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PubMed1983

Trypanosoma vivax, stock V953: inhibitory effect of type A influenza virus anti-HAV8 serum on in vitro neuraminidase (sialidase) activity.

Trypanosoma vivax stock V953 lysates were observed to produce neuraminidase (sialidase EC 3.2.1.18) in vitro, which cleaved neuraminic (sialic) acid from the substrate fetuin. The neuraminidase activity was proportional to the number of trypanosomes in the lysates, with 0.44, 0.88, and 1.75 X 10(6) trypanosomes producing 1.4 +/- 0.06, 3.1 +/- 0.1, and 6.7 +/- 0.1 micrograms of sialic acid liberated, respectively. Equal numbers of unlysed and lysed trypanosomes produced approximately the same amount of the enzyme. Trypanosome eluates stored at room temperature appeared to have lost neuraminidase activities within 4 days. An inhibition test for identifying the neuraminidase antigen on influenza viruses was performed in vitro on the T. vivax lysates. The inhibition test, using Type A influenza virus anti-HAV8 serum, showed a highly significant (P less than 0.0001) reduction in neuraminidase activities. The effect of equal amounts of influenza antiserum on serially diluted trypanosome lysates showed that 1 ml of influenza anti-HAV8 serum would inhibit a mean of 6.74 +/- 0.18 micrograms of T. vivax stock V953 neuraminidase activity.

Animals↗
PubMed1980

Neuraminidase treatment of human T lymphocytes: effect on Fc receptor phenotype and function.

Purified peripheral blood T cells or T mu cells from normal healthy donors were treated in vitro with neuraminidase and examined for the expression of IgM Fc and IgG Fc receptors. Increasing concentrations of neuraminidase selectively removed IgM Fc receptors, whereas the number of T cells expressing IgG Fc receptors was significantly increased. Following neuraminidase treatment, IgM Fc receptors could be regenerated by reincubation of T cells at 37 degrees C. The regeneration of IgM Fc receptors could be blocked by treatment with cycloheximide. Neuraminidase treatment of purified T mu cells resulted in the expression of IgG Fc receptors on a subpopulation of T mu lymphocytes. A small percentage of the neuraminidase-treated T cells expressed receptors for both IgG and IgM. Treatment of T cells with neuraminidase did not effect T cell-mediated spontaneous cytotoxicity (SLMC) or antibody-dependent cellular cytotoxicity (ADCC). Our results indicate that T cell Fc receptor phenotypes can be modulated in vitro without significantly altering their functional capacity.

Cytotoxicity, Immunologic↗
PubMedDate not supplied

[Changes in the brain neuraminidase activity under the action of tsiklozil and amizil].

The effect of cyclozyl and amizyl on the activity of soluble and membrane-bound neuraminidase of the rat brain is studied in the in vivo and in vitro experiments. Within 60 min after subcutaneous injection of cyclozyl in a dose of 0.5 microgram/kg of body weight the activity of soluble neuraminidase decreased by 45.5% whereas the activity of membrane-bound neuraminidase remained the same. In the experiments in vitro the activity of both enzyme forms did not change when the content of cyclozyl and mixture of general gangliosides in the incubation media was 2.0, 20.0, and 200.0 micrograms. Amizyl (2 micrograms) in the presence of general gangliosides increased the neuraminidase activity whereas in the presence of disialoganglioside GD1b reduced the activity. Various lipids (phospholipids, phospholipids + cholesterol, cerebroside + sulfatides) surrounding the enzyme exerted different effect on the activity of both neuraminidase forms. Thus we suggest active interaction of the system "gangliosides-soluble and membrane-bound neuraminidase" with M-cholinolytics (cyclozyl and amizyl) and important role of this "substate-enzyme" system in M-cholinoreceptor functioning.

Animals↗
PubMedDate not supplied

[Lymphocytes HLA antigens expressivity after neuraminidase treatment (author's transl)].

Neuraminidase treatment of lymphoid cells increases the cytotoxic action of antibodies and complement on these cells. We have studied the action of 25 human alloantisera on lymphocytes of 26 healthy subjects by the Trypan blue lymphocytotoxicity technic, before and after neuraminidase treatment of cells. The results show, as a rule, an increased cytotoxicity of sera, with a higher titer and/or a more important number of positive cells. In some sera a specific cytotoxic activity is found only with neuraminidase treated cells. The antibodies often reveal an anti-HLA specificity: that specificity was previously known in the serum or, in several cases, has been found only with neuraminidase treated cells. But in some cases the new specificity does not seem to be related to the HLA system. Different hypotheses are discussed in order to explain these results and the action of neuraminidase on membranes; lastly, applications of our neuraminidase treatment method to practical problems are presented.

