PHIDIAS: Pathogen-Host Interaction Data Integration and Analysis System

Phinet Name: Measles virus
Phinet Information
Pathogen Name: Measles virus
Pathogen NIAID Category: Others
Bio-objects
Bio-object 1: Immune suppression and cell apoptosis
Type: Pathway or action Location: Cytoplasm Description: Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. The mechanisms which contribute to the loss of the allostimulatory function of dendritic cells (DC) include both virus release and active suppression mediated by Measles virus-infected DC. The carriage of Measles virus by DC may facilitate virus spreading to secondary lymphoid organs and virus replication in DC may play a central role in the general immune suppression observed during measles disease.Immune suppression during acute measles is a well-documented phenomenon in man. Measles virus-infected DC undergo apoptosis. So far, it is not clear whether apoptosis is an effect induced by Measles virus in particular in contrast to other viruses or whether apoptosis of thymocytes, activated T cells and DCs is a general regulatory mechanism of the immune response.(<a href="#reference5413">Grosjean et al., 1997</a>)(<a href="#reference5414">Niewiesk et al., 1999</a>)
Bio-object 2: Measles virus
Type: Microorganism or its component Location: Extracellular Description: The measles virus is a spherical, nonsegmented, single-stranded RNA virus in the Morbillivirus family. The entire genome of the Measles virus has been sequenced and is approximately 16,000 nucleotides long. It encodes six structural proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin (H) and polymerase (L). The P cistron also encodes three nonstructural proteins C, V, and R whose functions remain poorly defined. The genomic RNA, encapsidated by N, and associated with the two RNA polymerase sub-units L and P, forms the ribonucleoprotein (RNP) core of the virus. The H and F proteins, with M protein underlying the phospholipids bilayer, constitute the virus envelope.(<a href="#reference5385">Radecke et al., 1996</a>)(<a href="#reference5386">Liston et al., 1995</a>)(<a href="#reference5387">Horikami et al., 1995</a>)(<a href="#reference5388">Liston et al., 1995</a>)(<a href="#reference5389">Vincent et al., 1999</a>)
Bio-object 3: Nucleocapsid assembly
Type: Pathway or action Location: Cytoplasm Description: The many fine details of current view of nucleocapsid assembly remain to be understood.The assembly of nucleocapsid requires specific interactions of newly synthesized viral genomes with a subset of the viral structural proteins, the N, P, and L proteins, as well as interactions between each of these three proteins. The general model is that RNA encapsidation by N is a process coupled to genome replication. A complex between the P and L proteins replicates the parental genome and simultaneously as nascent genomes appear they are enwrapped by N donated from a complex of the N and P proteins. (PMID: 1321276).RNA encapsidation signals and or the RNA replication process itself are such factors whose role in nucleocapsid formation remains to be better defined.(<a href="#reference5402">Spehner et al., 1997</a>)(<a href="#reference5403">Horikami et al., 1992</a>)
Bio-object 4: The C and V proteins
Type: Protein or gene Location: Cytoplasm Description: The P gene of Measles virus encodes C (21 kd) and V (40 kd) proteins in edition to P. Both proteins interact with cellular proteins.The V protein is distributed in the cytoplasm of infected cells. The V protein effects N-P interaction (this may be dependent on its interaction with N protein) acting to balance accumulation of viral gene products.The C and V proteins play a role in regulation of transcription and replication, possibly by modulating the intracellular environment for replication.The P protein oligomerizes and binds to L, N proteins and RNA to form the replicative complex.(<a href="#reference5386">Liston et al., 1995</a>)(<a href="#reference5401">Tober et al., 1998</a>)(<a href="#reference5402">Spehner et al., 1997</a>)
Bio-object 5: The F protein. Viral envelope and host cell plasma membrane fusion
