scholarly journals The substantia nigra is a major target for neurovirulent influenza A virus.

1995 ◽  
Vol 181 (6) ◽  
pp. 2161-2169 ◽  
Author(s):  
M Takahashi ◽  
T Yamada ◽  
S Nakajima ◽  
K Nakajima ◽  
T Yamamoto ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Gene Segment ◽  
Positive Staining ◽  
Influenza A Viruses ◽  
Postencephalitic Parkinsonism ◽  
Causative Agents ◽  
Immunohistochemical Studies

Clinical and immunohistochemical studies were done for 3-39 d on mice after intracerebral inoculation with the neurovirulent A/WSN/33 (H1N1; WSN) strain of influenza A virus, the nonneurovirulent A/Aichi/2/68 (H3N2; Aichi) strain, and two reassortant viruses between them. The virus strains with the WSN gene segment coding for neuraminidase induced meningoencephalitis in mice. The mice inoculated with the R96 strain, which has only the neuraminidase gene from the WSN strain, had mild symptoms and weak positive immunostaining to the anti-WSN antibody in meningeal regions. Both the WSN and R404BP strains, which contain the WSN gene segments coding for neuraminidase and matrix protein, were clearly neurovirulent both clinically and pathologically. On day 3 after inoculation with either of these two strains, WSN antigen was detected in meningeal and ependymal areas, neurons of circumventricular regions, the cerebral and cerebellar cortices, the substantia nigra zona compacta, and the ventral tegmental area. On day 7, meningeal reactions and neuronal staining were still seen, and advanced accumulation of the viral antigen was evident in the substantia nigra zona compacta and hippocampus. Double immunostaining demonstrated that the WSN antigen was only seen in neurons and not in microglia or reactive astrocytes. Immunostaining for the lectin maackia amurensis agglutinin, which recognizes the Neu5Ac alpha 2,3 Gal sequence, which serves as a binding site for influenza A virus on target cell membranes, showed that positive staining was localized in the ventral substantia nigra and hippocampus. These results suggest that neurovirulent influenza A viruses could be one of the causative agents for postencephalitic parkinsonism.

scholarly journals Cooperation between the Hemagglutinin of Avian Viruses and the Matrix Protein of Human Influenza A Viruses

2002 ◽  
Vol 76 (4) ◽  
pp. 1781-1786 ◽  
Author(s):  
Christoph Scholtissek ◽  
Jürgen Stech ◽  
Scott Krauss ◽  
Robert G. Webster
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Gene Products ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
M Gene ◽  
Human Virus ◽  
Ha Gene ◽  
M Proteins

ABSTRACT To analyze the compatibility of avian influenza A virus hemagglutinins (HAs) and human influenza A virus matrix (M) proteins M1 and M2, we doubly infected Madin-Darby canine kidney cells with amantadine (1-aminoadamantane hydrochloride)-resistant human viruses and amantadine-sensitive avian strains. By using antisera against the human virus HAs and amantadine, we selected reassortants containing the human virus M gene and the avian virus HA gene. In our system, high virus yields and large, well-defined plaques indicated that the avian HAs and the human M gene products could cooperate effectively; low virus yields and small, turbid plaques indicated that cooperation was poor. The M gene products are among the primary components that determine the species specificities of influenza A viruses. Therefore, our system also indicated whether the avian HA genes effectively reassorted into the genome and replaced the HA gene of the prevailing human influenza A viruses. Most of the avian HAs that we tested efficiently cooperated with the M gene products of the early human A/PR/8/34 (H1N1) virus; however, the avian HAs did not effectively cooperate with the most recently isolated human virus that we tested, A/Nanchang/933/95 (H3N2). Cooperation between the avian HAs and the M proteins of the human A/Singapore/57 (H2N2) virus was moderate. These results suggest that the currently prevailing human influenza A viruses might have lost their ability to undergo antigenic shift and therefore are unable to form new pandemic viruses that contain an avian HA, a finding that is of great interest for pandemic planning.

scholarly journals Human Cytotoxic T-Lymphocyte Repertoire to Influenza A Viruses

