Open AccessNK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection
Author(s) -
Daria Kveštak,
Vanda Juranić Lisnić,
Berislav Lisnić,
Jelena Tomac,
Mijo Golemac,
Ilija Brizić,
Daniela Indenbirken,
Maja Cokarić Brdovčak,
Giovanni Bernardini,
Fran Krstanović,
Carmen Rožmanić,
Adam Grundhoff,
Astrid Krmpotić,
William J. Britt,
Stipan Jonjić
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201503
Subject(s) - immunology , neuroinflammation , cxcl10 , biology , chemokine , inflammation , microglia , cytomegalovirus , neuroimmunology , human cytomegalovirus , immune system , virus , herpesviridae , viral disease
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.