Neuro-inflammation and Neuro-infection

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Department of Cell Biology & Infection

Sandrine Etienne-Manneville - Astrocytic responses to inflammatory situations

Astrocytes form the majority of glial cells of the central nervous system. They play a key role in brain homeostasis, they serve as physical and nutritional support for neurons and directly participate in synaptic transmission. In inflammatory situations, such as those induced by infections, traumas, autoimmune and neurodegenerative diseases and cancer, astrocytes undergo a reaction called astrogliosis, which is often detrimental to neuroregeneration. Astrogliosis is associated with changes in cell shape and polarity, proliferation and migration together with changes in protein expression.

The Cell Polarity, Migration and Cancer group aim to identify the keys factors controlling astrogliosis to eventually limit this reaction. We have shown that GFAP a glial intermediate filament protein overexpressed during astrogliosis plays a crucial role in astrocyte polarization and migration. Modulating GFAP-mediated cell responses paves the way to new therapeutic strategy to modulate astrogliosis and its consequences in inflammatory situations.

In addition, we develop a project on Alexander disease, a leukodystrophy characterized by abnormal protein deposits known as Rosenthal fibers. This genetic disorder is caused by GFAP mutations which leads to the disorganization of the intermediate filament network. We investigate the consequence of these mutations on astrocyte behaviour during the disease. 

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Marc Lecuit - Pathophysiology of central nervous system infections, a bedside-to-bench approach

Microbes can reach the central nervous system (CNS) and/or its envelopes, leading to encephalitis and meningitis. CNS infections are associated with high morbidity, mortality and long-term sequelae. Yet the etiology of up to half of CNS infections remains unknown, and the mechanisms by which microbes reach, disseminate in and induce long-term damages to the CNS are far from fully understood. We study the model bacterium Listeria monocytogenes, which in Western countries is a leading cause of encephalitis, as well as neurotropic emerging viruses, including SARS-CoV-2. Our research integrates clinical data (large cohorts of adults and children with CNS infection, MONALISA and SEAe cohorts) and experimental approaches that combine microbiology, cell biology and immunology. We are in particular interested in identifying the microbial and host factors that account for microbial invasion of and dissemination within the CNS, and for host susceptibility to central nervous system infections.

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Department of Developmental & Stem Cell Biology

Jean-Pierre Levraud – Viral infection / Neuro-inflammation and central nervous system development

Our team studies the impact of viral infection and neuroinflammation on the developing central nervous system (CNS), using the zebrafish larva as a transparent model system.  

We image and model how neurotropic viruses (such as Sindbis virus) spread from periphery to the CNS and within the CNS, and how the host response, particularly mediated by type I interferons (IFN), counteracts this dissemination. We also want to establish which ones of the many IFN-stimulated genes are toxic to neural cells and which ones can be safely expressed in the CNS to prevent viral infection.

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Department of Immunology

Gérard Eberl - Chronic inflammation and neurodegeneration

This unit has demonstrated that the symbiotic microbiota sets the reactivity of the immune system early in life. If this ontogenic regulation fails, individuals develop increased susceptibility to inflammatory pathologies later in life, such as allergy, autoimmunity and cancer. The scientists are now assessing whether this early life education of the immune system by the symbiotic microbiota affects cognition, susceptibility to brain disorders and later life neurodegeneration, and how this pathogenic pathway can be reversed.

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Department of Neurosciences

Aleksandra Deczkowska - Neuro-immune communication throughout life

 It is now clear that immune cells play key roles in brain development, homeostasis and disease. Our goal is to dissect the mechanisms of immune-brain cross-talk in physiology and aging and create a strong foundation for future immunotherapy approaches to neurological disease. We specifically focus on the choroid plexus - a site from which circulating immune cells can remotely shape brain function, and microglia - the brain resident macrophages.  Our approach encompasses scRNA-seq and other technologies of genomics, classical tools of immunology, behavioral testing, and everything else that could help us identify the mechanisms of brain-immune communication. 

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Pierre-Marie Lledo - How experience and time shape brain circuits.

The Lledo laboratory has developed a multi-scale approach to understand the function and the plasticity of neuronal circuits involved in sensory perception, memory and mood control. In particular, researches are aimed at the interface between neuroscience and behavioral science to elucidate complex neural systems underlying behaviors. The team gathers neuroscientists, psychiatrists, and computational scientists to combine modern neurophysiological techniques —in vitro and in vivo awake electrophysiology, optogenetics, awake 2-photon imaging, deep-brain fiber photometry— with behavioral analysis (both human and mice) and theoretical modeling in order to monitor and manipulate neuronal circuits during behavior and in pathological contexts. The team has solid expertise in animal models and behavior, having developed a wide range of behavioral tests to evaluate sensory modalities, mood states, cognitive functions and social interactions. The scientists visualize the dynamic re-wiring of connections (triggered by adult neurogenesis) in mouse models to provide further insight for translational research into mood disorders or viral infections.