Antibody Specificity↗
PubMed1987

Localization of functional sites on the hemagglutinin-neuraminidase glycoprotein of Sendai virus by sequence analysis of antigenic and temperature-sensitive mutants.

To locate the various functions associated with the hemagglutinin-neuraminidase (HN) glycoprotein of Sendai virus in the primary structure of the protein, a temperature-sensitive (ts) mutant and seven antigenic mutants were sequenced. The ts mutant was defective in its ability to agglutinate erythrocytes and infect host cells, while its neuraminidase activity was normal. Its sequence revealed two closely spaced amino acid substitutions (residues 262 and 264) and one distant substitution (residue 461). Revertants could not be isolated, suggesting that more than one of the substitutions is responsible for the defective hemagglutinating activity. The antigenic mutants were selected with monoclonal antibodies that delineate four nonoverlapping antigenic sites (I-IV) and separately inhibit hemagglutinating, neuraminidase, and hemolysis activities. Mutants selected with antibodies to antigenic sites I-III were used to map these functions on the primary sequence of HN. Each antigenic mutant had a single point mutation in the HN gene that resulted in an amino acid substitution in the protein. A site II mutant selected with an antibody which inhibits hemolysin activity had a substitution at amino acid 420, while a mutant selected with antibody that inhibits only erythrocyte binding (site III) had a substitution at amino acid 541. Two antigenic mutants selected with an antibody that inhibits hemagglutination and neuraminidase activities (site I) had amino acid substitutions in close proximity (residues 277 and 279) to the two closely spaced substitutions of the ts mutant. These findings suggest that the region defined by the ts mutant and these two antigenic mutants is involved in host cell binding. Antigenic mutants selected with another site I antibody had amino acid changes at residue 184, indicating that antigenic site I is discontinuous in the primary sequence. This antibody blocks only hemagglutination, but mutants selected with it had a decreased neuraminidase activity. This finding supports the idea that the neuraminidase site is close to, but distinct from, the hemagglutination site.

Antibodies, Monoclonal↗
PubMed1994

The structure of a complex between the NC10 antibody and influenza virus neuraminidase and comparison with the overlapping binding site of the NC41 antibody.

BACKGROUND: While it is well known that different antibodies can be produced against a particular antigen, and even against a particular site on an antigen, up until now there have been no structural studies of cross-reacting antibodies of this type. One antibody-antigen complex whose structure is known is that of the influenza virus antigen, neuraminidase, in complex with the NC41 antibody. Another anti-neuraminidase antibody, NC10, binds to an overlapping site on the antigen. The structure of the complex formed by this antibody with neuraminidase is described here and compared with the NC41-containing complex. RESULTS: The crystal structure of the NC10 Fab-neuraminidase complex has been refined to a nominal resolution of 2.5A. Approximately 80% of the binding site of the NC10 antibody on neuraminidase overlaps with that of the NC41 antibody. The epitope residues of neuraminidase are often engaged in quite different interactions with the two antibodies. Although the NC10 and NC41 antibodies have identical amino acid sequences within the first complementarity determining region of their heavy chains, this is not the basis of the cross-reaction. CONCLUSIONS: The capacity of two different proteins to bind to the same target structure on a third protein need not be based on the existence of identical or homologous amino acid sequences within those proteins. As we have demonstrated, amino acid residues on the common target structure may be in quite different chemical environments, and may also adopt different conformations within two protein-protein complexes.

Amino Acid Sequence↗
PubMedDate not supplied

Characterization of the hemagglutinin receptor specificity and neuraminidase substrate specificity of clinical isolates of human influenza A viruses.

Six clinical isolates of influenza A viruses were examined for hemagglutinin receptor specificity and neuraminidase substrate specificity. All of the viral isolates minimally passaged in mammalian cells demonstrated preferential agglutination of human erythrocytes enzymatically modified to contain NeuAc alpha 2,6Gal sequences, with no agglutination of cells bearing NeuAc alpha 2,3Gal sequences. This finding is consistent with the hemagglutination receptor specificity previously demonstrated for laboratory strains of influenza A viruses. The neuraminidase substrate specificities of the clinical isolates examined were also identical to that described for the N2 neuraminidase of recent laboratory strains of human influenza viruses. The H3N2 viruses all displayed the ability to release sialic acid from both alpha 2, 3 and alpha 2, 6 linkages. In addition, two clinical isolates of H1N1 viruses also demonstrated this dual neuraminidase substrate specificity, a characteristic which has not been previously described for the N1 neuraminidase. These results demonstrate that complementary hemagglutinin and neuraminidase specificities are found in recent isolates of both H1N1 and H3N2 influenza viruses.

