Thermolysin activation mutants with changes in the fusogenic region of an influenza virus hemagglutinin

Orlich, Michaela; Rott, R.

doi:10.1128/jvi.68.11.7537-7539.1994

Cited by 19 publications

(8 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, even single amino acid exchanges within viral proteins can alter the virulence and tropism of the respective viruses (34,51,52). This was shown with influenza A virus where a single amino acid exchange within the viral hemagglutinin-glycoprotein altered the antigenicity, the cell tropism and the pathogenetic property of the mutant (35). In the present study, no evidence for antigenic variation between BDV-ob and BDV-bi was found using the monoclonal BDV-antibody Bo18 specific for the putative nucleoprotein p38.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Borna Disease Virus in the Brain of Rats Infected with an Obesity‐inducing Virus Strain

et al. 2000

View full text Add to dashboard Cite

Experimental infection of Lewis rats with Borna disease virus (BDV), a nonsegmented, single-stranded RNA virus, usually causes an immune-mediated biphasic neurobehavioral disorder. Such animals develop a persistent infection of the CNS with viral antigen expression in all brain regions and a disseminated nonpurulent meningoencephalitis. Interestingly, intracerebral infection of Lewis rats with a BDV-variant (BDV-ob) causes a rapid increase of body weight with the development of an obesitysyndrome without obvious neurological signs. The obese phenotype is correlated with a characteristic distribution of inflammatory lesions and BDV-antigen in the rat brain. Infiltration with mononuclear immune cells and viral antigen expression are restricted to the septum, hippocampus, amygdala and ventromedian tuberal hypothalamus. Therefore, infection with the obesity-inducing BDV-ob results most likely in neuroendocrine dysregulations leading to the development of an obesity syndrome. This might be due to the restriction of viral antigen expression and inflammatory lesions to brain areas which are involved in the regulation of body weight and food intake. The BDV-induced obesity syndrome represents a model for the study of immune-mediated neuroendocrine disorders caused by viral infections of the CNS.

show abstract

Section: Discussionmentioning

confidence: 99%

Distribution of Borna Disease Virus in the Brain of Rats Infected with an Obesity‐inducing Virus Strain

et al. 2000

View full text Add to dashboard Cite

show abstract

“…The HA 2 NH 2 -terminal fusion peptide domain is the most highly conserved region in the HA. However, it is clear, particularly from site-specific mutagenesis experiments (8,34) and mutant selection studies (5,22), that a number of residues in this region can be substituted without a loss of fusion activity (Table 8). There appear to be two molecular requirements for the biological activity of fusion peptides.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Sendai virus is much less efficient as a fusogen than influenza virus (37), and these differences may be related to differences in the structures that their fusion peptides assume or the precise way in which they interact with membranes. It is also possible that differences in fusion rate or efficiency may account for the observation that HA mutants dependent on cleavage by thermolysin are infectious (22). The recent studies of Orlich and Rott (22) clearly show that HA mutants of A/Seal/Mass/80 virus (H7 subtype) with fusion peptide NH 2 -terminal sequences LFLG, LILG, and LLLG and in which the length of the fusion peptides has been maintained by leucine insertion are viable when cleaved by thermolysin.…”

Section: Discussionmentioning

confidence: 99%

“…These cleavages fail to activate infectivity and indicate a requirement for specific HA 0 cleavage. Together with observations of the structure and properties of the NH 2 terminus of HA 2 derived from mutant selection (5,22) and of site-specific mutagenesis (8,34), protein chemical studies (24), and direct analyses of the membrane fusion properties of analogous synthetic peptides (18,21,36), they have contributed to the designation of this region as the fusion peptide. Conserved hydrophobic NH 2terminal fusion peptides have been identified in the fusogenic glycoproteins of a number of enveloped viruses.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Studies of the membrane fusion activities of fusion peptide mutants of influenza virus hemagglutinin