Type: Protein or gene Location: Bacterial membrane or virus envelope Description: The fusion F protein (glycoprotein, 60 kd) is F1 - F2 heterodimer that leads to insertion of the hydrophobic fusion domain into the target host cell membrane. Conformational changes then occur and the N terminus of the F1 subunit becomes anchored in the membrane of the host cell.The viral envelope then fuses with the plasma membrane of the host cell, allowing the virus to enter the cell.(<a href="#reference5392">Baker et al., 1999</a>)
Bio-object 6: The H and F proteins-synthesis/maturation
Type: Protein or gene Location: Cytoplasm Description: The H and F proteins are synthesized on membrane-bound ribosomes, mature through the endoplasmic reticulum and the Golgi, and become integral host plasma membrane proteins. The F protein is synthesized as an inactive precursor (F0) that is cleaved in the trans-Golgi network to form the biologically active protein consisting of the disulfide-linked subunits F1 and F2. The nucleocapsid is packaged into an envelope protein complex composed of the two integral membrane glycoproteins H and F and the inner-membrane-associated M protein. Final Measles virus assembly would occur at the plasma membrane just prior to the virus budding.(<a href="#reference5387">Horikami et al., 1995</a>)(<a href="#reference5405">Bolt et al., 1998</a>)
Bio-object 7: The H protein. Virus particle binding to the host cell membrane
Type: Protein or gene Location: Bacterial membrane or virus envelope Description: Infection of the host cells with Measles virus begins with attachment of the virus particles to receptors on surface of the host plasma membrane.The virus hemagglutinin H (glycoprotein, 78 kd) binds to the human CD46 receptor which is a disulfide-linked homodimer of several isoforms and which serves as a co-factor for serine protease degradation of C3b and C4b complement proteins, bringing about inhibition of complement activation on host cells.Interaction of the H protein with its cellular receptor CD150 triggers the conformational changes within the F protein.(<a href="#reference5390">Karp, 1999</a>)(<a href="#reference5391">Manchester et al., 1994</a>)
Bio-object 8: The L protein
Type: Protein or gene Location: Cytoplasm Function: Nucleic acid binding Description: The large L protein (200 kd) is a highly conserved and contains a motif common to the RNA polymerases of negative-strand viruses.The L protein is present in small quantities in the infected cell, interacts with and functions in association with P, and is part of the viral nucleocapsid in the cell.The N, P, and L proteins, in association with the RNA genome, form the transcriptional and replicative unit or ribonucleoparticle.(<a href="#reference5398">Sidhu et al., 1993</a>)(<a href="#reference5399">Stallcup et al., 1979</a>)(<a href="#reference5400">Vincent et al., 2000</a>)
Bio-object 9: The M protein
Type: Protein or gene Location: Cytoplasm Description: M viral protein (matrix protein, 38 kd) is synthesized on free cytoplasmic ribosomes.The M protein lines the inner surface of the host cell plasma membrane, from which the Measles virus lipid envelope will be derived during the budding process. The M protein appears to act by concentrating the F and H proteins, as well as the nucleocapsid, at the sites of virus assembly.(<a href="#reference5387">Horikami et al., 1995</a>)(<a href="#reference5404">Cathomen et al., 1998</a>)
Bio-object 10: The N protein
Type: Protein or gene Location: Nucleocapsid/Cytoplasm Function: Nucleic acid binding Description: The N protein (nucleoprotein, 60 kd), the most abundant of the viral proteins, is synthesized on free ribosome and folded in the host cytoplasm. Free N protein is phosphorylated on serine whereas nucleocapsid associated N is phosporelated on serine and threonine.N protein can be transported to the nucleus but is usually retained in the cytoplasm by binding to P protein.(<a href="#reference5394">Gombart et al., 1993</a>)(<a href="#reference5395">Gombart et al., 1995</a>)(<a href="#reference5396">Huber et al., 1991</a>)
Bio-object 11: The P protein
Type: Protein or gene Location: Cytoplasm Function: Unknown Description: The P protein (phosphoprotein, 72 kd) is activated by phosphorylation. Serine/threonine phosphorylation of P is carried out by cellular kinases, primarily casein kinase II.(<a href="#reference5397">Das et al., 1995</a>)
Bio-object 12: Viral RNA replication
