Neuroinflammation and Neuroinfection*
Date/Time: Sunday, September 10, 2023 - 3:30 PM – 5:00 PM
Track: Cross-Cutting Special Interest Group (SIG)
Room: Franklin Hall 3 (4th Floor)
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Session Evaluation Form: https://myana.org/form/ana2023-session-evaluation-nn
Chair: Kiran Thakur, MD
Co-Chair: Felicia Chow, MD
The inflammatory response in the nervous systems plays a key role in the development and spread of infectious diseases in the nervous system. Animal and human based studies are providing critical insights into the interplay of infectious pathogens and the immune system. Here, we aim to understand the interactions between the invaders and the body’s defense mechanisms, the importance of the inflammatory response for the progression of diseases, and current developments of new forms of therapy for neuroimmunological diseases. Our session will address mechanistic insights in neuroinflammation in neuroinfectious diseases, and will highlight genetic host factors and pathogen specific factors in animal studies. We will highlight how these mechanistic insights inform human-based treatment studies, specifically highlighting clinical trials for novel treatments in progressive multifocal leukoencephalopathy. Our speakers are accomplished scientists leading the field of neuroinflammation and neuroinfection.
- Develop knowledge on mechanistic studies on neuroinflammation in Animal Models in Neuroinfectious Diseases
- To describe genetic factors associated with neuroinflammation and neuroinfectious diseases.
- Define ongoing clinical trials in neurological infections, including progressive multifocal leukoencephalopathy.
Leveraging Mechanistic Knowledge on Neuroinflammation in Treatment Trials for Progressive Multifocal Leukoencephalopathy
Speaker: Irene Cortese, MD
Progressive multifocal leukoencephalopathy (PML) was most widely known as an AIDS-defining illness until 2005 when the first cases of PML in natalizumab-treated multiple sclerosis shocked the MS community. PML results from reactivation of the ubiquitous human polyomavirus (JCV) in the setting of impaired cellular immunity. No antiviral therapies are available and survival depends on rapid reversal of immune suppression. In HIV and natalizumab-related PML, this can often be achieved readily; however for patients treated with cell-depleting biologicals and other modern regimens for cancer, organ transplantation and chronic inflammatory disease, immune competence can be difficult to restore. With the improvement of HIV care, today these iatrogenic cases represent a progressively larger proportion of PML, posing unique challenges for treatment. Emerging evidence supports use of novel immunotherapeutic approaches as a promising strategy for PML. Advancement of these will require improved understanding of JCV pathophysiology, PML disease course and mechanism of action of these therapeutics in order to optimize outcomes. To this end, establishment of collaborative research networks, engagement with regulatory agencies, and development of creative strategies to overcome barriers to patient participation in research will also be key.
Mechanistic Studies on Neuroinflammation in Animal Models of Neuroinfectious Diseases
Speaker: Robyn Klein, MD, PhD
Following acute SARS-CoV-2 infection (COVID-19), a majority of people recover within a few weeks; however, >50% of recovered individuals continue to experience neurological diseases, including severe memory disturbances, which is one form of post-acute sequelae of SARS-CoV-2 infection (neuroPASC). While there is little evidence of SARS-CoV-2 neuroinvasion, clinical studies report blood-brain barrier (BBB) disruption, and microglial activation in various brain regions upon post-mortem examination. We and others have linked mild disease with evidence of neuroinflammation in animal models of COVID-19. While pathological underpinnings of neuroPASC are not known, innate immunity essential for peripheral virologic control may contribute to ongoing inflammation long after SARS-CoV-2 is cleared. My lab has been developing models of post-infectious cognitive impairment for almost ten years. We have established behavioral, cellular and molecular approaches to examine virus-mediated impairments in learning and memory. These studies utilized transcriptional profiling in good and poor learners to identify genes and mechanisms associated with poor learning and Cre-Lox technology to interrogate identified mechanisms. We were the first to show that innate immune molecules, including classical complement proteins C1q and C3, IFNg and IL-1, expressed within the inflamed CNS led to persistent cognitive dysfunction without significant neuronal loss or ongoing apoptosis after recovery from infection with neurotropic RNA viruses. These studies focused on neural correlates of learning within the hippocampus, including synapses within the trisynaptic circuit between the entorhinal cortex and hippocampus, and adult neurogenesis within the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). In this presentation we will discuss results using a murine model of post-infectious cognitive impairment after infection of mice with SARS-CoV-2 (B.1.351 variant), which causes moderate pulmonary infection without neuroinvasion, similar that observed in human patients. These animals exhibit learning and memory impairments long after viral clearance in the periphery, disruption of hippocampal synapses and neurogenesis, and persistence of infiltrated myeloid cells within the CNS.
Genetics in Neuroinflammation and Neuroinfectious Diseases
Using case examples, this session will explore important genetic mimics of encephalitis, many of which are autoinflammatory diseases of the innate immune system, rather than the typical autoimmune paradigm in neuro-immunology. We will briefly review a tiered approach to clinical genomic testing options available. This session will highlight that early genetic testing in unusual or refractory cases of neuroinflammation or neuroinfectious diseases is crucial as it can inform novel treatment options.
