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.

Previous work on hepatitis C virus (HCV) led to the discovery of a new form of virus particle associating virus and lipoprotein elements. These hybrid particles (LVP for lipo-viro-particles) are enriched in triglycerides and contain at least apolipoprotein B (apoB), HCV RNA and core protein. These findings suggest that LVP synthesis could occur in liver and intestine, the two main organs specialized in the production of apoB-containing lipoprotein. To identify the site of LVP production, the genetic diversity and phylogenetic relationship of HCV quasispecies from purified LVP, whole serum and liver biopsies from chronically infected patients were studied. HCV quasispecies from LVP and liver differed significantly, suggesting that LVP were not predominantly synthesized in the liver but might also originate in the intestine. The authors therefore searched for the presence of HCV in the small intestine. Paraffin-embedded intestinal biopsies from 10 chronically HCV-infected patients and from 12 HCV RNA-negative controls (10 anti-HCV antibody-negative and two anti-HCV antibody-positive patients) were tested for HCV protein expression. HCV NS3 and NS5A proteins were stained in small intestine epithelial cells in four of the 10 chronically infected patients, and not in controls. Cells expressing HCV proteins were apoB-producing enterocytes but not mucus-secreting cells. These data indicate that the small intestine can be infected by HCV, and identify this organ as a potential reservoir and replication site. This further emphasizes the interaction between lipoprotein metabolism and HCV, and offers new insights into hepatitis C infection and pathophysiology. INTRODUCTIONHepatitis C virus (HCV) infects over 170 million people worldwide and is a major cause of chronic liver infection, often leading to chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV possesses a single-stranded, positivesense RNA genome encoding a single polyprotein, and the virus has been classified in the family Flaviviridae with the flaviviruses and pestiviruses (Pringle, 1999). Although the flaviviruses infect many tissues in a large number of hosts from insects to primates, and replicate in numerous cell lines in vitro, HCV replication is extremely limited and occurs mainly in the human liver (Hoofnagle, 2002;Rice, 1996). Studies on the virus replication and biology have been hampered by the lack of an efficient and reliable cell culture system, and because chimpanzee is the only animal model. HCV may be envisioned as a flavivirus whose replication relies on specific cellular functions present in specific organs such as the liver. A recent report on replication of HCV subgenomic replicons, without production of virus particles, in non-hepatic epithelial human and mouse hepatoma cells indicates that the specific cellular factors required for translation and replication of HCV RNA are not restricted to hepatocytes or cells of human origin (Zhu et al., 2003). Therefore, the apparent tropism of HCV for hepatocytes is probably also determi...

A chimeric fusion protein encompassing the CD46 ectodomain linked to the C-terminal part of the C4b binding protein (C4bp) ␣ chain (sCD46-C4bp␣) was produced in eukaryotic cells. This protein, secreted as a disulfide-linked homo-octamer, was recognized by a panel of anti-CD46 antibodies with varying avidities. Unlike monomeric sCD46, the octameric sCD46-C4bp␣ protein was devoid of complement regulatory activity. However, sCD46-C4bp␣ was able to bind to the measles virus hemagglutinin protein expressed on murine cells with a higher avidity than soluble monomeric sCD46. Moreover, the octameric sCD46-C4bp␣ protein was significantly more efficient than monomeric sCD46 in inhibiting virus binding to CD46, in blocking virus induced cell-cell fusion, and in neutralizing measles virus in vitro. In addition, the octameric sCD46-C4bp␣ protein, but not the monomeric sCD46, fully protected CD46 transgenic mice against a lethal intracranial measles virus challenge.

Measles virus (MV) infection causes acute childhood disease, associated in certain cases with infection of the central nervous system (CNS) and development of neurological disease.To develop a murine model of MV-induced pathology, we generated several lines of transgenic mice ubiquitously expressing as the MV receptor a human CD46 molecule with either a Cyt1 or Cyt2 cytoplasmic tail. All transgenic lines expressed CD46 protein in the brain. Newborn transgenic mice, in contrast to nontransgenic controls, were highly sensitive to intracerebral infection by the MV Edmonston strain. Signs of clinical illness (lack of mobility, tremors, and weight loss) appeared within 5 to 7 days after infection, followed by seizures, paralysis, and death of the infected animals. Virus replication was detected in neurons from infected mice, and virus was reproducibly isolated from transgenic brain tissue. MV-induced apoptosis observed in different brain regions preceded the death of infected animals. Similar results were obtained with mice expressing either a Cyt1 or Cyt2 cytoplasmic tail, demonstrating the ability of different isoforms of CD46 to function as MV receptors in vivo. In addition, maternally transferred immunity delayed death of offspring given a lethal dose of MV. These results document a novel CD46 transgenic murine model where MV neuronal infection is associated with the production of infectious virus, similarly to progressive infectious measles encephalitis seen in immunocompromised patients, and provide a new means to study pathogenesis of MV infection in the CNS.Measles virus (MV) infection is one of the leading causes of infant death in developing countries, and sporadic outbreaks of acute measles still occur in industrialized countries despite vaccination (52). This virus causes acute respiratory infection in children, which can be followed in certain cases by invasion of the central nervous system (CNS) and development of three different forms of measles encephalitis (27). Acute postinfectious encephalomyelitis occurs during or shortly after acute measles and is characterized by perivascular inflammation in the brain and demyelinization. Virus replication cannot be detected in the brains of affected patients, and this encephalitis seems to be associated with autoimmune pathogenesis. In contrast to acute encephalitis, subacute sclerosing panencephalitis (SSPE) presents a late complication of measles, with an incubation time of 1 to 10 years. It is based on the persistent MV infection of brain cells, where virus has been found to be only cell associated, presenting numerous mutations in its genome (10). This fatal disease occurs in the presence of a competent immune response and is followed by general destruction of the brain tissue, causing a progressive dementia, seizures, and ataxia. The third form of MV-induced CNS disease, progressive infectious encephalitis (also known as a measles inclusion body encephalitis) occurs in immunosuppressed patients 1 to 6 months following measles infection. Seizures, motor and...