Type: Pathway or action Location: Cytoplasm Description: The viral replication of the entire genome requires production of a full-length, positive-sense antigene as the template for synthesis of negative-sense genomic RNAs. Viral RNA replication then involves full length strand synthesis. Full length strand is coated with nucleocapsid proteins as they are made.(<a href="#reference5387">Horikami et al., 1995</a>)
Bio-object 13: Viral RNA transcription and translation
Type: Pathway or action Location: Cytoplasm Description: Fusion enables entry of the virus into the host cell. Once inside, the process of virus uncoating releases the RNA inside the host cell. The genome of Measles virus comprises a single-stranded RNA molecule of negative polarity. Viral mRNA is transcribed directly from the genomic RNA. The viral mRNA is then translated to produce viral proteins. Viral genes direct the production of proteins by the cellular machinery.(<a href="#reference5393">Parks et al., 2001</a>)
Bio-object 14: Virus particle assembly
Type: Pathway or action Location: Cytoplasm Description: The nucleocapsid assembly occurs in the cytoplasm and is then directed to the host plasma membrane, where it can contact the viral envelope protein complex.(<a href="#reference5402">Spehner et al., 1997</a>)
Bio-object 15: Virus particles escape the host cell by budding
Type: Pathway or action Location: Cell membrane Description: Expression of the H and F glycoproteins at the host cell surface is required for successful budding, which involves complex interactions between all viral proteins.The M protein appears to interact with the intracytoplasmic regions of H and F transmembrane glycoproteins, perhaps stabilizing or organizing the membrane environment in preparation for budding of virions.After intracellular assembly of these complexes, virus particles are released by budding out from the host cell membrane.Measles virus obtains its lipid envelope from the host cell plasma membrane during the budding process.The budding process of Measles virus is not fully understood and only little evidence is available.(<a href="#reference5404">Cathomen et al., 1998</a>)(<a href="#reference5406">Meertens et al., 2003</a>)(<a href="#reference5407">Cathomen et al., 1998</a>)(<a href="#reference5408">Pathak et al., 1990</a>)
Bio-object 16: Virus spread
Type: Pathway or action Location: Cell membrane Description: The two Measles virus surface H and F glycoproteins are abundantly expressed on the basolateral surface of epithelia. Both glycoproteins contain a tyrosine-based sorting signal in their cytoplasmic domains, which is required for basolateral protein expression and for the fusogenic activity of H and F complexes in host cells. The F and H proteins mediate virus spread from epithelia by direct cell-to-cell contacts and cell fusion.Measles virus disseminates to draining lymph nodes via infected macrophages and replicates in local lymphatic tissues followed by systemic spread of infection.(<a href="#reference5409">Maisner et al., 1998</a>)(<a href="#reference5410">Moll et al., 2001</a>)(<a href="#reference5411">Moench et al., 1988</a>)(<a href="#reference5412">Roscic-Mrkic et al., 2001</a>)
Interactions
Interaction 1: I1
Input Objects: Measles virus Output Objects: The H protein. Virus particle binding to the host cell membrane GO Evidence Code: Inferred from Direct Assay Description: Measles virus infection begins with binding of the virus particles to receptors on surface of the host plasma membrane. The two receptor molecules (CD46 and CD150 also known as SLAM - Signaling lymphocyte activation molecule) specifically bound to the H protein with distinct binding modes. The CD46 and CD150 recognize overlapping sites in H protein.(<a href="#reference5415">Santiago et al., 2002</a>)
Interaction 2: I2
Input Objects: The H protein. Virus particle binding to the host cell membrane Output Objects: The F protein. Viral envelope and host cell plasma membrane fusion GO Evidence Code: Inferred from Direct Assay Description: The Measles virus F protein is responsible for fusion of virus envelope and host cell membrane.(<a href="#reference5416">Plemper et al., 2004</a>)
Interaction 3: I3
Input Objects: The F protein. Viral envelope and host cell plasma membrane fusion Output Objects: Viral RNA transcription and translation GO Evidence Code: Inferred from Direct Assay Description: Measles virus particles penetrate into their host cells after fusing their envelope with the host plasma membrane and the process of virus uncoating releases the RNA. Viral genes begin to express leading to the synthesis of viral proteins.(<a href="#reference5393">Parks et al., 2001</a>)
