of paratenic hosts, including humans, and may be accompanied by severe neurological symptoms. Host- or parasite-induced immunoregulatory processes contribute to the pathogenesis, but detailed data on pathogenic mechanisms and involvement of signalling molecules during cerebral Toxocara species infections are scarce.MethodsTo elucidate alterations in immunomodulatory mediator pattern, comprehensive multiplex bead array assays profiling comprising 23 different cytokines and chemokines were performed during the course of T. canis- and T. cati-induced NT. To this end, cerebra and cerebella of experimentally infected C57Bl/6?J mice serving as paratenic host models were analysed at six different time points (days 7, 14, 28, 42, 70 and 98) post infectionem (pi).ResultsBrain-body mass ratios of T. canis and T. cati-infected mice were significantly lower than those of the uninfected control group at day 14 pi, and also at day 28 pi for T. canis-infected mice. Both infection groups showed a continuous decrease of pro-inflammatory cytokine concentrations, including TNF-?, IFN-?, GM-CSF and IL-6, in the cerebrum over the course of infection. Additionally, T. canis but not T. cati-induced neurotoxocarosis was characterised by significantly elevated levels of anti-inflammatory IL-4 and IL-5 in the cerebrum in the acute and subacute phase of the disease. The higher neuroaffinity of T. canis led to a prominent increase of eotaxin and MIP-1? in both the cerebrum and cerebellum, while in T. cati-infected mice, these chemokines were significantly elevated only in the cerebellum.ConclusionsThe direct comparison of T. canis- and T. cati-induced NT provides valuable insights into key regulatory mechanisms of Toxocara species in paratenic hosts. The cerebral cyto-/chemokine milieu is shifted to a predominantly anti-inflammatory immune response during NT, possibly enabling both survival of the parasite and the neuroinfected paratenic host. Alteration of eotaxin and MIP-1? concentrations are congruent with the higher neuroaffinity of T. canis and species-specific tropism of T. canis to the cerebrum and T. cati to the cerebellum.

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Toxocara canis- and Toxocara cati-Induced Neurotoxocarosis Is Associated with Comprehensive Brain Transcriptomic Alterations.

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