Biology subjects

Belloy, M.

Publications and source records attributed to Belloy, M..

7 recordsLinked to original sources

bioRxiv2024

Toxoplasma gondii chronic infection decreases visceral nociception through peripheral opioid receptor signaling

By eliciting immune activation in the digestive tract, intestinal pathogens may perturb gut homeostasis. Some gastrointestinal infections can indeed increase the risk of developing post-infectious irritable bowel syndrome (PI-IBS). Intriguingly, the prevalent foodborne parasite Toxoplasma gondii has not been linked to the development of PI-IBS and the impact of this infection on colon homeostasis remains ill-defined. We show in a mouse model that latent T. gondii decreases visceral nociceptive responses in an opioid signaling-dependent manner. Despite the accumulation of Th1 and cytotoxic T cells in the colon of latently infected mice, the selective invalidation of enkephalin gene in T cells ruled out the involvement of T cell-derived enkephalins in hypoalgesia. These findings provide clues about how this widespread infection durably shapes the gut immune landscape and modifies intestinal physiological parameters. They suggest that in contrast to other gut microbes, T. gondii infection could be negatively associated with abdominal pain. TeaserLatent toxoplasmosis decreases gut nociception in the mouse, suggesting a negative association with abdominal pain in humans

physiology↗

bioRxiv2024

Id2 levels determine the development of effector vs. exhausted tissue-resident memory CD8+ T cells during CNS chronic infection

Tissue-resident memory T cells (Trm) are essential for regional immunity in non-lymphoid tissues. Although single-cell transcriptomics have revealed Trm heterogeneity in various diseases, the molecular mechanisms behind this diversity are unclear. To investigate this, we used Toxoplasma gondii (T. gondii) infection, which persists in the central nervous system (CNS) and is controlled by brain CD8+ Trm. Our single-cell transcriptomic analysis of brain CD8+ T cells from T. gondii-infected mice showed heterogeneous expression of the transcriptional regulator Id2, correlating with different functional states. Using mixed bone marrow chimeras, we found that Id2-deficiency in T cells caused parasite-specific Trm to develop an altered phenotype with diminished effector functions and reduced expression of CD49a. Furthermore, loss of Id2 in brain-infiltrating CD8+ T cells led to the accumulation of exhausted PD1+Tox+CD8+ Trm cells, while Id2 overexpression repressed T cell exhaustion. Overall, our study shows that Id2 levels dictate the acquisition of effector vs. exhausted phenotypes in CD8+ Trm during chronic CNS infection. One sentence SummaryId2 expression level regulates the functional heterogeneity of brain Trm during CNS chronic infection

immunology↗

bioRxiv2024

Protective function and differentiation cues of brain-resident CD8+ T cells during immune surveillance of chronic latent Toxoplasma gondii infection

Chronic T. gondii infection induces brain-resident CD8+ T cells (bTr) but their protective functions and differentiation cues remain undefined. Here, we used a mouse model of latent infection by T. gondii leading to effective CD8+ T cell-mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are sufficient to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a and CD103 are sequentially acquired by brain parasite-specific CD8+ T cells throughout infection, and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell-dependent manner, and is associated with effective parasite control during chronic stage. Conditional invalidation of TAP-mediated MHC class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulate the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses upon T. gondii latency vs. encephalitis revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr. In summary, parasite-specific brain-resident CD8+ T cells are functionally heterogeneous and autonomously ensure parasite control during T. gondii latent infection. Their differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell-mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections.

immunology↗

bioRxiv2024

Chronic IL-1-induced DNA double-strand break response in hippocampal neurons drives cognitive deficits

Chronic inflammation characterized by increased cytokine levels, such as interleukin-1 (IL-1), accompanies many neurological diseases but little is known about IL-1 contribution to cognitive impairment and its interplay with epigenetic processes, including the DNA double-strand break (DSB) response. Here, we demonstrate that H2A.X-dependent DSB signaling in hippocampal neurons drives cognitive deficits upon chronically elevated IL-1. Mice persistently and latently infected with Toxoplasma gondii display impaired spatial memory consolidation along with elevated IL-1{beta} in the hippocampus. We find that neuronal IL-1 signaling in excitatory neurons is required for the spatial memory deficits caused by T. gondii infection and by chronic systemic infusion of IL-1{beta}. In both cases, the deficit in spatial memory was prevented by the abrogation of neuronal H2A.X-dependent signaling. Our results highlight the instrumental role of cytokine-induced DSB-dependent signaling in spatial memory defects. This novel pathological mechanism in inflammation control of neuronal function may extend to several neurological diseases.

animal behavior and cognition↗

bioRxiv2021

A toxic friend: Genotoxic and mutagenic activity of the probiotic strain Escherichia coli Nissle 1917