Interaction 4: I4
Input Objects: Viral RNA transcription and translation Output Objects: The N protein GO Evidence Code: Inferred from Direct Assay Description: The N protein is synthesized and phosphorylated, and this modification appears to regulate its function.(<a href="#reference5394">Gombart et al., 1993</a>)
Interaction 5: I5
Input Objects: Viral RNA transcription and translation Output Objects: The P protein GO Evidence Code: Inferred from Direct Assay Description: The P protein is activated by phosphorylation and modulates assembly of nucleocapsid.(<a href="#reference5397">Das et al., 1995</a>)
Interaction 6: I6
Input Objects: Viral RNA transcription and translation Output Objects: The L protein GO Evidence Code: Inferred from Direct Assay Description: The large L protein interacts with N, P proteins and functions in association with RNA.(<a href="#reference5400">Vincent et al., 2000</a>)
Interaction 7: I7
Input Objects: The N protein, The P protein, The L protein Output Objects: Viral RNA replication GO Evidence Code: Inferred from Direct Assay Description: Viral RNA replication involves full length strand synthesis to be coated with nucleocapsid proteins.(<a href="#reference5386">Liston et al., 1995</a>)(<a href="#reference5402">Spehner et al., 1997</a>)
Interaction 8: I8
Input Objects: Viral RNA replication Output Objects: The C and V proteins GO Evidence Code: Inferred from Direct Assay Description: The C and V proteins are involved in regulation of RNA transcription and replication.(<a href="#reference5386">Liston et al., 1995</a>)
Interaction 9: I9
Input Objects: The C and V proteins, Viral RNA replication Output Objects: Nucleocapsid assembly GO Evidence Code: Inferred from Direct Assay Description: The nucleocapsid assembly requires interactions of the N, P, L proteins and RNA that is encapsidated by N donated from a complex of the N and P proteins.(<a href="#reference5402">Spehner et al., 1997</a>)
Interaction 10: I10
Input Objects: Nucleocapsid assembly Output Objects: Virus particle assembly GO Evidence Code: Inferred from Direct Assay Description: The nucleocapsid is directed to the host cell plasma membrane to contact the viral envelope proteins.(<a href="#reference5402">Spehner et al., 1997</a>)
Interaction 11: I11
Input Objects: Virus particle assembly Output Objects: The M protein GO Evidence Code: Inferred from Direct Assay Description: The M protein interacts with the intracytoplasmic regions of the viral envelope proteins H, F and the viral ribonucleoprotein complex.(<a href="#reference5404">Cathomen et al., 1998</a>)
Interaction 12: I12
Input Objects: Virus particle assembly Output Objects: The H and F proteins-synthesis/maturation GO Evidence Code: Inferred from Direct Assay Description: The H and F proteins are synthesized and mature in the endoplasmic reticulum and the Golgi apparatus and then the nucleocapsid is packaged into an envelope protein complex composed of the two glycoproteins H and F and the M protein. Virus assembly occurs just prior to the virus budding.(<a href="#reference5387">Horikami et al., 1995</a>)(<a href="#reference5405">Bolt et al., 1998</a>)
Interaction 13: I13
Input Objects: The M protein, Virus particle assembly, The H and F proteins-synthesis/maturation Output Objects: Virus particles escape the host cell by budding GO Evidence Code: Inferred from Direct Assay Description: The new Measles virus particles escape the host cells by budding process.(<a href="#reference5408">Pathak et al., 1990</a>)
Interaction 14: I14
Input Objects: Virus particles escape the host cell by budding Output Objects: Virus spread, Immune suppression and cell apoptosis GO Evidence Code: Inferred from Direct Assay Description: After person-to-person transmission by the respiratory route, the Measles virus spreads from the upper respiratory tract mucosa and lungs to lymphoid tissues, where replication occurs. Virus infection may result in immune suppression due to the apoptosis of dendritic cells and of the contacted T cells.(<a href="#reference5412">Roscic-Mrkic et al., 2001</a>)
Pathways

Phinet Name: Measles virus