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Influenza virus regulates protein synthesis during infection by repressing autophosphorylation and activity of the cellular 68,000-Mr protein kinase.

Katze MG, Tomita J, Black T, Krug RM, Safer B, Hovanessian A.

Department of Microbiology, School of Medicine, University of Washington, Seattle 98195.

We investigated the mechanisms by which influenza virus prevents shutoff of protein synthesis by a cellular protein kinase normally activated during infection. Earlier work has shown that influenza virus superinfection of cells previously infected by the adenovirus VAI RNA-negative mutant dl331 resulted in selective translation of influenza virus mRNAs and suppression of the elevated protein kinase levels normally found in cells infected by the mutant alone (M. G. Katze, B. M. Detjen, B. Safer, and R. M. Krug, Mol. Cell. Biol. 6:1741-1750, 1986). We elucidated the mechanisms of this kinase repression and can now report that influenza virus encodes a gene product which functions to directly block the autophosphorylation and activity of the interferon-induced, double-stranded-RNA-activated protein kinase, P68. Suppressed P68 activity was found not only in doubly infected cells but also in cells infected by influenza virus alone. Moreover, the decrease in P68 activity correlated with a decrease in the endogenous levels of phosphorylation of the alpha subunit of the eucaryotic initiation factor eIF-2, the natural substrate of the protein kinase. Suppression of P68 activity occurred as early as 2 h after influenza virus infection and required viral gene expression beyond the level of primary mRNA transcription to take place. We confirmed our in vivo observations with in vitro mixing experiments which showed that the influenza virus inhibitor can act in trans to block P68 activity. Combined repression of P68 function and eIF-2 alpha phosphorylation during influenza virus infection is essential for continued catalytic recycling of eIF-2 and efficient mRNA translation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3418783&dopt=Abstract flu, influenza



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Protein synthesis by HepG2 cells infected with influenza B virus.

Barnard JA, Snyder PN, Werner MJ, Greene HL, Edwards KM.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232.

Reye's syndrome is an acute hepatopathy and encephalopathy affecting children during the convalescent period of a viral infection, frequently influenza B. The role of influenza B in the pathogenesis of Reye's syndrome is unknown. To investigate this relationship, an in vitro system was designed to examine the interaction of influenza B virus with a cell line of human hepatocytes (HepG2) which retains many specific hepatic synthetic characteristics. HepG2 was capable of supporting a productive infection by influenza B, although greater virus inputs were required than in fully permissive Madin-Darby canine kidney cells. Because of the recent association of Reye's syndrome with aspirin use, the kinetics of influenza B growth were studied in the presence of acetylsalicylic acid (25 and 100 micrograms/ml) and were not found to be altered. Protein synthesis by HepG2 cells was decreased by 80% in influenza B-infected cells when compared to uninfected controls. Acetylsalicylic acid, 100 micrograms/ml, did not affect the rate of 35S-methionine incorporation by infected or uninfected HepG2 cells. The rates of synthesis of specific proteins (albumin, transferrin, and apoprotein B) by HepG2 cells were determined by immunoprecipitation of 35S-methionine labeled cell lysates. After 12 h of infection, synthesis of all three plasma proteins was decreased by 40-60%. These studies describe a useful system for delineation of mechanisms by which influenza B virus interacts with host hepatocytes and the host-cell protein synthetic machinery. The studies could be pertinent to the pathogenesis of Reye's syndrome.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2832818&dopt=Abstract flu, influenza



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Influenza A viral nucleoprotein detection in isolates from human and various animal species.

Siebinga JT, de Boer GF.

Central Veterinary Institute, Department of Virology, Lelystad, The Netherlands.