Acute Neurological Inflammatory Diseases in Colombia during the COVID-19 Pandemic: A Multi-Center Observational Study
Oral Abstract Presenter: Susana Dominguez-Penuela, MD
Objective: To evaluate clinical, laboratory, and epidemiological features of acute neuroinflammatory disorders (ANIDs) during the COVID-19 pandemic in Colombia. Background: The Neuroinfections Emerging in the Americas Study (NEAS) network, was established in 2016 as a multicenter-based observatory of ANIDs to investigate the role of emerging infections as etiological factors in neuroinflammatory disorders. The NEAS Network is based in 10 hospitals across 7 cities in Colombia. Methods: We conducted a combined retrospective and prospective, longitudinal, cohort study of newly diagnosed patients (<30 days of symptom onset) who fulfilled established criteria for Guillain-Barre Syndrome (GBS), encephalitis, myelitis, meningoencephalitis, or cranial nerve disorders, of unknown etiology, accrued between January 2020 and December 2022. Results: 439 patients with ANIDs were recruited during the study period. 54.0% of cases were male and had a median age of 39 (IQR 21-58) years. The most common preceding events during the 4 weeks prior to the onset of neurological symptoms were upper respiratory tract infection (12.9%) and gastroenteritis (11.3%), although the majority of the population (70.3%) denied preceding events. The most frequent ANIDs were GBS (46.0%), facial nerve palsy (16.9%), and optic neuritis (10.5%). The diagnosis of encephalitis (7.6%), myelitis/encephalomyelitis (7.8%), and meningitis (3.4%) were less frequent. Patients with GBS were predominantly male (65.6%) and had a median age of 49 (IQR 25-63) years. Conclusions: ANIDs continued to present during the recent COVID-19 pandemic in Colombia. However, we did not observe a significant increase in the incidence of GBS or other ANIDs in our centers, as compared to the ZIKV epidemic (2015-2016) or endemic phase (2017-2019). SARS-CoV2 did not produce a significant impact in the incidence of ANIDs in Colombia.
Satellite Microglia Have a Role in Regulation of Neuronal Excitability and Change in Response to Injury
Oral Abstract Presenter: Amber Nolan, MD, PhD
Microglia, the primary mediators of innate immune activation in the brain, are increasingly recognized as key modulators of neuronal activity and excitability. There is growing evidence in many neurological diseases, including traumatic brain injury (TBI), that prolonged activation of the innate immune system can impede repair and promote disease, and it is not understood if or how microglia’s impact on neuronal activity might contribute. One interesting microglial subtype that may be critical in the monitoring and feedback of neuronal excitability is the perineuronal satellite microglia. These microglia are juxtaposed adjacent to neurons with their soma and processes entwined around the neuronal cell body. To understand how these microglia modify neuronal excitability and change their interactions with neurons after injury, we utilized patch clamp recordings, immunohistochemistry, light microscopy and confocal imaging. We found an increase in the numbers of satellite microglia in the orbitofrontal cortex in both a murine model of TBI that is associated with network hyperexcitability and behavioral dysfunction with deficits in reversal learning several moths after TBI, as well as human tissues from donors with a history of chronic TBI compared to sham and controls, respectively. Whole cell recordings in adult transgenic mice with GFP-labeled microglia (Tmem119-EGFP), utilized to record activity in neurons adjacent to and away from satellite microglia, also indicate that satellite microglia suppress neuronal excitability as measured by the action potential and firing frequency response to a series of depolarizing current steps. However, this effect is lost at chronic time points after TBI. These findings support continued investigation of satellite microglial response and neuronal interaction after chronic injury.
Cortical Microglia Heterogeneity in Remyelination and Aging
Oral Abstract Presenter: Hannah Loo, BS
We previously showed that regeneration of cortical oligodendrocytes following demyelination declines with cortical depth (Orthmann-Murphy et al eLife 2020). The mechanisms contributing to this depth-dependent effect remain unknown. Microglia, the innate immune cells of the brain, are a good candidate to mediate these differences in remyelination, as they play an important role in clearing myelin debris during demyelination. In the aging brain, microglia may contribute differently to remyelination, as they are less effective at clearing myelin debris. The goal of this study is to determine a) whether microglia adopt depth-dependent reactive states after demyelination that may contribute to impaired remyelination in deep cortex and b) whether these reactive states are altered in the aged brain. We administered cuprizone to young adult mice to induce oligodendrocyte death, followed by 2- and 5- weeks of recovery. Subsequently, cortical sections were stained with microglia-specific and reactive-state markers. We found that deep - but not superficial - cortical microglia upregulate activation marker CD68 and downregulate homeostatic marker P2RY12 in response to cuprizone treatment, indicating that deep cortical microglia lose homeostatic signatures and adopt an activated phenotype that persists through the early recovery period. Contrary to young adult mice, the timing of oligodendrocyte loss after cuprizone treatment was delayed in aged mice. In addition, aged microglia upregulated CD68 prior to treatment with cuprizone, suggesting aging itself may prime cortical microglia to adopt reactive phenotypes. To determine the role of deep cortical ‘activated’ microglia, young adult mice were treated with a CSF1R antagonist to deplete microglia during the post-cuprizone recovery period. We found that more oligodendrocytes are present in deep cortical regions when microglia are depleted compared to untreated young adult mice. This effect occurred during the early (2 weeks), but not late (5 weeks), post-cuprizone recovery period, and suggests an important role for microglia in early recovery. Together, our data indicate that in the young adult brain cortical microglia adopt spatially restricted responses to demyelination, and directly contribute to oligodendrocyte population density dynamics during the early recovery period. These dynamics are disrupted in the aging brain. Future studies will test how microglia alter oligodendrocyte population density in the early recovery period, as well as investigate how aging alters microglial function, leading to the delay in oligodendrocyte loss.