Pattern recognition via Toll-like receptors (TLR) by antigen-presenting cells is an important element of innate immunity. We report that wild-type measles virus but not vaccine strains activate cells via both human and murine TLR2, and this is a property of the hemagglutinin (H) protein. The ability to activate cells via TLR2 by wild-type MV H protein is abolished by mutation of a single amino acid, asparagine at position 481 to tyrosine, as is found in attenuated strains, which is important for interaction with CD46, the receptor for these strains. TLR2 activation by MV wild-type H protein stimulates induction of proinflammatory cytokines such as interleukin-6 (IL-6) in human monocytic cells and surface expression of CD150, the receptor for all MV strains. Confirming the specificity of this interaction, wild-type H protein did not induce IL-6 release in macrophages from TLR2 ؊/؊ mice. Thus, the unique property of MV wild-type strains to activate TLR2-dependent signals might essentially contribute not only to immune activation but also to viral spread and pathogenicity by upregulating the MV receptor on monocytes.In the course of acute measles, an efficient virus-specific immune response is generated which mediates viral clearance from the host and confers protection against reinfection. Paradoxically, a general immunosuppression is also induced favoring secondary infections, which are the major reason for the annual high morbidity and mortality rates associated with measles. The magnitude and duration of immune activation and immune suppression differ between natural or experimental infection and vaccination (20,60). Studies addressing measles virus (MV)-induced immune suppression mainly have focused on alterations of T-cell functions and viability as a consequence of direct MV infection or contact-mediated signaling (53). In vitro observations suggest that MV infection also enhances apoptosis of monocytes and dendritic cells (DC) and affects their antigen-presenting capacity and cytokine release (31, 53). MV interaction with DC and monocytes is, however, also associated with their maturation or activation, respectively, and thus is important for induction of virus-specific immune responses (32,39,45,54,56). Strains expressing an MV wildtype-derived hemagglutinin (H) protein reveal a particular tropism for DC and are more efficient in inducing both DC maturation and immunosuppression (32,48,54). The mechanisms by which MV leads to these functional alterations are largely unknown. Downregulation of interleukin-12 (IL-12) production in monocytes was linked to MV-or antibody-mediated cross-linking of CD46, the receptor for certain MV strains (29). Lymphotropic MV wild-type strains and clinical isolates, with few known exceptions (43), fail to interact with CD46 but require CD150 for cell entry (15,26,49,59). This molecule is absent from unstimulated monocytes and immature DC (33,45,48), and it is thus unknown how infection of these cells by CD150-dependent MV strains occurs.Mammalian Toll-like receptors (TLRs) wer...

Measles virus (MV) interacts

Identification and quantification of complement regulator CD46 on normal human tissues. Immunology 79, 341-347.

No abstract

The measles virus (MV) hemagglutinin binds to the complement control protein (CCP) CD46 primarily through the two external modules, CCP-I and -II. To define the residues involved in binding, 40 amino acids predicted to be solvent-exposed on the CCP-I-II module surface were changed to either alanine or serine. Altered proteins were expressed on the cell surface, and their abilities to bind purified MV particles, a soluble form of hemagglutinin (sH) and nine CD46-specific antibodies competing to different levels with sH attachment, were measured. All proteins retained, at least in part, MV and sH binding, but some completely lost binding to certain antibodies. Amino acids essential for binding of antibodies weakly or moderately competing with sH attachment are situated in the membrane-distal tip of CCP-I, whereas residues involved in binding of strongly sH competing antibodies cluster in the center of CCP-I (Arg-25, Asp-27) or in CCP-II (Arg-69, Asp-70). Both clusters face the same side of CCP-I-II and map close to amino acid exchanges impairing sH binding (E11A, R29A, P39A, and D70A) or MV binding (D70A and E84A) and to a six-amino acid loop, previously shown to be necessary for sH binding.