A double antibody sandwich, enzyme-linked immunosorbent assay (DAS-ELISA) was developed to detect influenza A viral antigen, employing a monoclonal antibody directed against type-specific influenza A nucleoprotein (McAb anti-NP). McAb anti-NP was used to coat ELISA plates as well as to prepare the peroxidase conjugate. Influenza A viruses of avian, equine, swine, and human origin were detected in allantoic fluids of inoculated eggs with higher sensitivity by the DAS-ELISA than by hemagglutination (HA) assays. Minimal concentrations of 8 ng/ml influenza virus protein were detected in Nonidet P40-treated virus preparations. Viral antigen detection in tissues of experimentally infected chickens and pigs was successful, but in pigs yielded a lower positive score than the conventional method of virus isolation in eggs. The test is sensitive, rapid, and easy to perform, but does not permit influenza A subtyping. In avian species, the McAb anti-NP DAS-ELISA differentiates between influenza and Newcastle disease viruses. In pigs, the test distinguishes between influenza and Aujeszky's disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2839132&dopt=Abstract flu, influenza



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Upper respiratory tract infection and serum antibody responses in nursing home patients.

Arroyo JC, Jordan W, Milligan L.

Medicine Service, Dorn Veterans Administration Hospital, Columbia, SC 29201.

Residents of a Veterans Administration nursing home care unit (NHCU) were observed for the development of upper respiratory tract infection (URI) during 12 consecutive months to determine the frequency of sporadic cases or outbreaks of URI and to characterize them clinically and by laboratory means. Fifty-nine episodes of URI occurred in 56 residents during the study period. Serologic testing or virus isolation proved or suggested an etiologic agent on 22 occasions. URI was more common in late Fall and Winter and was caused by various agents, including influenza, Mycoplasma pneumoniae, respiratory syncytial virus, and parainfluenza viruses. A minor outbreak of influenza B in February 1986 contrasted with previous cases of URI in that the patients had a higher mean temperature and abnormal breath sounds, and they were clinically sicker. This suggests that clinical and epidemiologic surveillance during the influenza season may allow the early recognition of influenza in elderly nursing home residents. Over a 4-year period 147 serum antibody responses after influenza infection or influenza vaccination were compiled. Antibody responses to individual influenza vaccine components were measured 75 to 90 days after vaccination. The geometric mean titer (GMT) and the percentage of samples with antibody levels greater than 1:40 were determined for each of the three antigenic subtypes on 3 consecutive years. The GMT to individual vaccine components was consistently greater than 1:40, except to influenza B/Singapore in 1984 and A/Chile and B/U.S.S.R. in 1985, when these subtypes were first included in the vaccine, suggesting the NHCU residents responded less vigorously to unfamiliar vaccine subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2847597&dopt=Abstract flu, influenza



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Influenza subtype-specific IgA, IgM and IgG responses in patients on hemodialysis after influenza vaccination.

Rautenberg P, Teifke I, Schlegelberger T, Ullmann U.

Abt. fur Medizinische Mikrobiologie, Universitat Kiel.

The isotype-specific antibody response to influenza vaccination in 36 patients undergoing chronic intermittent hemodialysis was analyzed by an influenza subtype-specific immunofluorescence test. The immune response was recorded at regular intervals over five months. On the basis of fourfold IgG titer rises as the classical parameter protection from infection was assumed to occur in more than 85% of healthy adults to each of the influenza antigens. In contrast, about 70% of the patients on hemodialysis had responded to influenza A H1N1 and H3N2 vaccines while only 50% of the patients on hemodialysis had responded to influenza B antigen. However, patients showed decreased rates and lower peak responses in IgA, IgM and IgG antibodies to influenza A and B antigens. Probably as a result of the underlying renal disease the different kinetics of antibody responses and the lower influenza specific immunoglobulin levels resulted in lower seroconversion rates in hemodialysis patients compared to those in healthy volunteers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3065242&dopt=Abstract flu, influenza



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Epidemiological and virological influenza survey in Dakar, Senegal: 1996-1998.

Dosseh A, Ndiaye K, Spiegel A, Sagna M, Mathiot C.

Departement de Virologie, Institut Pasteur de Dakar, Senegal.