HN Protein↗
PubMed2025

Evolution of antibody cross-reactivity to influenza H5N1 neuraminidase from an N2-specific germline.

The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and its occasional spillover to humans have raised concerns about a potential H5N1 pandemic. Although recent studies have shown that pre-existing human antibodies can recognize H5N1 neuraminidase, the molecular basis of how this cross-reactivity develops remains poorly understood. In this study, we used a phage display antibody library derived from 245 healthy donors to isolate an antibody, HB420, that cross-reacts with neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo. Cryogenic electron microscopy analysis reveals that HB420 targets the neuraminidase active site by mimicking sialic acid binding through a single Asp residue. Furthermore, the inferred germline of HB420 is N2 specific but acquires cross-reactivity to H5N1 neuraminidase through somatic hypermutation. Overall, our findings provide insights into how neuraminidase antibody evolves breadth, which has important implications for the development of broadly protective influenza vaccines.

Influenza A Virus, H5N1 Subtype↗
PubMed2003

Neuraminidase inhibitors for preventing and treating influenza in children.

BACKGROUND: During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include immunisation, amantadine and rimantadine, and the neuraminidase inhibitors: zanamivir and oseltamivir. OBJECTIVES: Our objective was to assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prophylaxis of influenza infection in children. SEARCH STRATEGY: We searched the Cochrane Acute Respiratory Infections Group Specialised Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the GlaxoSmithKline Clinical Trials Register, generally from inception through to December 2002. We also screened the references of retrieved articles and scrutinised relevant web sites. We also screened references of retrieved articles and other systematic reviews, scrutinised web sites of European and US regulatory bodies, and contacted manufacturers and authors. SELECTION CRITERIA: Double-blind randomised controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included. DATA COLLECTION AND ANALYSIS: Four reviewers applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir. MAIN RESULTS: We identified three randomised controlled trials reporting data from 1500 children with a clinical case definition of influenza, of whom 798 had laboratory confirmed influenza infection. Two were trials of oseltamivir (in healthy children and in children with asthma) and one was a trial of zanamivir (in healthy children). Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in previously healthy children with laboratory confirmed influenza (p < 0.0001) and by 17% (21 hours) in the intention-to-treat population (p = 0.0002). Zanamivir reduced the median duration of illness by 24% (1.25 days) in previously healthy children with laboratory confirmed influenza (p < 0.001) and by 10% (0.5 days) in the intention-to-treat population (p = 0.011). Both drugs also significantly reduced the time to return to normal activity. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. No data on the use of zanamivir in 'at risk' children were available. The reduction in time to resolution of illness in 'at risk' children (with asthma) treated with oseltamivir was not statistically significant. Although we identified three trials of neuraminidase inhibitors in the prevention of influenza in families (including children), Roche and GlaxoSmithKline were not willing to break-out data for paediatric populations, and so no data were eligible for inclusion in the review. The adverse events profile of zanamivir was no worse than placebo and we found no reports of zanamivir-induced bronchospasm in children. Vomiting was more common in children treated with oseltamivir (p = 0.008), but study withdrawals were similar (<2%) between oseltamivir and placebo. REVIEWER'S CONCLUSIONS: Neuraminidase inhibitors were effective in shortening illness duration and hastening return to normal activity in previously healthy children with a clinical or laboratory diagnosis of influenza. Oseltamivir was effective in reducing the incidence of secondary complications. Efficacy in 'at risk' children remains to be proven. The drugs are safe, but oseltamivir can cause vomiting.

Acetamides↗
PubMed1979

Neuraminidase in cultured fibroblasts and leucocytes of homozygotes and heterozygotes for the mucolipidosis II gene (I-cell disease).

The significance of neuraminidase deficiency reported to be the primary defect in mucolipidosis II has been evaluated by determination of this enzyme activity in cultured fibroblasts, culture medium, and leucocytes from homozygote and heterozygous carriers of the disease. A new and sensitive fluorometric assay of neuraminidase was used with sodium (4-methylumbeliferyl-alpha-D-N-acetylneuraminate) as substrate. We report: 1) nearly total deficiency of neuraminidase in mucolipidosis fibroblasts, 2) partial deficiency of this enzyme in leucocytes of one patient, 3) this decreased activity ceases to exist following Triton X-100 treatment, and 4) intermediary mean neuraminidase activity in fibroblasts and leucocytes from obligate heterozygotes. Although these results would be consistent with the suggestion that neuraminidase deficiency is the primary defect in this disease, evidence from the work of other authors suggests that the enzyme deficiency results from a secondary effect of the mucolipidosis II mutation.

