Mechanism of Measles Virus–Induced Suppression of Inflammatory Immune Responses

Abstract

Measles virus (MV) causes profound immunosuppression, resulting in high infant mortality. The mechanisms are poorly understood, largely due to the lack of a suitable animal model. Here, we report that particular MV proteins, in the absence of MV replication, could generate a systemic immunosuppression in mice through two pathways: (1) via MV-nucleoprotein and its receptor FcgammaR on dendritic cells; and (2) via virus envelope glycoproteins and the MV-hemagglutinin cellular receptor, CD46. The effects comprise reduced hypersensitivity responses associated with impaired function of dendritic cells, decreased production of IL-12, and the loss of antigen-specific T cell proliferation. These results introduce a novel model for testing the immunosuppressive potential of anti-measles vaccines and reveal a specific mechanism of MV-induced modulation of inflammatory reactions.

The C-terminal Domain of the Measles Virus Nucleoprotein Is Intrinsically Disordered and Folds upon Binding to the C-terminal Moiety of the Phosphoprotein

“…The pattern of interactions of N TAIL is consistent with this hypothesis; N TAIL takes part in numerous interactions with different protein partners, including P (both within N°⅐P and N NUC ⅐P), the polymerase complex P⅐L, M (27), the interferon regulatory factor 3 (81), and possibly components of the cell cytoskeleton (76,77). Moreover, N TAIL within viral nucleocapsids released from infected cells also binds to the human immunoglobulin G receptor Fc␥RII, provoking partial immunosuppression (82,83). Finally, a conserved, hydrophobic patch at the extreme C terminus of Morbillivirus N TAIL has been described to bind to the heat-shock protein Hsp72, which modulates the level of viral RNA synthesis (25).…”

Tropism illuminated: Lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system

“…Moreover, MV interactions with the ubiquitous regulator of complement activation membrane cofactor protein (MCP, CD46) (7-10) have been documented. Not only receptor choice but also postentry host cell control and immune evasion mechanisms determine MV tropism (11)(12)(13).…”

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

“…As PI3K/ Akt pathway is one of the signaling pathways linked to CD150 engagement in lymphocytes 20,22 , we have assumed that MV may also trigger Akt in monocyte-derived human DCs. Our previous studies demonstrated that both infectious and UV-inactivated MV particles, in addition to the presence of viral envelope glycoproteins, contain an important quantity of free MV nucleoprotein, which can stimulate Fc receptor expressed on numerous cells, including DCs 34,35 . To be able to analyze DC-MV-H interaction in the absence of infectious context, we have generated CHO cell line stably expressing MV-H (CHO-H cells).…”

“…To be able to analyze DC-MV-H interaction in the absence of infectious context, we have generated CHO cell line stably expressing MV-H (CHO-H cells). This line allowed us to focus our study to the role of MV-H protein in the absence of other MV proteins, including fusion protein and nucleoprotein, both known to have biological activity [33][34][35] . Obtained CHO-H cell line stably expresses MV-H from the wt MV strain at the level comparable to MV-H expression on PBLs, infected with wt MV (Figure 1).…”