CNS infection and immune privilege

Forrester, John V.; McMenamin, Paul G.; Dando, Samantha J.

doi:10.1038/s41583-018-0070-8

Cited by 209 publications

(197 citation statements)

References 238 publications

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“…Furthermore, SARS-CoV has been shown to infiltrate the brain via the olfactory epithelium-olfactory bulb axis 127 ; olfactory transmission for SARS-CoV-2 has been recently proposed 128 . Other possible transmission routes could be through the infection of ACE2 + TMPRSS2 + enteric neurons synapsing with vagal afferents, or entry through blood-CNS interfaces such as the choroid plexus or meninges 121,[129][130][131] . Profiling immune cells at these sites after infection is an important future step to better understand how the viral response may lead to encephalitis.…”

Section: Discussionmentioning

confidence: 99%

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Muus

Luecken

Eraslan

et al. 2020

Preprint

245

326

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The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Muus

Luecken

Eraslan

et al. 2020

Preprint

245

326

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“…The central nervous system is an immune-privileged site, which is due to the presence of the blood-brain barrier (BBB) comprised of endothelial cells, pericytes, and astrocytes. This barrier restricts the entry of cells and microorganisms [82]. A study showed that penetration of the BBB by pathogenic T H 17 cells in a multiple sclerosis mouse model depended on RANKL signaling; T H 17 cells expressing RANKL interact with RANK-expressing astrocytes, which in turn secrete C-C motif chemokine ligand 20 (CCL20), further attracting C-C motif chemokine receptor 6 (CCR6)-expressing cells into the central nervous system (CNS) ( Fig.…”

Section: Inflammation In the Central Nervous Systemmentioning

confidence: 99%

RANKL biology: bone metabolism, the immune system, and beyond

et al. 2020

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Receptor activator of NF-κB (RANK) ligand (RANKL) induces the differentiation of monocyte/macrophage-lineage cells into the bone-resorbing cells called osteoclasts. Because abnormalities in RANKL, its signaling receptor RANK, or decoy receptor osteoprotegerin (OPG) lead to bone diseases such as osteopetrosis, the RANKL/RANK/OPG system is essential for bone resorption. RANKL was first discovered as a T cell-derived activator of dendritic cells (DCs) and has many functions in the immune system, including organogenesis, cellular development. The essentiality of RANKL in the bone and the immune systems lies at the root of the field of "osteoimmunology." Furthermore, this cytokine functions beyond the domains of bone metabolism and the immune system, e.g., mammary gland and hair follicle formation, body temperature regulation, muscle metabolism, and tumor development. In this review, we will summarize the current understanding of the functions of the RANKL/RANK/ OPG system in biological processes.

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“…This is known as the Trojan horse route. Although the brain has been considered a site of immune-privilege, it has an active immune surveillance system that involves the recruitment of non-specific leukocytes such as phagocytes and lymphocytes into the meninges and cerebrospinal fluid (CSF) (Forrester et al, 2018). Indeed, it has been shown that the CSF contains a trafficking population of mononuclear…”

Section: Cns Invasionmentioning

confidence: 99%

Enterovirus and Encephalitis

Chen

Lee

et al. 2020

Front. Microbiol.

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Enterovirus-induced infection of the central nervous system (CNS) results in acute inflammation of the brain (encephalitis) and constitutes a significant global burden to human health. These viruses are thought to be highly cytolytic, therefore normal brain function could be greatly compromised following enteroviral infection of the CNS. A further layer of complexity is added by evidence showing that some enteroviruses may establish a persistent infection within the CNS and eventually lead to pathogenesis of certain neurodegenerative disorders. Interestingly, enterovirus encephalitis is particularly common among young children, suggesting a potential causal link between the development of the neuroimmune system and enteroviral neuroinvasion. Although the CNS involvement in enterovirus infections is a relatively rare complication, it represents a serious underlying cause of mortality. Here we review a selection of enteroviruses that infect the CNS and discuss recent advances in the characterization of these enteroviruses with regard to their routes of CNS infection, tropism, virulence, and immune responses.

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CNS infection and immune privilege

Cited by 209 publications

References 238 publications

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

RANKL biology: bone metabolism, the immune system, and beyond

Enterovirus and Encephalitis

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