The roles of microglia in viral encephalitis: from sensome to therapeutic targeting

Chhatbar, Chintan; Prinz, Marco

doi:10.1038/s41423-020-00620-5

Cited by 73 publications

(85 citation statements)

References 97 publications

(108 reference statements)

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“…Here, we report that cell-dependent factors determine RABV tropism: the simple presence of glial cells in co-cultures as well as the transfer of supernatant from glial cells influences Tha tropism (Fig 2). Additionally, the presence of hiMicros reduces the profound neurotropism of Tha-eGFP (Fig 3B ), suggesting a role in microglial-induced communication with neighbouring cells and phagocytosis of debris from infected neurons which was previously shown to be critical in inhibiting viral spread in the CNS (37). Possible underlying mechanisms comprise glial-mediated signalling directly via cell-to-cell contacts or via the secretion of inflammatory proteins (Fig 2 and 3), the induction of inflammatory genes (Fig 4) as well as the induction of cell type-specific inflammatory proteins (Fig 5) which can induce secondary signalling cascades in surrounding cells.…”

Section: Discussionmentioning

confidence: 67%

Cell-type specific innate immune responses shape rabies virus tropism

Feige

Kozaki

Melo

et al. 2021

Preprint

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Viral tropism, or the specificity of a particular virus to infect a certain cell type, is crucial in determining virus replication, viral spread, and ultimately host survival. Rabies, one of the deadliest known zoonotic diseases, is still causing 60.000 human deaths annually. Upon central nervous system (CNS) entry, neurotropic rabies virus (RABV) preserves the neural network by limiting apoptosis and inflammation. To date, we do not fully understand the factors determining RABV tropism and why glial cells are unable to clear RABV from the infected brain. Here, we compare susceptibilities and innate immune responses of CNS cell types towards infection with virulent dog RABV Tha and less virulent Th2P-4M in vitro , highlighting differences in cellular susceptibility and antiviral responses. Less virulent Th2P-4M bears mutations introduced in viral phosphoprotein (P-protein) and matrix protein (M-protein) thereby hindering viral immune evasion of the host nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Janus kinase (JAK) - signal transducer and activator of transcription protein (STAT) pathways. Our results reveal that human neural stem cell (hNSC)-derived neurons and astrocytes, in contrast to human iPSC-derived microglia, are highly susceptible to Tha and Th2P-4M infection in vitro . Surprisingly, Th2P-4M presents a stronger neurotropism in hNSC-derived CNS cultures compared to Tha suggesting that NF-κB- and JAK-STAT-mediated antiviral host responses are defining RABV replication and thereby its tropism. Further, we show that astrocyte-like (SVGp12) and microglia-like (HMC3) cells protect neuroblastoma cells (SK-N-SH) from Tha infection in vitro . Transcription profiles and quantification of intracellular protein levels revealed major differences in antiviral immune responses mediated by neurons, astrocytes ( IFN B1 , CCL5 , CXCL10 , IL1 B , IL6 , LIF ), and microglia ( CCL5 , CXCL10 , ISG15 , MX1 , IL6 ) upon virulent Tha infection. Overall, we provide evidence that RABV tropism depends on its capability to evade cell-type specific immune responses via P- and M-proteins.

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Section: Discussionmentioning

confidence: 67%

Cell-type specific innate immune responses shape rabies virus tropism

Feige

Kozaki

Melo

et al. 2021

Preprint

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“…On the contrary, when the activity of these cells is prolonged, overproduction of proinflammatory cytokines may exacerbate neuroinflammation and promote neurodegenerative effects. The main function played by activated microglia is the phagocytosis of invading viruses [ 61 ], bacteria and potentially neurotoxic molecules, ranging from misfolded peptides to cell debris and whole apoptotic neurons. According to the main functional path of active macrophages, this clearance process can be summarized by three sequential steps: (i) the “find me” step that involves migration of microglia towards the target; (ii) the “eat me” step that refers to the phagocytic process; (iii) the “digest me” step that consists of the degradation of the engulfed cargo.…”

Section: Microgliamentioning

confidence: 99%

Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale

Nosi

Lana

Giovannini

et al. 2021

Cells

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Different cell populations in the nervous tissue establish numerous, heterotypic interactions and perform specific, frequently intersecting activities devoted to the maintenance of homeostasis. Microglia and astrocytes, respectively the immune and the “housekeeper” cells of nervous tissue, play a key role in neurodegenerative diseases. Alterations of tissue homeostasis trigger neuroinflammation, a collective dynamic response of glial cells. Reactive astrocytes and microglia express various functional phenotypes, ranging from anti-inflammatory to pro-inflammatory. Chronic neuroinflammation is characterized by a gradual shift of astroglial and microglial phenotypes from anti-inflammatory to pro-inflammatory, switching their activities from cytoprotective to cytotoxic. In this scenario, the different cell populations reciprocally modulate their phenotypes through intense, reverberating signaling. Current evidence suggests that heterotypic interactions are links in an intricate network of mutual influences and interdependencies connecting all cell types in the nervous system. In this view, activation, modulation, as well as outcomes of neuroinflammation, should be ascribed to the nervous tissue as a whole. While the need remains of identifying further links in this network, a step back to rethink our view of neuroinflammation in the light of the “whole system” scale, could help us to understand some of its most controversial and puzzling features.

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“…During development, microglia populate the CNS and establish a long-lived cell pool [81]. This cell type possesses an abundance of specific proteins referred to as the sensome, that enable microglia to efficiently respond to neurotropic viruses and other microbes that invade the CNS, rendering them essential in protection against viral encephalitis [82]. Early in vitro analyses of HCMV infection of enriched microglia cell cultures reported opposing results on HCMV's ability to infect this cell type (Table 1) [72,74,83,84].…”

Section: Cytomegalovirus Infection Of Neurons and Glial Cellsmentioning

confidence: 99%

Cytomegalovirus Infection and Inflammation in Developing Brain

Krstanović

Britt

Jonjić

et al. 2021

Viruses

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Human cytomegalovirus (HCMV) is a highly prevalent herpesvirus that can cause severe disease in immunocompromised individuals and immunologically immature fetuses and newborns. Most infected newborns are able to resolve the infection without developing sequelae. However, in severe cases, congenital HCMV infection can result in life-threatening pathologies and permanent damage of organ systems that possess a low regenerative capacity. Despite the severity of the problem, HCMV infection of the central nervous system (CNS) remains inadequately characterized to date. Cytomegaloviruses (CMVs) show strict species specificity, limiting the use of HCMV in experimental animals. Infection following intraperitoneal administration of mouse cytomegalovirus (MCMV) into newborn mice efficiently recapitulates many aspects of congenital HCMV infection in CNS. Upon entering the CNS, CMV targets all resident brain cells, consequently leading to the development of widespread histopathology and inflammation. Effector functions from both resident cells and infiltrating immune cells efficiently resolve acute MCMV infection in the CNS. However, host-mediated inflammatory factors can also mediate the development of immunopathologies during CMV infection of the brain. Here, we provide an overview of the cytomegalovirus infection in the brain, local immune response to infection, and mechanisms leading to CNS sequelae.

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The roles of microglia in viral encephalitis: from sensome to therapeutic targeting

Cited by 73 publications

References 97 publications

Cell-type specific innate immune responses shape rabies virus tropism

Cell-type specific innate immune responses shape rabies virus tropism

Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale

Cytomegalovirus Infection and Inflammation in Developing Brain

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