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Christine Petit (and the Hearing Institute) - Hearing and associated disorders, from mechanisms to treatment

Exploring the neuronal network functional connectivity of auditory central pathways and cortices, associated plasticity and multimodal sensory integration as well as how they are altered by hearing deficits of genetic and non-genetic origins including those present in schizophrenia and autism... Understanding the link between auditory impairment and dementia (Alzheimer), with prospects of prevention and curing. Noise-Induced Hearing Loss, the major environmental cause of hearing loss and presbycusis (age-related hearing impairment): development of corresponding biomarkers for multiparametric diagnosis (innovative audiometric tests, brain imaging, psychoacoustics, genomics, epigenomics, other biological markers with integration by Artificial Intelligence), rationalization of clinical trials (stratification of populations) for the testing candidate therapeutic agents and search for new therapeutic agents. Gene therapy for curing monogenic severe to profound deafness. The strategy is based on a continuous back and forth movement between patients and animal models. Collaborative works in perspective with the Immunology Department.

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Uwe Maskos - Nicotinic receptors and brain disease

This unit is studying nicotinic acetylcholine receptors (nAChRs) and the role of their human polymorphisms in a number of models like Alzheimer's disease, schizophrenia, and nicotine addiction. This team is specifically interested in "humanising" our models by the use of human induced pluripotent stem cells (hiPSC). 

Our "neuro-infection/inflammation" approaches aim at "humanizing" mouse models to express the uniquely human CHRFAM7A gene. It was shown that CHRFAM7A blocks ligand binding to both mouse and human α7 nAChR, and hypothesized that CHRFAM7A transgenic mice would allow to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the Systemic Inflammatory Response Syndrome that accompanies severe injury and sepsis. They found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. It was also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice, that also had increased immune cell mobilization, myeloid cell differentiation, and a shift from granulocytes to inflammatory monocytes in their inflamed lungs.  

Together, the findings point to a pathophysiological inflammatory consequence of the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate, that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7 nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, and potentially the onset of neurodegenerative and psychiatric disease. 

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Timothy Wai - Dysfunctional mitochondria in inherited neuromuscular diseases

The morphology of mitochondria is inextricably linked to its many essential functions in the cell and we are interested in understanding the relationship between mitochondrial shape changes and metabolism in the context of acquired and inborn human diseases. 

Balanced fusion and fission events shape mitochondria to meet metabolic demands and to ensure removal of damaged organelles. The dynamism of mitochondria is highlighted by the dramatic changes in morphology they undergo in response to metabolic inputs. Mitochondrial fragmentation occurs in response to nutrient excess and cellular dysfunction and has been observed in mitochondrial genetic diseases that are characterized by neuromuscular dysfunction in human patients.  We use genetic screens to identify factors novel regulators and modulators of mitochondrial morphology in cells from patients that suffer from mitochondrial genetic diseases and the lessons we are learning regarding the importance of balanced mitochondrial dynamics.  Through these approaches we seek to identify and understand the role of novel regulators of mitochondrial morphology and design strategies that capable of rebalancing mitochondrial dynamics in cellular and animal models of mitochondrial genetic disease.

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Department of Global Health

Hervé Bourhy - Deciphering the interplay between immunity and neural functions during viral encephalitis 

The research activities of our group focus on the understanding of the complex relationship between immunity and neural functions during rabies virus (RABV) infection, which should ultimately help to the comprehension of viral encephalitis physiopathology that could be shared with other neurotropic viruses. Our team holds a large experience in the production of recombinant and mutant RABV, in development of antiviral therapy, in animal models and in culturing primary neuronal and glial cells in different supports and devices in order to investigate host-rabies virus interaction. It also developed a strong expertise in studying the capacity of RABV to modulate the innate immune response during the early steps of infection. The most relevant objectives of our group are i) to decrypt the dynamics of cooperation between the different human brain cells (mainly neurons, astrocytes and microglial cells) during RABV infection; ii) to determine how the crosstalk between these cells, in particular glial cells and neurons, is correlated with the dysfunction of neurons, and iii) to decipher how RABV spread affects the neural network connectivity using mice models, organ on chip model, single cell sequencing, proteomics, high-throughput fluorescence microscopy and multielectrode arrays readouts on RABV-infected neural networks.

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Department of Virology

Monique Lafon - Pathology of viruses that target the nervous system

Research in the Viral NeuroImmunology Laboratory aims to establish the molecular basis for the pathogenicity of viruses that infect the nervous system, such as rabies virus. The team has discovered this virus has the intriguing property to promote the survival of the neurons it infects. Elucidation of the mechanisms of action and identification of the critical domain of the viral protein that controls survival have resulted in the development of a new drug candidate for the treatment of neurodegenerative diseases such as retina diseases or Amyotrophic Lateral Sclerosis (Charcot Disease).

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