The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood–brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.

Rabies is caused by neurotropic rabies virus (RABV), contributing to 60,000 human deaths annually. Even though rabies leads to major public health concerns worldwide, we still do not fully understand factors determining RABV tropism and why glial cells are unable to clear RABV from the infected brain. Here, we compare susceptibilities and immune responses of CNS cell types to infection with two RABV strains, Tha and its attenuated variant Th2P-4M, mutated on phospho- (P-protein) and matrix protein (M-protein). We demonstrate that RABV replicates in human stem cell-derived neurons and astrocytes but fails to infect human iPSC-derived microglia. Additionally, we observed major differences in transcription profiles and quantification of intracellular protein levels between antiviral immune responses mediated by neurons, astrocytes (IFNB1, CCL5, CXCL10, IL1B, IL6, and LIF), and microglia (CCL5, CXCL10, ISG15, MX1, and IL6) upon Tha infection. We also show that P- and M-proteins of Tha mediate evasion of NF-κB- and JAK-STAT-controlled antiviral host responses in neuronal cell types in contrast to glial cells, potentially explaining the strong neuron-specific tropism of RABV. Further, Tha-infected astrocytes and microglia protect neurons from Tha infection via a filtrable and transferable agent. Overall, our study provides novel insights into RABV tropism, showing the interest in studying the interplay of CNS cell types during RABV infection.

Rabies virus (RABV), the causative agent for rabies disease is still presenting a major public health concern causing approximately 60,000 deaths annually. This neurotropic virus (genus Lyssavirus, family Rhabdoviridae) induces an acute and almost always fatal form of encephalomyelitis in humans. Despite the lethal consequences associated with clinical symptoms of rabies, RABV limits neuro-inflammation without causing major histopathological lesions in humans. Nevertheless, information about the mechanisms of infection and cellular response in the central nervous system (CNS) remain scarce. Here, we investigated the expression of inflammatory genes involved in immune response to RABV (dog-adapted strain Tha) in mice, the most common animal model used to study rabies. To better elucidate the pathophysiological mechanisms during natural RABV infection, we compared the inflammatory transcriptome profile observed at the late stage of infection in the mouse brain (cortex and brain stem/cerebellum) with the ortholog gene expression in post-mortem brain biopsies of rabid patients. Our data indicate that the inflammatory response associated with rabies is more pronounced in the murine brain compared to the human brain. In contrast to murine transcription profiles, we identified CXC motif chemokine ligand 16 (CXCL16) as the only significant differentially expressed gene in post-mortem brains of rabid patients. This result was confirmed in vitro, in which Tha suppressed interferon alpha (IFN-α)-induced CXCL16 expression in human CNS cell lines but induced CXCL16 expression in IFN-α-stimulated murine astrocytes. We hypothesize that RABV-induced modulation of the CXCL16 pathway in the brain possibly affects neurotransmission, natural killer (NK) and T cell recruitment and activation. Overall, we show species-specific differences in the inflammatory response of the brain, highlighted the importance of understanding the potential limitations of extrapolating data from animal models to humans.

Listeria monocytogenes can cause severe illness in individuals with weakened immune systems. In March 2023, L. monocytogenes was isolated from blood (n = 2) or pleural fluid (n = 1) of three febrile patients receiving synthetic glucocorticoids in a tertiary hospital in Germany. Food supply records suggested sliced parboiled sausage as the likely source, and L. monocytogenes was isolated from four samples of sealed packaged sliced sausages and ham from one manufacturer. The patient and food isolates clustered within 0–4 allelic differences. Counts of L. monocytogenes in all four food samples were < 100 colony-forming units (CFU)/g, a threshold in the European Union legislation for ready-to-eat products with specific conditions. Our findings, aligned with previous evidence, highlight that persons with weakened immune systems should not be exposed to L. monocytogenes in food. We advocate for a clear communication of deli meats as high-risk foods, so individuals with weakened immune systems can adjust their diet to reduce their risk for invasive listeriosis. We recommend an update of dietary and hygiene guidelines for care settings and private homes where food is prepared, handled and stored for persons with weakened immune systems.