Cells, Cultured↗
PubMed1982

Neuraminidase deficiency and accumulation of sialic acid in lymphocytes in adult type sialidosis with partial beta-galactosidase deficiency.

Neuraminidase deficiency has been demonstrated in cultured skin fibroblasts of patients who have adult type sialidosis with partial beta-galactosidase deficiency. A substantial amount of residual enzyme activity has been observed in leukocytes, however. To explain this discrepancy, the nature and distribution of the enzyme were studied. Neuraminidase activity was higher in lymphocytes than in granulocytes of normal controls. In patients' lymphocytes, neuraminidase activity was profoundly decreased and total sialic acid contents were increased 2.3-fold. Two neuraminidases, one sonication-labile and the other sonication-stable, were found in lymphocytes; the former was predominant in cultured skin fibroblasts. The defective enzyme in this disorder was found to be the sonication-labile neuraminidase in both cultured skin fibroblasts and lymphocytes.

Cerebellar Ataxia↗
PubMed1988

Neuraminidase induces capacitation and acrosome reaction in mammalian spermatozoa.

The treatment of epididymal spermatozoa of guinea pig and ejaculated spermatozoa of rabbit with neuraminidase from Arthrobacter ureafaciens induced significant acrosome reaction while the neuraminidase from Cl. perfringens failed to do so. The addition of the neuraminidase inhibitors kept the enzyme induced acrosome reaction to the control level. The zona-free hamster ova test showed that the treatment of spermatozoa with Arthrobacter neuraminidase rendered 82% of the guinea pig and 69% of the rabbit spermatozoa capable of fertilization. Thus, neuraminidase seems to enhance the rate of acrosome reaction by first capacitating spermatozoa in vitro.

Acrosome↗
PubMed1993

Possible role of myelin-associated neuraminidase in membrane adhesion.

Previous studies from our laboratory have demonstrated the presence of a specific interaction between myelin-associated neuraminidase and GM1 (Saito and Yu, J Neurochem 47:632-641, 1986). In the present study, we further characterized this neuraminidase-GM1 interaction and examined its role in the adhesion of rat oligodendroglial cells to GM1. Hydrolysis of N-acetylneuramin-lactitol by the enzyme was inhibited by GM1 in a competitive manner; GM1 itself was not hydrolyzed, suggesting that GM1 may serve as a competitive inhibitor of the enzyme. Asialo-GM1 had no inhibitory effect. When a soluble enzyme preparation was applied to a GM1-linked affinity column, the enzyme activity was retained on the column and was recovered from the column only by elution with a buffer containing 5 mM 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (Neu2en5Ac), a competitive inhibitor of neuraminidase. A binding study with 51Cr-labeled rat oligodendroglial cells showed that oligodendroglial cells bound preferentially to GM1 developed on a thin-layer plate, but not to other gangliosides such as GM3, GD1a, GD1b, and GT1b. The binding reaction to GM1 was inhibited by Neu2en5Ac (5 mM). These results suggest that myelin-associated neuraminidase specifically interacts with GM1 and may be involved in adhesion of oligodendroglial cells to GM1. This neuraminidase-GM1 interaction may play an important role in the formation and stabilization of the multilamellar structure of the myelin sheath.

Animals↗
PubMed1999

Genetic analysis reveals that both haemagglutinin and neuraminidase determine the sensitivity of naturally occurring avian influenza viruses to zanamivir in vitro.

The basis of differential sensitivity of replication of influenza viruses to the neuraminidase-specific inhibitor zanamivir was examined using four avian influenza viruses and reassortants produced between them. IC(50) values for inhibition of neuraminidase activity by zanamivir were similar for each of the four viruses, whereas the haemagglutinating activity of each of the viruses was relatively insensitive to zanamivir. However, the four viruses showed distinct zanamivir-sensitivity profiles in tissue culture. Analysis of the reassortant viruses showed that sensitivity was determined by the haemagglutinin gene (segment 4) and the neuraminidase gene (segment 6) and was independent of the remaining six RNA segments. Decreased sensitivity to zanamivir was associated with possession of a haemagglutinin that is released from cells with decreased dependence on neuraminidase and with possession of a neuraminidase that has a short stalk region.

