Wild type measles virus attenuation independent of type I IFN.

BACKGROUND: Measles virus attenuation has been historically performed by adaptation to cell culture. The current dogma is that attenuated virus strains induce more type I IFN and are more resistant to IFN-induced protection than wild type (wt). RESULTS: The adaptation of a measles virus isolate (G954-PBL) by 13 passages in Vero cells induced a strong attenuation of this strain in vivo. The adapted virus (G954-V13) differs from its parental strain by only 5 amino acids (4 in P/V/C and 1 in the M gene). While a vaccine strain, Edmonston Zagreb, could replicate equally well in various primate cells, both G954 strains exhibited restriction to the specific cell type used initially for their propagation. Surprisingly, we observed that both G954 strains induced type I IFN, the wt strain inducing even more than the attenuated ones, particularly in human plasmacytoid Dendritic Cells. Type I IFN-induced protection from the infection of both G954 strains depended on the cell type analyzed, being less efficient in the cells used to grow the viral strain. CONCLUSION: Thus, mutations in M and P/V/C proteins can critically affect MV pathogenicity, cellular tropism and lead to virus attenuation without interfering with the alpha/beta IFN system.

Cellular receptors, differentiation and endocytosis requirements are key factors for type I IFN response by human epithelial, conventional and plasmacytoid dendritic infected cells by measles virus.

While the antiviral response during measles virus (MeV) infection is documented, the contribution of the hosting cell type to the type I interferon (IFN-alpha/beta) response is still not clearly established. Here, we report that a signature heterogeneity of the IFN-alpha/beta response according to the cell type. The MeV tropism dictated by the expression of appropriate cellular receptor appeared to be crucial for epithelial cells. For conventional DCs (cDCs), the maturation state played a prominent role. In response to both wild type MeV isolates and laboratory/vaccine strains, immature cDCs produced higher levels of IFN-alpha than mature cDCs, despite the reduced expression levels of both CD46 and CD150 receptors by the former ones. While in epithelial cells and cDCs the MeV transcription was required to activate the IFN-alpha/beta response, plasmacytoid DCs (pDCs) rapidly produced large amounts of IFN-alpha mostly independently of the viral infection cycle. This argues for a significant contribution of pDCs in response to MeV infection and/or vaccination.

Interplay between virus-specific effector response and Foxp3 regulatory T cells in measles virus immunopathogenesis.

Measles is a highly contagious childhood disease associated with an immunological paradox: although a strong virus-specific immune response results in virus clearance and the establishment of a life-long immunity, measles infection is followed by an acute and profound immunosuppression leading to an increased susceptibility to secondary infections and high infant mortality. In certain cases, measles is followed by fatal neurological complications. To elucidate measles immunopathology, we have analyzed the immune response to measles virus in mice transgenic for the measles virus receptor, human CD150. These animals are highly susceptible to intranasal infection with wild-type measles strains. Similarly to what has been observed in children with measles, infection of suckling transgenic mice leads to a robust activation of both T and B lymphocytes, generation of virus-specific cytotoxic T cells and antibody responses. Interestingly, Foxp3(+)CD25(+)CD4(+) regulatory T cells are highly enriched following infection, both in the periphery and in the brain, where the virus intensively replicates. Although specific anti-viral responses develop in spite of increased frequency of regulatory T cells, the capability of T lymphocytes to respond to virus-unrelated antigens was strongly suppressed. Infected adult CD150 transgenic mice crossed in an interferon receptor type I-deficient background develop generalized immunosuppression with an increased frequency of CD4(+)CD25(+)Foxp3(+) T cells and strong reduction of the hypersensitivity response. These results show that measles virus affects regulatory T-cell homeostasis and suggest that an interplay between virus-specific effector responses and regulatory T cells plays an important role in measles immunopathogenesis. A better understanding of the balance between measles-induced effector and regulatory T cells, both in the periphery and in the brain, may be of critical importance in the design of novel approaches for the prevention and treatment of measles pathology.

Immunosuppression caused by measles virus: role of viral proteins.

Measles virus (MV) causes transient but profound immunosuppression resulting in increased susceptibility to secondary bacterial and viral infections. Due to the development of these opportunistic infections, measles remains the leading vaccine-preventable cause of child death worldwide. Different immune abnormalities have been associated with measles, including disappearance of delayed-type hypersensitivity reactions, impaired lymphocyte and antigen-presenting cell functions, down-regulation of pro-inflammatory interleukin 12 production and altered interferon alpha/beta signalling pathways. Several MV proteins have been suggested to hinder immune functions: hemagglutinin, fusion protein, nucleoprotein and the non-structural V and C proteins. This review will focus on the novel functions attributed to MV proteins in the immunosuppression associated with measles. Here, we highlight new advances in the field, emphasising the interaction between MV proteins and their cellular targets, in particular the cell membrane receptors, CD46, CD150, TLR2 and FcgammaRII in the induction of immunological abnormalities associated with measles.