1998 ◽  
Vol 72 (11) ◽  
pp. 8682-8689 ◽  
Author(s):  
Julie Jameson ◽  
John Cruz ◽  
Francis A. Ennis
Keyword(s):  
Cell Line ◽  
Influenza A Virus ◽  
Cell Lines ◽  
T Lymphocyte ◽  
Influenza A ◽  
Matrix Protein ◽  
Cytotoxic T Lymphocyte ◽  
Viral Proteins ◽  
Influenza A Viruses ◽  
Nonstructural Protein 1

ABSTRACT The murine CD8+ cytotoxic-T-lymphocyte (CTL) repertoire appears to be quite limited in response to influenza A viruses. The CTL responses to influenza A virus in humans were examined to determine if the CTL repertoire is also very limited. Bulk cultures revealed that a number of virus proteins were recognized in CTL assays. CTL lines were isolated from three donors for detailed study and found to be specific for epitopes on numerous influenza A viral proteins. Eight distinct CD8+ CTL lines were isolated from donor 1. The proteins recognized by these cell lines included the nucleoprotein (NP), matrix protein (M1), nonstructural protein 1 (NS1), polymerases (PB1 and PB2), and hemagglutinin (HA). Two CD4+ cell lines, one specific for neuraminidase (NA) and the other specific for M1, were also characterized. These CTL results were confirmed by precursor frequency analysis of peptide-specific gamma interferon-producing cells detected by ELISPOT. The epitopes recognized by 6 of these 10 cell lines have not been previously described; 8 of the 10 cell lines were cross-reactive to subtype H1N1, H2N2, and H3N2 viruses, 1 cell line was cross-reactive to subtypes H1N1 and H2N2, and 1 cell line was subtype H1N1 specific. A broad CTL repertoire was detected in the two other donors, and cell lines specific for the NP, NA, HA, M1, NS1, and M2 viral proteins were isolated. These findings indicate that the human memory CTL response to influenza A virus is broadly directed to epitopes on a wide variety of proteins, unlike the limited response observed following infection of mice.

scholarly journals Interaction of NS2 with AIMP2 Facilitates the Switch from Ubiquitination to SUMOylation of M1 in Influenza A Virus-Infected Cells

2014 ◽  
Vol 89 (1) ◽  
pp. 300-311 ◽  
Author(s):  
Shijuan Gao ◽  
Jiaoxiang Wu ◽  
Ran-Yi Liu ◽  
Jiandong Li ◽  
Liping Song ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A Virus ◽  
Nuclear Export ◽  
Influenza A ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Attachment Site ◽  
Influenza A Viruses ◽  
Screening Assay ◽  
Range Restriction

ABSTRACTInfluenza A viruses (IAVs) rely on host factors to support their life cycle, as viral proteins hijack or interact with cellular proteins to execute their functions. Identification and understanding of these factors would increase our knowledge of the molecular mechanisms manipulated by the viruses. In this study, we searched for novel binding partners of the influenza A virus NS2 protein, the nuclear export protein responsible for overcoming host range restriction, by a yeast two-hybrid screening assay and glutathioneS-transferase-pulldown and coimmunoprecipitation assays and identified AIMP2, a potent tumor suppressor that usually functions to regulate protein stability, as one of the major NS2-binding candidates. We found that the presence of NS2 protected AIMP2 from ubiquitin-mediated degradation in NS2-transfected cells and AIMP2 functioned as a positive regulator of IAV replication. Interestingly, AIMP2 had no significant effect on NS2 but enhanced the stability of the matrix protein M1. Further, we provide evidence that AIMP2 recruitment switches the modification of M1 from ubiquitination to SUMOylation, which occurs on the same attachment site (K242) on M1 and thereby promotes M1-mediated viral ribonucleoprotein complex nuclear export to increase viral replication. Collectively, our results reveal a new mechanism of AIMP2 mediation of influenza virus replication.IMPORTANCEAlthough the ubiquitination of M1 during IAV infection has been observed, the precise modification site and the molecular consequences of this modification remain obscure. Here, we demonstrate for the first time that ubiquitin and SUMO compete for the same lysine (K242) on M1 and the interaction of NS2 with AIMP2 facilitates the switch of the M1 modification from ubiquitination to SUMOylation, thus increasing viral replication.

