NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection.
Animals
Animals, Newborn
Brain
/ immunology
Chemokine CXCL10
/ genetics
Chemokine CXCL9
/ genetics
Cytomegalovirus
/ immunology
Cytomegalovirus Infections
/ immunology
Gene Expression Regulation
/ immunology
Humans
Immunity, Innate
/ immunology
Inflammation
/ genetics
Killer Cells, Natural
/ immunology
Lymphocytes
/ immunology
Mice, 129 Strain
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Microglia
/ immunology
Receptors, CXCR3
/ genetics
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
03 05 2021
03 05 2021
Historique:
received:
16
07
2020
revised:
11
12
2020
accepted:
29
01
2021
entrez:
25
2
2021
pubmed:
26
2
2021
medline:
5
10
2021
Statut:
ppublish
Résumé
Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti-IFN-γ antibodies.
Identifiants
pubmed: 33630019
pii: 211828
doi: 10.1084/jem.20201503
pmc: PMC7918636
pii:
doi:
Substances chimiques
Chemokine CXCL10
0
Chemokine CXCL9
0
Cxcr3 protein, mouse
0
Receptors, CXCR3
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDCD NIH HHS
ID : R01 DC015980
Pays : United States
Informations de copyright
© 2021 Kveštak et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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