Amino Acid Sequence↗
PubMed1983

Effect of neuraminidase treatment on serum reactivity to autologous leukemic blast cells.

The sera of 35 patients with acute lymphoblastic leukemia (ALL) and acute non-lymphoblastic leukemia (ANLL) were tested for reactivity against cell surface antigens of autologous leukemic blast cells by protein A assay (PA), immune adherence assay (IA), and anti-C3 mixed hemadsorption assay (C3-MHA). Autologous serum reactivity was detectable by PA in four cases and by IA and C3-MHA in about half the patients. Autologous serum reactivity occurred more often in ALL than in ANLL. Absorption studies revealed that in one patient only the autologous reactivity was directed against a restricted antigen, which could be detected only on the individual T-ALL blast cells. All other autologous antibodies detected unspecific antigens. Neuraminidase treatment had two effects: first, it increased antibody attachment to antigens which are also present on untreated cells; secondly, after neuraminidase treatment an antigen was detectable on the cell surface which could also be demonstrated on neuraminidase-treated non-leukemic cells (e.g., erythrocytes). Neither of these two effects of neuraminidase treatment seems to be tumor-specific. Possible therapeutic effects of neuraminidase are probably caused by unspecific adjuvant effects of the enzyme.

Adolescent↗
PubMed1980

Deficiency of neuraminidase in the sialidoses and the mucolipidoses.

Neuraminidase activity in cultured fibroblasts from patients either with various forms of sialidosis or with I-cell disease (ICD) or mucolipidosis (ML) III has been determined by both a colorimetric and a fluorometric method. The former applied to frozen fibroblast pellets demonstrated a specific deficiency of neuraminidase in patients with the sialidoses. The enzyme was also deficient in I-cells, as were other lysosomal hydrolases. With the fluorogenic substrate these data could be confirmed and extended, and elementary kinetics of neuraminidase studied. In unfrozen freshly harvested fibroblasts, neuraminidase activity was severalfold that in frozen aliquots. A comparative and simultaneous study could not reveal substantial differences between the residual neuraminidase activity found in the various clinical forms of sialidosis. And, in fibroblasts from patients with ICD, also called ML II, the deficiency of this enzyme is quantitatively similar to that in the sialidoses, but the residual activity in ML III is three times higher. In both ML II and ML III the defect is probably secondary to the unknown metabolic error.

Cells, Cultured↗
PubMed1980

Blocking action of intracellularly injected neuraminidase on central synapses in vivo.

The effect of neuraminidase on synaptic transmission was studied at cholinergic and noncholinergic contacts in the buccal and cerebral ganglion of Ap]lysia. The amplitudes of monosynaptic unitary postsynaptic potentials generated by intracellular stimulation of identified presynaptic neurones were measured as indication for the efficacy of synaptic transmission. Neuraminidase was either intrasomatically injected into a presynaptic neurone, or the whole ganglion was incubated with the enzyme. Intrasomatic injection of the enzyme resulted in complete failure of synaptic transmission. This effect occurred independently of the transmitter used. The synaptic failure was presynaptic in origin. The biophysical characteristics of an injected neurone, particularly the amplitude and propagation of its action potential, did not appear to be affected by neuraminidase. Synaptic transmission and biophysical membrane properties were unaffected by extracellular neuraminidase. We conclude that the synaptic blockade is due to the enzyme's action inside the presynaptic nerve ending. It seems most likely that neuraminidase cleaves sialic-acid-containing-compounds associated with the nerve terminal surface membrane, probably thus causing failure of transmitter release.

Animals↗
PubMed1993

Binding affinity of influenza virus N9 neuraminidase with Fab fragments of monoclonal antibodies NC10 and NC41.

Sedimentation equilibrium centrifugation has been applied to determine the affinity and stoichiometry of the interaction between Fab fragments, derived from monoclonal antibodies NC10 and NC41, with influenza virus neuraminidase N9 isolated from either tern or whale. Although the two neuraminidase epitopes recognized by NC10 and NC41 Fab overlap, crystallographic studies have shown that the modes of binding of each Fab are different. The sedimentation equilibrium experiments described here reveal that the binding affinities are also different, with NC10 Fab binding more strongly to each neuraminidase. Furthermore, comparison of the affinity of binding of each antibody fragment reveals a stronger interaction with tern neuraminidase than with whale neuraminidase. Although the respective epitopes recognized by each antibody on the two antigens are similar, this technique shows that they do nevertheless possess sufficient differences to affect significantly the binding of antibody.

Animals↗