scholarly journals Investigating Influenza A Virus Infection: Tools To Track Infection and Limit Tropism: TABLE 1

2015 ◽  
Vol 89 (12) ◽  
pp. 6167-6170 ◽  
Author(s):  
Jessica K. Fiege ◽  
Ryan A. Langlois
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Therapeutic Interventions ◽  
Microrna Target ◽  
Influenza A Viruses ◽  
Host Interactions ◽  
Target Sites ◽  
Recent Developments ◽  
Cellular Tropism ◽  
The Relationship

Influenza A viruses display a broad cellular tropism within the respiratory tracts of mammalian hosts. Uncovering the relationship between tropism and virus immunity, pathogenesis, and transmission will be critical for the development of therapeutic interventions. Here we discuss recent developments of several recombinant strains of influenza A virus. These viruses have inserted reporters to track tropism, microRNA target sites to restrict tropism, or barcodes to assess transmission dynamics, expanding our understanding of pathogen-host interactions.

scholarly journals Unexpected Functional Divergence of Bat Influenza Virus NS1 Proteins

2017 ◽  
Vol 92 (5) ◽  
Author(s):  
Hannah L. Turkington ◽  
Mindaugas Juozapaitis ◽  
Nikos Tsolakos ◽  
Eugenia Corrales-Aguilar ◽  
Martin Schwemmle ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Virulence Factor ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Functional Divergence ◽  
Protein A ◽  
Regulatory Subunit ◽  
Ns1 Protein ◽  
Influenza A Viruses ◽  
Hydrophobic Patch

ABSTRACT Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85β, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85β interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85β-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species-independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs. IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or pandemics. The recent discovery of influenza A-like viruses in bats has raised questions over whether these entities could be a threat to humans. Understanding unique properties of the newly described bat influenza A-like viruses, such as their mechanisms to infect cells or how they manipulate host functions, is critical to assess their likelihood of causing disease. Here, we characterized the bat influenza A-like virus NS1 protein, a key virulence factor, and found unexpected functional divergence of this protein from counterparts in other influenza A viruses. Our study dissects the molecular changes required by bat influenza A-like virus NS1 to adopt classical influenza A virus properties and suggests consequences of bat influenza A-like virus infection, potential future evolutionary trajectories, and intriguing virus-host biology in bat species.

scholarly journals Characterization of a Human H5N1 Influenza A Virus Isolated in 2003

2005 ◽  
Vol 79 (15) ◽  
pp. 9926-9932 ◽  
Author(s):  
Kyoko Shinya ◽  
Masato Hatta ◽  
Shinya Yamada ◽  
Ayato Takada ◽  
Shinji Watanabe ◽  
...  
Keyword(s):  
Hong Kong ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Mainland China ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
H5n1 Avian Influenza Virus ◽  
H5n1 Influenza ◽  
Avian Influenza A Virus

ABSTRACT In 2003, H5N1 avian influenza virus infections were diagnosed in two Hong Kong residents who had visited the Fujian province in mainland China, affording us the opportunity to characterize one of the viral isolates, A/Hong Kong/213/03 (HK213; H5N1). In contrast to H5N1 viruses isolated from humans during the 1997 outbreak in Hong Kong, HK213 retained several features of aquatic bird viruses, including the lack of a deletion in the neuraminidase stalk and the absence of additional oligosaccharide chains at the globular head of the hemagglutinin molecule. It demonstrated weak pathogenicity in mice and ferrets but caused lethal infection in chickens. The original isolate failed to produce disease in ducks but became more pathogenic after five passages. Taken together, these findings portray the HK213 isolate as an aquatic avian influenza A virus without the molecular changes associated with the replication of H5N1 avian viruses in land-based poultry such as chickens. This case challenges the view that adaptation to land-based poultry is a prerequisite for the replication of aquatic avian influenza A viruses in humans.