Steinhauer¹,

Wharton²,

Skehel³

et al. 1995

J Virol

160

View full text Add to dashboard Cite

Influenza virus hemagglutinin (HA) fuses membranes at endosomal pH by a process which involves extrusion of the NH 2-terminal region of HA 2 , the fusion peptide, from its buried location in the native trimer. We have examined the amino acid sequence requirements for a functional fusion peptide by determining the fusion capacities of site-specific mutant HAs expressed by using vaccinia virus recombinants and of synthetic peptide analogs of the mutant fusion peptides. The results indicate that for efficient fusion, alanine can to some extent substitute for the NH 2-terminal glycine of the wild-type fusion peptide but that serine, histidine, leucine, isoleucine, or phenylalanine cannot. In addition, mutants containing shorter fusion peptides as a result of single amino acid deletions are inactive, as is a mutant containing an alanine instead of a glycine at HA 2 residue 8. Substitution of the glycine at HA 2 residue 4 with an alanine increases the pH of fusion, and valine-for-glutamate substitutions at HA 2 residues 11 and 15 are without effect. We confirm previous reports on the need for specific HA 0 cleavage to generate functional HAs, and we show that both inappropriately cleaved HA and mutant HAs, irrespective of their fusion capacities, upon incubation at low pH undergo the structural transition required for fusion.

show abstract

“…In most cases, influenza viruses overcome the tropism restrictions by mutating the HA cleavage site to utilize other unconventional proteases for activation without interacting with other pathogens (Orlich, Linder, and Rott, 1995;Orlich and Rott, 1994). For instance, WSN, the neurovirulent mouse-adapted strain of influenza, gains its tropism in brain tissue by alteration of HA cleavability by using plasmin (Sun et al, 2010).…”

Section: Author Manuscriptmentioning

confidence: 99%

Modification of the hemagglutinin cleavage site allows indirect activation of avian influenza virus H9N2 by bacterial staphylokinase

Tse

Whittaker

2015

Virology

View full text Add to dashboard Cite

Influenza H9N2 is considered to be a low pathogenicity avian influenza (LPAI) virus that commonly infects avian species and can also infect humans. In 1996, the influenza virus, A/chicken/Korea/MS96-CE6/1996/H9N2 (MS96) was isolated from an outbreak in multiple farms in South Korea that resulted in upwards of 30% mortality in infected chickens, with the virus infecting a number of extrapulmonary tissues, indicating internal spread. However, in experimental infections, complete recovery of specific pathogen free (SPF) chickens occurred. Such a discrepancy indicated an alternative pathway for MS96 virus to gain virulence in farmed chickens. A key determinant of influenza pathogenesis is the susceptibility of the viral hemagglutinin (HA) to proteolytic cleavage/activation. Here, we identified that an amino acid substitution, Ser to Tyr found at the P2 position of the MS96 HA cleavage site optimizes cleavage by the protease plasmin (Pm). Importantly, we identified that certain Staphylococcus sp. are able to cleave and activate MS96 HA by activating plasminogen (Plg) to plasmin by use of a virulence factor, staphylokinase. Overall, these studies provide an in-vitro mechanism for bacterially mediated enhancement of influenza activation, and allow insight into the microbiological mechanisms underlying the avian influenza H9N2 outbreak in Korea in1996.

show abstract

Thermolysin activation mutants with changes in the fusogenic region of an influenza virus hemagglutinin

Cited by 19 publications

References 18 publications

Distribution of Borna Disease Virus in the Brain of Rats Infected with an Obesity‐inducing Virus Strain

Distribution of Borna Disease Virus in the Brain of Rats Infected with an Obesity‐inducing Virus Strain

Studies of the membrane fusion activities of fusion peptide mutants of influenza virus hemagglutinin

Modification of the hemagglutinin cleavage site allows indirect activation of avian influenza virus H9N2 by bacterial staphylokinase

Contact Info

Product

Resources

About