The probiotic Escherichia coli strain Nissle 1917 (DSM 6601, Mutaflor), generally considered as beneficial and safe, has been used for a century to treat various intestinal diseases. However, Nissle 1917 hosts in its genome the pks pathogenicity island that codes for the biosynthesis of the genotoxin colibactin. Colibactin is a potent DNA alkylator, suspected to play a role in colorectal cancer development. We show in this study that Nissle 1917 is functionally capable of producing colibactin and inducing interstrand crosslinks in the genomic DNA of epithelial cells exposed to the probiotic. This toxicity was even exacerbated with lower doses of the probiotic, when the exposed cells started to divide again but exhibited aberrant anaphases and increased gene mutation frequency. DNA damage was confirmed in vivo in mouse models of intestinal colonization, demonstrating that Nissle 1917 produces the genotoxin in the gut lumen. Although it is possible that daily treatment of adult humans with their microbiota does not produce the same effects, administration of Nissle 1917 as a probiotic or as a chassis to deliver therapeutics might exert long term adverse effects and thus should be considered in a risk versus benefit evaluation. ImportanceNissle 1917 is sold as a probiotic and considered safe even though it is known since 2006 that it encodes the genes for colibactin synthesis. Colibactin is a potent genotoxin that is now linked to causative mutations found in human colorectal cancer. Many papers concerning the use of this strain in clinical applications ignore or elude this fact, or misleadingly suggest that Nissle 1917 does not induce DNA damage. Here, we demonstrate that Nissle 1917 produces colibactin in vitro and in vivo and induces mutagenic DNA damage. This is a serious safety concern that must not be ignored, for the interests of patients, the general public, health care professionals and ethical probiotic manufacturers.

microbiology↗

bioRxiv2018

Bottom-up sensory processing can decrease activity and functional connectivity in the default mode like network in rats.

The default mode network is a large-scale brain network that is active during rest and internally focused states and deactivates as well as desynchronizes during externally oriented (top-down) attention demanding cognitive tasks. However, it is not sufficiently understood if unpredicted salient stimuli, able to trigger bottom-up attentional processes, could also result in similar reduction of activity and functional connectivity in the DMN. In this study, we investigated whether bottom-up sensory processing could influence the default mode like network (DMLN) in rats. DMLN activity was examined using block-design visual functional magnetic resonance imaging (fMRI) while its synchronization was investigated by comparing functional connectivity during a resting versus a continuously stimulated brain state by unpredicted light flashes. We demonstrated that activity in DMLN regions was decreased during visual stimulus blocks and increased during blanks. Furthermore, decreased inter-network functional connectivity between the DMLN and visual networks as well as decreased intra-network functional connectivity within the DMLN was observed during the continuous visual stimulation. These results suggest that triggering of bottom-up attention mechanisms in anesthetized rats can lead to a cascade similar to top-down orienting of attention in humans and is able to deactivate and desynchronize the DMLN.

neuroscience↗

bioRxiv2018

Quasi-periodic patterns contribute to functional connectivity in the brain

Functional connectivity is widely used to study the coordination of activity between brain regions over time. Functional connectivity in the default mode and task positive networks is particularly important for normal brain function. However, the processes that give rise to functional connectivity in the brain are not fully understood. It has been postulated that low-frequency neural activity plays a key role in establishing the functional architecture of the brain. Quasi-periodic patterns (QPPs) are a reliably observable form of low-frequency neural activity that involve the default mode and task positive networks. Here, QPPs from resting-state and working memory task-performing individuals were acquired. The spatiotemporal pattern, strength, and frequency of the QPPs between the two groups were compared and the contribution of QPPs to functional connectivity in the brain was measured. In task-performing individuals, the spatiotemporal pattern of the QPP changes, particularly in task-relevant regions, and the QPP tends to occur with greater strength and frequency. Differences in the QPPs between the two groups could partially account for the variance in functional connectivity between resting-state and task-performing individuals. The QPPs contribute strongly to connectivity in the default mode and task positive networks and to the strength of anti-correlation seen between the two networks. Many of the connections affected by QPPs are also disrupted during several neurological disorders. These findings contribute to understanding the dynamic neural processes that give rise to functional connectivity in the brain and how they may be disrupted during disease.\n\nHighlightsO_LIQuasi-periodic patterns (QPPs) of low-frequency activity contribute to functional connectivity\nC_LIO_LIThe spatiotemporal pattern of QPPs differs between resting-state and task-performing individuals\nC_LIO_LIQPPs account for significant functional connectivity in the DMN and TPN during rest and task performance\nC_LIO_LIChanges in functional connectivity in these networks may reflect differences in QPPs\nC_LI

neuroscience↗