Rôle des cellules gliales dans l'infection de la rage: La rage, l'une des zoonoses les plus mortelles connues, cause toujours 60 000 décès humains chaque année (Fooks et al., 2014). Dès son entrée dans le système nerveux central (SNC), le virus de la rage (RABV) préserve le réseau neuronal en limitant l'apoptose et l'inflammation (Baloul et Lafon, 2003). L'évasion immunitaire est médiée par les fonctions accessoires des protéines rabique, en particulier la protéine de matrice (protéine M) et la phosphoprotéine (protéine P) qui interfèrent avec la réponse antivirale médiée par la cellule hôte en modulant les voies NF-kB et JAK-STAT (Wiltzer et al., 2012, 2014 ; Lieu et al., 2013 ; Ben Khalifa et al., 2016 ; Besson et al., 2017). À ce jour, nous ne comprenons pas pleinement les facteurs déterminant le tropisme du RABV et pourquoi les cellules gliales sont incapables d'éliminer le virus du cerveau infecté. Le tropisme viral, ou la spécificité d'un virus particulier à infecter un certain type de cellules, est crucial pour déterminer la réplication du virus, la propagation virale et, finalement, la survie de l'hôte. Le tropisme cellulaire repose sur deux déterminants majeurs, l'expression des récepteurs d'entrée qui permettent l'entrée du virus et la réponse immunitaire cellulaire qui permet ou restreint la réplication virale (McFadden et al., 2009). Bien que classiquement qualifiée de strictement neurotrope, une publication récente a souligné la sensibilité des cellules gliales, en particulier des astrocytes et des cellules de Schwann, à l'infection par le RABV in vivo (Potratz, LM Zaeck, et al., 2020 ; Potratz, L. Zaeck, et al., 2020). Le RABV utilise plusieurs récepteurs pour pénétrer dans les cellules via l'endocytose médiée par la clathrine (Etessami et al., 2000 ; Le Blanc et al., 2005 ; Piccinotti, Kirchhausen et Whelan, 2013). Cependant, ces récepteurs largement exprimés ne sont pas essentiels pour l'entrée du RABV en soi (Dietzschold et al., 1985) remettant en cause un tropisme cellulaire marqué. Ainsi, l'objectif global de ce projet de recherche visait à étudier les susceptibilités et les réponses immunitaires innées des neurones et des cellules gliales au cours de l'infection par le RABV in vitro afin de comprendre leurs rôles respectifs et complémentaires au cours de la physiopathologie de la rage. Les réponses inflammatoires et le mécanisme antiviral ont été étudiés à l'aide de deux souches RABV: la souche Tha hautement pathogène pour le chien et la souche Th2P-4M moins virulente. Th2P-4M possède le même bagage fond génétique que Tha, à l'exception de six mutations introduites artificiellement dans les protéines virales P et M qui abolissent l'interférence impliquant les voies NF-kB et JAK-STAT (Sonthonnax et al., 2019). L'étude de la susceptibilité de différents types cellulaires a révélé que les neurones et les astrocytes dérivés des cellules souches neuronales étaient très sensibles à l'infection par Tha-eGFP et Th2P-4M-eGFP, tandis que la microglie dérivée d'iPSC n'était pas sensible à Tha-eGFP ni à Th2P-4M-eGFP in vitro. De plus, j'ai montré que la réponse immunitaire innée des cellules du SNC à l'infection par le RABV in vitro varie fortement selon le type de cellules étudié. Alors que les neurones activent peu de voies de signalisation antivirales pour restreindre l'infection par Tha, les astrocytes et la microglie montrent de fortes réponses immunitaires antivirales contre Tha. Outre le rôle des cellules gliales dans la restriction de la réplication du RABV, nous apportons la preuve que le neurotropisme du RABV ne dépend pas seulement de la structure de la protéine G du RABV (Mebatsion, Konig et Conzelmann, 1996 ; Etessami et al., 2000) ou de l'expression des récepteurs de surface au RABV (Lafon, 2005), mais aussi des fonctions accessoires des protéines virales P et M dans l'évasion immunitaire à médiation virale.