An influenza survey was conducted in seven sentinel sites in Dakar, Senegal from June 1996 to December 1998. Throat or nasal swab cultures were randomly collected from 804 patients suffering from influenza-like symptoms. Influenza viruses were isolated at a similar proportion in adults and in children (P = 0.29). Strains of influenza B viruses were isolated from sporadic cases in 1997, whereas type A virus was associated with an isolated peak. Proportions of influenza virus isolation varied from 17.5% to 40.0% between 1996 and 1998 during the peak period (July/September) of acute respiratory infection in Dakar. Rainfall, humidity, and temperatures rose during the same period. Influenza in Dakar seems to be an-all-age groups respiratory infection characterized by high transmission during the hot and rainy season. The antigenic similarity of the A(H3N2) and B viruses to those circulating elsewhere in the world at the same time was confirmed. However, the A(H1N1) strains were found to be more closely related to an Asiatic strain which had not been isolated outside Asia previously. Consequently, the strain close to the A(H1N1)/Wuhan/371/95 strain isolated in Dakar was included in the composition of the 1998/1999 influenza vaccine. This reinforces the importance of setting up a national influenza control strategy in tropical regions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11289677&dopt=Abstract flu, influenza



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Influenza B virus evolution: co-circulating lineages and comparison of evolutionary pattern with those of influenza A and C viruses.

Yamashita M, Krystal M, Fitch WM, Palese P.

Department of Microbiology, Mount Sinai School of Medicine, City University of New York, New York 10029.

Sequence analyses and comparison of the genes coding for the nonstructural (NS) and hemagglutinin (HA) proteins of different influenza B viruses isolated between 1940 and 1987 reveal that the number of substitutions is not always proportional to the time between isolates. Examination of 14 influenza B virus NS gene and 10 HA gene sequences by the maximum parsimony method suggested that--as with influenza C viruses--there are multiple evolutionary lineages which can coexist for considerable periods of time. Comparison of the sequence divergence among genes of viruses belonging to type A, B, and C virus suggests that, in man, influenza B viruses evolve slower than A viruses and faster than C viruses. We propose an evolutionary model for influenza B viruses that is intermediate between the pattern for human influenza A viruses and that for influenza C viruses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3267218&dopt=Abstract flu, influenza



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Influenza vaccination in MS: absence of T-cell response against white matter proteins.

Moriabadi NF, Niewiesk S, Kruse N, Jung S, Weissbrich B, ter Meulen V, Toyka KV, Rieckmann P.

Clinical Research Unit for Multiple Sclerosis and Neuroimmunology, Department of Neurology, Julius-Maximilians-Universitat, Wurzburg, Germany. neville.moriabadi bkr-regensburg.de

BACKGROUND: Natural infections bear the risk of triggering MS bouts, whereas epidemiologic studies have not delineated an increased risk for disease activity after influenza virus vaccination. OBJECTIVE: To examine influenza A virus-specific and myelin protein-reactive T-cell frequencies by interferon gamma (IFNgamma)-enzyme-linked immunospot and the response of these cells by IFNgamma-reverse transcription (RT) PCR after immunization and any incidental upper respiratory tract infection (URI) in 12 patients with MS (seven with a relapsing-remitting course; five with a secondary progressive course; Kurtzke Expanded Disability Status Scale [EDSS] score from 1.0 to 6.5, without immunosuppressive treatment) and 28 healthy volunteers. RESULTS: A cellular immune response against influenza A virus was mounted in both populations at 2 weeks after vaccination. Patients with MS showed a higher relative increase (p = 0.008) than controls with respect to the number of influenza-specific T cells. Mean antibody responses against influenza A virus were increased in both populations after 2 weeks (p < 0.01). Despite these virus-specific reactions, no increase in T-cell frequencies responsive to human myelin basic protein (MBP) or recombinant human myelin oligodendrocyte protein (MOG) was observed after immunization, arguing against a general immune stimulation by influenza vaccination. In contrast, MBP-specific T-cell responses became detectable in several individuals after febrile infection. CONCLUSION: These data support the clinical observations that influenza vaccination is effective and safe in patients with MS with respect to cellular immunoreactivity against two main CNS myelin proteins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11294933&dopt=Abstract flu, influenza



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Is routine influenza immunization indicated for people over 65 years of age? An affirmative view.

Thompson MP.

Department of Family Medicine, Medical College of Georgia, Augusta 30912.

