Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.
Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.
复制标题
对感染 MCMV 的新生小鼠进行糖皮质激素治疗可减轻中枢神经系统炎症并限制小脑发育缺陷。
DOI：
10.1371/journal.ppat.1003200
复制
发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Britt WJ
中科院分区：
文献类型：
--
作者：
Kosmac K;Bantug GR;Pugel EP;Cekinovic D;Jonjic S;Britt WJ
Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV. Intrauterine infection with human cytomegalovirus (HCMV) is a leading cause of developmental brain damage. In the U.S., an estimated 2,000 infants a year develop brain damage as a result of intrauterine infection with HCMV. In this study, we examined the contribution of host immune responses induced by CMV infection to abnormal development of the CNS by treating neonatal mice infected with MCMV with glucocorticoids. We found that glucocorticoid treatment of infected mice decreased the inflammatory response within the CNS without altering the level of virus replication. In addition, abnormalities in the structure of the cerebellum, as well as abnormalities in granule neuron precursor cell proliferation were normalized in MCMV infected mice following glucocorticoid treatment. These studies suggest that the host immune response to CMV infection is damaging to the developing CNS and that it may be possible to limit CNS disease by modulating inflammation. Moreover, understanding how inflammation and the immune response may alter the developmental program within the CNS could offer important insight into the mechanisms of disease leading to abnormal brain development following intrauterine infection.
登录
查看更多内容
DOI：
10.4049/jimmunol.181.3.2111
发表时间：
2008-08-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bantug GR;Cekinovic D;Bradford R;Koontz T;Jonjic S;Britt WJ
通讯作者：
Britt WJ
影响因子：
5.3
作者：
Aruga, J;Inoue, T;Mikoshiba, K
通讯作者：
Mikoshiba, K
影响因子：
5.3
作者：
Amankulor, Nduka M.;Hambardzumyan, Dolores;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
2.1
作者：
Bale, JF;Murph, JR
通讯作者：
Murph, JR
影响因子：
5.3
作者：
Choi, Y;Borghesani, PR;Segal, RA
通讯作者：
Segal, RA