Organotypic modeling of SARS-CoV-2 lung and brainstem infection

Abstract SARS-CoV-2 has caused a global pandemic of Covid-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also lead to central nervous system infection and neurological sequelae. We developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer the unique opportunity to study the early steps of the pathogenesis and screening of antivirals. Using these models, we validated the early tropism of the virus in the lung and demonstrated that SARS-CoV2 can infect brainstem and cerebellum, mainly by targeting granular neurons. Viral infection induced specific interferon and innate immune responses with patterns specific to each organ along with apoptotic, necroptotic, and pyroptotic cell death. Overall, our data illustrate the potential of rapidly modeling complex tissue level interactions of viral infection in a newly emerged virus.

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Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection

Nature Communications ◽

10.1038/s41467-021-26096-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marion Ferren ◽

Valérie Favède ◽

Didier Decimo ◽

Mathieu Iampietro ◽

Nicole A. P. Lieberman ◽

...

Keyword(s):

Immune Responses ◽

Viral Infection ◽

Tissue Level ◽

Innate Immune ◽

Innate Immune Responses ◽

Organotypic Cultures ◽

Neurological Sequelae ◽

Global Pandemic ◽

Rapid Modeling ◽

The Brain

AbstractSARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also spread to central nervous system leading to neurological sequelae. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. However, they allow validating the early tropism of the virus in the lungs and demonstrating that SARS-CoV-2 could infect the brainstem and the cerebellum, mainly by targeting granular neurons. Viral infection induces specific interferon and innate immune responses with patterns specific to each organ, along with cell death by apoptosis, necroptosis, and pyroptosis. Overall, our data illustrate the potential of rapid modeling of complex tissue-level interactions during infection by a newly emerged virus.

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Th1 and Th17 Cells Regulate Innate Immune Responses and Bacterial Clearance during Central Nervous System Infection

The Journal of Immunology ◽

10.4049/jimmunol.1101660 ◽

2011 ◽

Vol 188 (3) ◽

pp. 1360-1370 ◽

Cited By ~ 31

Author(s):

Monica M. Holley ◽

Tammy Kielian

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune Responses ◽

Th17 Cells ◽

Central Nervous System Infection ◽

Innate Immune ◽

Bacterial Clearance ◽

Innate Immune Responses

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Viral Induction of Central Nervous System Innate Immune Responses

Journal of Virology ◽

10.1128/jvi.79.7.4369-4381.2005 ◽

2005 ◽

Vol 79 (7) ◽

pp. 4369-4381 ◽

Cited By ~ 34

Author(s):

J. D. Rempel ◽

L. A. Quina ◽

P. K. Blakely-Gonzales ◽

M. J. Buchmeier ◽

D. L. Gruol

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune Responses ◽

Viral Infection ◽

Hepatitis Virus ◽

Gene Array ◽

Innate Immune ◽

Cns Infection ◽

Innate Immune Responses ◽

Infected Cells

ABSTRACT The ability of the central nervous system (CNS) to generate innate immune responses was investigated in an in vitro model of CNS infection. Cultures containing CNS cells were infected with mouse hepatitis virus-JHM, which causes fatal encephalitis in mice. Immunostaining indicated that viral infection had a limited effect on culture characteristics, overall cell survival, or cell morphology at the early postinfection times studied. Results from Affymetrix gene array analysis, assessed on RNA isolated from virally and sham-infected cultures, were compared with parallel protein assays for cytokine, chemokine, and cell surface markers. Of the 126 transcripts found to be differentially expressed between viral and sham infections, the majority were related to immunological responses. Virally induced increases in interleukin-6 and tumor necrosis factor alpha mRNA and protein expression correlated with the genomic induction of acute-phase proteins. Genomic and protein analysis indicated that viral infection resulted in prominent expression of neutrophil and macrophage chemotactic proteins. In addition, mRNA expression of nonclassical class I molecules H2-T10, -T17, -M2, and -Q10, were enhanced three- to fivefold in virus-infected cells compared to sham-infected cells. Thus, upon infection, resident brain cells induced a breadth of innate immune responses that could be vital in directing the outcome of the infection and, in vivo, would provide signals which would summon the peripheral immune system to respond to the infection. Further understanding of how these innate responses participate in immune protection or immunopathology in the CNS will be critical in efforts to intervene in severe encephalitis.

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CXC Chemokine Ligand 10 Controls Viral Infection in the Central Nervous System: Evidence for a Role in Innate Immune Response through Recruitment and Activation of Natural Killer Cells

Journal of Virology ◽

10.1128/jvi.78.2.585-594.2004 ◽

2004 ◽

Vol 78 (2) ◽

pp. 585-594 ◽

Cited By ~ 68

Author(s):

Matthew J. Trifilo ◽

Cynthia Montalto-Morrison ◽

Linda N. Stiles ◽

Kelley R. Hurst ◽

Jenny L. Hardison ◽

...

Keyword(s):

Central Nervous System ◽

Immune Response ◽

Immune Responses ◽

Viral Infection ◽

Innate Immune ◽

Innate Immune Responses ◽

Cxc Chemokine ◽

Chemokine Ligand ◽

The Central Nervous System ◽

Coronavirus Infection

ABSTRACT How chemokines shape the immune response to viral infection of the central nervous system (CNS) has largely been considered within the context of recruitment and activation of antigen-specific lymphocytes. However, chemokines are expressed early following viral infection, suggesting an important role in coordinating innate immune responses. Herein, we evaluated the contributions of CXC chemokine ligand 10 (CXCL10) in promoting innate defense mechanisms following coronavirus infection of the CNS. Intracerebral infection of RAG1−/− mice with a recombinant CXCL10-expressing murine coronavirus (mouse hepatitis virus) resulted in protection from disease and increased survival that correlated with a significant increase in recruitment and activation of natural killer (NK) cells within the CNS. Accumulation of NK cells resulted in a reduction in viral titers that was dependent on gamma interferon secretion. These results indicate that CXCL10 expression plays a pivotal role in defense following coronavirus infection of the CNS by enhancing innate immune responses.

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