Influenza is usually a minor, self-limiting illness, but for the elderly, especially the elderly who have chronic illnesses, it may be a severe or fatal disease. During influenza epidemics this disease may not always be recognized clinically as influenza but may appear as an acute decompensation in a patient with a known chronic illness. The influenza vaccine is not perfect, but it has been shown to be effective in the elderly. Reactions to the vaccine are usually minor and administration costs are low. Experience with influenza vaccine since the early 1940s has led to an improved, more pure vaccine formulation, has developed worldwide systems of tracking the dominant circulating viral strains, and has refined recommendations for vaccine usage based on clinical studies of its efficacy and cost effectiveness. Physicians should be aware of the present limitations of the existing studies and the imperfections of the vaccines, but in the elderly population, a proven intervention that will offer a substantial degree of protection during the influenza season should not be withheld. Most of the existing evidence suggests that the vaccine is effective and that physicians should be more stringent in their influenza immunization practices with the elderly. The elderly who are at high risk should be of high priority for receiving influenza vaccine, and the vaccine should also be recommended to healthy individuals aged 65 years and older because of its proven efficacy for reducing attack rates when appropriate viral strains are used.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3339325&dopt=Abstract flu, influenza



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Is routine influenza immunization indicated for people over 65 years of age? An opposing view.

Frame PS.

Tri-County Family Medicine, Cohocton, New York 14826.

It is true that persons aged over 65 years have greater morbidity and mortality from influenza. This increased morbidity and mortality, however, is mostly the result of a higher prevalence of other chronic diseases in the elderly. There is no evidence that vaccination, even in epidemic years when the antigenic match of the influenza strain and the vaccine is good, benefits the 60 percent of the noninstitutionalized population over the age of 65 years who do not have other high-risk diseases. In fact, the grade II-3 evidence cited by the US Preventive Services Task Force actually supports not immunizing this population group. Even among high-risk patients, the benefit from influenza vaccination is highly variable and difficult to demonstrate. In some years there will be little influenza, and little benefit will accrue; in other years the vaccine-influenza antigenic match will not be good, and little benefit will be obtained. In a few years (two of the 12 years during which Barker's studies were done), a reduction in morbidity can be demonstrated for high-risk elderly persons. Even then, vaccine efficacy is only about 33 percent. Patients are telling physicians that they do not feel influenza vaccination is worthwhile. Less than 25 percent of high-risk persons are vaccinated annually. Many of those vaccinated do so because they falsely believe influenza vaccination will prevent the common cold. In accordance with the ACIP recommendation, high-risk patients with concomitant chronic disease (priority 1) should be immunized, because at least some benefit can be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3339326&dopt=Abstract flu, influenza



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The glycoprotein of influenza C virus is the haemagglutinin, esterase and fusion factor.

Herrler G, Durkop I, Becht H, Klenk HD.

Institut fur Virologie, Philipps-Universitat Marburg, F.R.G.

Of the biological activities of influenza C virus, haemagglutination, receptor inactivation and fusion, only the latter has been conclusively correlated with its surface glycoprotein (gp). We have purified the gp by octylglucoside treatment of influenza C virions followed by centrifugation into a sucrose gradient. Evidence was obtained that gp also represents the receptor-destroying enzyme of influenza C virus, which has been characterized as a neuraminate 9-O-acetylesterase: (i) it inactivated the receptors for influenza C virus on chicken erythrocytes; (ii) it had acetylesterase activity as indicated by the release of acetate from bovine submandibulary mucin; (iii) monoclonal antibodies directed against gp inhibited the acetylesterase activity of influenza C virus. Although purified gp was unable to agglutinate chicken red blood cells, it blocked haemagglutination by viruses. This finding as well as the haemagglutination inhibition activity of monoclonal anti-gp antibodies indicate that gp is also responsible for the haemagglutinating activity of influenza C virus. Thus, as the influenza C glycoprotein is the only myxovirus glycoprotein with three different activities, we propose the designation HEF in order to describe its function as a haemagglutinin (H), an esterase (E) and a fusion factor (F).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3356980&dopt=Abstract flu, influenza