Influenza type A virus M protein expression on infected cells is responsible for cross-reactive recognition by cytotoxic thymus-derived lymphocytes

1980 ◽  
Vol 29 (2) ◽  
pp. 719-723 ◽  
Author(s):  
C S Reiss ◽  
J L Schulman
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rabbit Antiserum ◽  
Type A ◽  
M Protein ◽  
Cytotoxic T Cell ◽  
Influenza A Viruses ◽  
Infected Cells ◽  
Cytotoxic T Cell Responses

M protein of influenza A virus was detected with rabbit antiserum by both indirect immunofluorescence and by antibody plus complement-mediated cytolysis on the cell surfaces of both productively and nonproductively infected cells. In contrast, antiserum to nucleoprotein failed to react with unfixed infected cells, but did bind to fixed infected cells, especially in the perinuclear area. Incorporation of antiserum to M protein in a T-cell-mediated cytotoxicity assay produced almost complete abrogation of lysis of H-2-compatible cells infected with an influenza A virus of a subtype which differed from that used to elicit the cytotoxic T cells. However, the antibody did not significantly block 51Cr release from cells infected with the homotypic type A influenza virus. These observations are in accord with the hypothesis that the cross-reactive cytotoxic T-cell responses seen with cells infected by heterotypic influenza A viruses are due to recognition of a common M protein.

scholarly journals Unseasonal Transmission of H3N2 Influenza A Virus During the Swine-Origin H1N1 Pandemic

2010 ◽  
Vol 84 (11) ◽  
pp. 5715-5718 ◽  
Author(s):  
Elodie Ghedin ◽  
David E. Wentworth ◽  
Rebecca A. Halpin ◽  
Xudong Lin ◽  
Jayati Bera ◽  
...  
Keyword(s):  
New York ◽  
Influenza A Virus ◽  
Influenza A ◽  
New York State ◽  
The United States ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
York State ◽  
Low Incidence ◽  
H3n2 Influenza

ABSTRACT The initial wave of swine-origin influenza A virus (pandemic H1N1/09) in the United States during the spring and summer of 2009 also resulted in an increased vigilance and sampling of seasonal influenza viruses (H1N1 and H3N2), even though they are normally characterized by very low incidence outside of the winter months. To explore the nature of virus evolution during this influenza “off-season,” we conducted a phylogenetic analysis of H1N1 and H3N2 sequences sampled during April to June 2009 in New York State. Our analysis revealed that multiple lineages of both viruses were introduced and cocirculated during this time, as is typical of influenza virus during the winter. Strikingly, however, we also found strong evidence for the presence of a large transmission chain of H3N2 viruses centered on the south-east of New York State and which continued until at least 1 June 2009. These results suggest that the unseasonal transmission of influenza A viruses may be more widespread than is usually supposed.

Rapid subtyping of influenza A virus isolates by membrane fluorescence

1979 ◽  
Vol 9 (2) ◽  
pp. 269-273
Author(s):  
M Fishaut ◽  
K McIntosh ◽  
G Meiklejohn
Keyword(s):  
Influenza A Virus ◽  
Hemagglutination Inhibition ◽  
Influenza A ◽  
Cultured Cells ◽  
Fluorescent Antibody ◽  
Accurate Method ◽  
Kidney Cells ◽  
Influenza A Viruses ◽  
Indirect Immunofluorescence Technique ◽  
Virus Isolates

During the winter of 1977-1978 three influenza A virus serotypes (A/Vic/3/75, A/Texas/1/77 [both H3N2], and A/USSR/90/77 [H1N1]) circulated in Denver, offering us the opportunity to apply fluorescent antibody techniques to the specific identification of these viruses. Surface antigens of infected, unfixed primary monkey kidney cells were stained in suspension by an indirect immunofluorescence technique with anti-H3N2 and anti-H1N1 antisera. In tests of cells infected with known viruses, the members of the H3N2 family could not be distinguished from one another, but were easily distinguished from H1N1 strains. A total of 101 hemadsorption-positive clinical specimens were evaluated over a 6-month period. Forty-five of 48 influenza A H3N2 and 24 of 29 H1N1 specimens confirmed by hemagglutination inhibition were correctly identified by membrane fluorescence of cultured cells, with no misidentifications among influenza strains and with 1 false positive among 24 non-influenza isolates. The average time to identification by this technique was 4 days compared to 7 days by hemagglutination inhibition. Live cell membrane fluorescence is a simple, rapid, and accurate method for identifying and grouping influenza A viruses.

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