Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

Abstract

Cytomegalovirus (CMV) is considered the most common infectious agent causing permanent neurological dysfunction in the developing brain. We have previously shown that CMV infects developing brain cells more easily than it infects mature brain cells and that this preference is independent of the host B-and T-cell responses. In the present study, we examined the innate antiviral defenses against mouse (m) and human ( Cytomegalovirus (CMV), a double-stranded DNA virus of the betaherpesvirus family, is considered the most common infectious agent that causes permanent neurological dysfunction of the developing brain (2, 62). Human CMV (hCMV) infections in the developing brain can lead to mental retardation, epilepsy, microcephaly, microgyria, hydrocephalus, and deafness (4, 21, 37). The developing brain is particularly sensitive to CMV infection (6,29,54,55,58) due to both the immature state of the systemic immune system and a preference of CMV for developing glia and neurons (61). CMV in the mature brain is less of a concern, except in immunocompromised individuals (22,23,32).Outside the brain, interferon (IFN) has been reported to limit some CMV infections (27,30,66). A number of reports have suggested that brain cells differ from cells of other organs relative to innate and systemic antiviral immune responses. The brain has some characteristics of an immunologically privileged region. For instance, although most cells outside the brain express major histocompatibility complex (MHC) class I molecules, neurons in the brain either do not express MHC class I or do so at a substantially reduced level (45). This may be beneficial due to the fact that neurons do not replicate, and so a vigorous attack by the immune system on virally infected postmitotic neurons may cause more problems than the virus itself. In the brain, functional receptors for IFN-␥ are expressed in all cells, but they are expressed at different levels, and actions of IFN-␣/␤ on microglia, astrocytes, and neurons have also been described (12,13,31,43). Most cells, including astrocytes and microglia, are able to produce IFN-␣/␤ as an initial nonspecific immune response against virus infection (52, 64); IFN-␥ is released by activated T lymphocytes as part of the specific immune response. The intrinsic IFN system provides the first line of defense against viral infections, including systemic CMV infections, and can delay viral replication allowing the activation of the systemic adaptive immune responses.One explanation for the increased pathogenesis in the developing brain compared to that in the mature brain is that the systemic immune system is too immature during development to fight CMV infection. T and B lymphocytes of the adaptive immune system, as well as other cells of the systemic immune system, including natural killer cells and macrophages/monocytes, are involved in combating CMV infections (2,5,8,9,10,20,46,49), and the efficacies of these systems increase with development. Another mechanism that might underlie the susceptibility of developing...

Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

“…Both CMV infection and cytolysis were prevented in astrocytes treated with PIC. These results are similar to those recently reported for adult astrocytes (81). The role of IDO in PIC (and IFN-␥)-induced anti-CMV activity was demonstrated by tryptophan supplementation, confirming previous results obtained with cytokine-stimulated human retinal epithelial cells (6).…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…Increased expression of a number of pro-inflammatory genes is readily observed in brains of MCMV-infected, newborn mice (IFN and IFNinducible genes, chemokine receptors genes). 28,69 These findings suggest a host inflammatory response in the developing CNS as a possible mechanism behind impaired brain morphogenesis. Likewise, CNS disease associated with inflammatory responses in the CNS has been described in newborn mice infected with non-lytic viruses such as murine leukemia virus or Borna disease virus.…”

“…25,56,74,75 MCMV infection of newborn mice brain following intracranial injection upregulates the expression of IFN-stimulated genes by 10-to 100-fold. 69 Induced IFNs substantially reduce the number of MCMV-infected cells in the CNS and prevent virus-mediated cell death. 69 Glial cells respond to CMV infections through a highly regulated network of cytokines and chemokines that orchestrate the subsequent immune response.…”

“…69 Induced IFNs substantially reduce the number of MCMV-infected cells in the CNS and prevent virus-mediated cell death. 69 Glial cells respond to CMV infections through a highly regulated network of cytokines and chemokines that orchestrate the subsequent immune response. 75 MCMV-infected astrocytes primarily produce the chemokine CCL2, and less so, CXCL8, CCL3 and CCL5, which recruit microglial cells to the sites of infection.…”

Interleukin-29 Functions Cooperatively with Interferon to Induce Antiviral Gene Expression and Inhibit Hepatitis C Virus Replication

“…Reverse transcription and quantitative real-time PCR were performed as previously described (31). Briefly, 1 g of total RNA was reverse transcribed using the TaqMan reverse transcription kit (Applied Biosystems, Foster City, CA) with random hexamers.…”