engleski

Activation of macrophages/microglia during MCMV infection of the CNS

Congenital human cytomegalovirus (HCMV) infection is a leading infectious cause of long-term neurodevelopmental sequelae, including microcephaly, mental retardation and sensorineural hearing loss. The pathogenesis of the central nervous system (CNS) infection may arise as a result of direct damage of CMV-infected neurons or indirectly secondary to inflammatory response to infection. CMV infection of the CNS initiates the production of chemokines and proinflammatory cytokines, resulting in microglial activation and recruitment of systemic inflammatory cells to the CNS. The early cellular immune response is characterized by the efflux of innate immune constituents such as natural killer cells and macrophages. Depending on the tissue microenvironment, macrophages and microglia can acquire distinct functional phenotypes. Two well-established polarized phenotypes are often referred to as classically activated (M1) which have enhanced proinflammatory cytokine production, generate nitric oxide and participate in the elimination of intracellular pathogens, and alterna¬tively activated (M2) which participate in the blockade of inflammatory responses and in the promotion of tissue repair. To investigate the pathogenesis of congenital HCMV infection, we employed a newborn mouse model that recapitulates the major characteristics of CNS infection in human infants, including the route of neuroinvasion and neuropathological findings (Koontz et al., 2008). We showed that an M1 macrophage response is rapidly induced following MCMV infection of the CNS. At later time points post infection we observed phenotypic switch in brain macrophages. Macrophages isolated from brain at later time points express hallmarks of polarization toward an alternatively activated state. During MCMV infection of the CNS, microglia showed persistently activated phenotype and produced TNF-α. Chronic production of this proinflammatory mediator could have adverse effects on the brain, keeping it in a state of constant inflammation. Further studies to evaluate the effects of prolonged neuroimmune activation are necessary to determine its contribution to long-term neuropathological sequelae.

Congenital cytomegalovirus infection; microglia

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