Measles Virus-Induced Immunosuppression

Expression of the measles virus (MV) F/H complex on the surface of viral particles, infected cells, or cells transfected to express these proteins (presenter cells [PC]) is necessary and sufficient to induce proliferative arrest in both human and rodent lymphoid cells (responder cells [RC]). This inhibition was found to occur independent of apoptosis and soluble mediators excluded by a pore size filter of 200 nm released from either PC or RC. We now show that reactive oxygen intermediates which might be released by RC or PC also do not contribute to MV-induced immunosuppression in vitro. Using an inhibitor of Golgi-resident mannosidases (deoxymannojirimycin), we found that complex glycosylation of the F and H proteins is not required for the induction of proliferative arrest of RC. As revealed by our previous studies, proteolytic cleavage of the MV F protein precursor into its F1 and F2 subunits, but not of F/H-mediated cellular fusion, was found to be required, since fusion-inhibitory peptides such as Z-D-Phe-L-Phe-Gly (Z-fFG) did not interfere with the induction of proliferative inhibition. We now show that Z-fFG inhibits cellular fusion at the stage of hemifusion by preventing lipid mixing of the outer membrane layer. These results provide strong evidence for a receptormediated signal elicited by the MV F/H complex which can be uncoupled from its fusogenic activity is required for the induction of proliferative arrest of human lymphocytes.In the course of acute measles, an efficient virus-specific immune response is generated which leads to viral clearance from the peripheral blood and the establishment of lifelong immunity to reinfection. Paradoxically, measles virus (MV) also causes a marked suppression of the host's immune responses that accounts for high susceptibility to opportunistic infections; that is the major reason for the high rates of measles-related morbidity and mortality worldwide (7). It is a key finding in MV-induced immunosuppression that peripheral blood lymphocytes (PBL) isolated during and for weeks after acute measles largely fail to proliferate in response to mitogenic, allogenic, and recall antigen stimulation (5, 33). Although MV infects cells of the lymphoid/monocytic lineage and induces cell cycle arrest in these cells (21)(22)(23)40), the frequency of infected peripheral blood mononuclear cells (PBMC) is usually low at any stage of the disease. This indicates that the general failure of lymphocytes to response to mitogenic stimulation is not likely to result from directly infection-dependent cell loss or cell cycle arrest. Thus, independent mechanisms such as the release of inhibitory soluble mediators from infected PBMC (12, 36) or surface contactmediated negative signaling between MV glycoproteins and cellular receptor molecules have been suggested. These include MV H-protein-mediated downregulation of CD46 from the surface of uninfected cells or downregulation of interleukin-12 release from uninfected monocytes following CD46 cross-linking by MV or CD46 ligation by specific ant...

Section: Generation Of Reactive Oxygen Intermediates Is Not Involved mentioning

confidence: 99%

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confidence: 99%

Measles Virus-Induced Immunosuppression In Vitro Is Independent of Complex Glycosylation of Viral Glycoproteins and of Hemifusion

Weidmann

Fischer

Ohgimoto

et al. 2000

“…orbilliviruses, including measles virus (MeV), which infects humans and certain nonhuman primates, and the carnivore morbillivirus canine distemper virus (CDV), cause a severe acute disease characterized by rash, fever, and respiratory and gastrointestinal symptoms, followed by generalized immunosuppression (1)(2)(3). This rapid and profound immunosuppression facilitates secondary infections, which make important contributions to morbillivirus-associated morbidity and mortality (4,5).…”

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confidence: 99%

Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets

Svitek

Gerhauser

Gonçalves

et al. 2014

The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus Morbillivirus interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties. IMPORTANCEThe V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors. M orbilliviruses, including measles virus (MeV), which infects humans and certain nonhuman primates, and the carnivore morbillivirus canine distemper virus (CDV), cause a severe acute disease characterized by rash, fever, and respiratory and gastrointestinal symptoms, followed by generalized immunosuppression (1-3). This rapid and profound immunosuppression facilitates secondary infections, which make important contributions to morbillivirus-associated morbidity and mortality (4, 5). The morbillivirus V protein is the primary viral immune interference protein, targeting the innate host response at multiple levels (6-8). The V-protein mRNA is transcribed from the phosphoprotein (P) gene by insertion of a nontemplated guanosine at an editing site located in the middle of the gene (9, 10). Consequently, V shares i...

“…It is still a major cause of death in children of developing countries, mainly due to opportunistic secondary infections facilitated by MV-induced immune suppression (12,29). Transient but severe immune suppression is explained at least in part by the rapid spread of MV infection in immune cells (6,37,41).…”

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confidence: 99%

Measles Virus Selectively Blind to Signaling Lymphocytic Activation Molecule (SLAM; CD150) Is Attenuated and Induces Strong Adaptive Immune Responses in Rhesus Monkeys

Léonard

Hodge

Valle

et al. 2010

The signaling lymphocytic activation molecule (SLAM; CD150) is the immune cell receptor for measles virus (MV). To assess the importance of the SLAM-MV interactions for virus spread and pathogenesis, we generated a wild-type IC-B MV selectively unable to recognize human SLAM (SLAM-blind). This virus differs from the fully virulent wild-type IC-B strain by a single arginine-to-alanine substitution at amino acid 533 of the attachment protein hemagglutinin and infects cells through SLAM about 40 times less efficiently than the isogenic wild-type strain. Ex vivo, this virus infects primary lymphocytes at low levels regardless of SLAM expression. When a group of six rhesus monkeys (Macaca mulatta) was inoculated intranasally with the SLAM-blind virus, no clinical symptoms were documented. Only one monkey had low-level viremia early after infection, whereas all the hosts in the control group had high viremia levels. Despite minimal, if any, viremia, all six hosts generated neutralizing antibody titers close to those of the control monkeys while MV-directed cellular immunity reached levels at least as high as in wild-type-infected monkeys. These findings prove formally that efficient SLAM recognition is necessary for MV virulence and pathogenesis. They also suggest that the selectively SLAM-blind wild-type MV can be developed into a vaccine vector.Measles virus (MV) is an enveloped virus with a negativesense RNA genome (2). It is still a major cause of death in children of developing countries, mainly due to opportunistic secondary infections facilitated by MV-induced immune suppression (12, 29). Transient but severe immune suppression is explained at least in part by the rapid spread of MV infection in immune cells (6,37,41). MV targets immune cells through its hemagglutinin (H) that binds cellular receptors and triggers the other glycoprotein F to fuse cellular membranes (22).Two MV receptors have been identified. The first one was the membrane cofactor protein (MCP; CD46), a ubiquitously expressed regulator of complement activation sustaining infection by the MV vaccine strain (8, 21) but not by wild-type (WT) strains (24). Wild-type MV strains, as well as the vaccine strain, enter cells through the signaling lymphocytic activation molecule (SLAM; CD150) (10,15,35). SLAM is an immune cellspecific protein expressed on the surface of thymocytes, activated lymphocytes, mature dendritic cells, and activated macrophages (4, 31). The existence of another receptor on cells derived from human lung and bladder epithelium has been inferred (18,33). While this epithelial receptor (EpR) has not been identified yet, it appears to be a basolateral protein expressed by cells forming tight junctions (18).We are characterizing the mechanisms by which MV spreads in its host and the pathogenic consequences of the interactions with different receptors. We previously showed that an MV unable to recognize EpR remains virulent in rhesus monkeys but cannot cross the epithelium and is not shed (18). This result is consistent with the model ...