Single-Cell RNA Sequencing Reveals the Diversity of the Immunological Landscape following Central Nervous System Infection by a Murine Coronavirus

Syage, Amber R.; Ekiz, H. Atakan; Skinner, Dominic D; Stone, Colleen; O’Connell, Ryan M.; Lane, Thomas E.

doi:10.1128/jvi.01295-20

Cited by 22 publications

(29 citation statements)

References 79 publications

(117 reference statements)

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“…Elevated expression of transcripts encoding PD-1 ( Pdcd1 ) and CTLA-4 ( Ctla4 ), the corresponding T cell inhibitory receptors, was also observed in effector CD8 + subsets particularly in CD8-C7-Itgb1 (fig. S8C), which is consistent with previous research ( 21 ). These results might be due to the feedback mechanisms: (i) The released IFN-γ can trigger the inducible expression of PD-L1 and CTLA-4 ( 22 ); (ii) the proliferating subsets are more likely to express receptors PD-1 and CTLA-4 ( 23 ).…”

Section: Resultssupporting

confidence: 93%

Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

et al. 2021

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Section: Resultssupporting

confidence: 93%

Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

et al. 2021

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“…In addition, transcripts specific for the B cell chemoattractant CCL19 were also detected. The chemokine elicited in response to CNS infection of K18-hACE2 by SARS-CoV-2 infection is remarkably similar to the chemokine response following CNS infection of mice with the neuroadapted strains of murine coronaviruses ( 36 , 37 ). This is interesting in that murine coronavirus are primarily tropic for glial cells, e.g., astrocytes, microglia and oligodendrocytes with relative sparing of neurons while neurons appear to be exclusively targeted by SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 65%

“…We have recently determined that in response to JHMV infection of the CNS of immunocompetent mice, there are inflammatory monocyte/macrophage subpopulations that differentially express CD115/CSF-1R and this highlights the highly inflammatory nature of these cells in models of neurodegeneration ( 37 ). Expression of CD115-expressing macrophages and microglia have also been detected in other models of neuroinflammation demonstrating important roles for these cells in contributing to inflammatory responses ( 38 – 40 ).…”

Section: Discussionmentioning

confidence: 99%

Microglia Do Not Restrict SARS-CoV-2 Replication following Infection of the Central Nervous System of K18-Human ACE2 Transgenic Mice

Olivarria

Cheng

Furman

et al. 2022

J Virol

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Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine ( Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19 ) and cytokine ( Ifn-λ and Tnf-α ) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. Importance Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

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“…In addition, transcripts specific for the B cell chemoattractant CCL19 were also detected. The chemokine elicited in response to CNS infection of K18-hACE2 by SARS-CoV-2 infection is remarkably similar to the chemokine response following CNS infection of mice with the neuroadapted strains of murine coronaviruses [36, 37]. This is interesting in that murine coronavirus are primarily tropic for glial cells e.g.…”

Section: Discussionmentioning

confidence: 79%

Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

Olivarria

Cheng

Pachow

et al. 2021

Preprint

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Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease.ImportanceUnderstanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

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Single-Cell RNA Sequencing Reveals the Diversity of the Immunological Landscape following Central Nervous System Infection by a Murine Coronavirus

Cited by 22 publications

References 79 publications

Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

Microglia Do Not Restrict SARS-CoV-2 Replication following Infection of the Central Nervous System of K18-Human ACE2 Transgenic Mice

Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

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