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PubMed2005

Characterization of live influenza vaccine donor strain derived from cold-adaptation of X-31 virus.

A human influenza A virus X-31 (high-yielding strain) was cold-adapted for possible future use as live attenuated vaccine. Mutant influenza viruses were selected during successive serial passage in embryonated hens' eggs at progressively lower sub-optimal temperature (30, 27 degrees C followed by 24 degrees C). The cold-passaged mutant exhibited both temperature-sensitivity (ts) and cold-adapted (ca) phenotypes. The pathogenicity and immunogenicity of X-31 ca virus were studied in mice following intranasal inoculation. The mice did not show clinical signs even at high titer infection. Immunization of mice with X-31 ca virus elicited high titers of neutralizing antibody and provided complete protection against homologous and heterologous virus challenges. To assess the genetic stability, the X-31 ca virus was passaged at 37 degrees C in MDCK cells or inoculated into mice. Revertant virus was not found in the lungs of any of the mice and the supernatants of the MDCK culture. We conclude that the X-31 ca candidate vaccine virus exhibits the desired level of attenuation, immunogenicity, and protective efficacy required for live attenuated vaccine and merits further evaluation at clinical level.

Adaptation, Physiological↗

PubMed2004

Different roles of electrostatics in heat and in cold: adaptation by citrate synthase.

Electrostatics plays a major role in heat adaptation by thermophilic proteins. Here we ask whether electrostatics similarly contributes to cold adaptation in psychrophilic proteins. We compare the sequences and structures of citrate synthases from the psychrophile Arthobacter Ds2-3R, from chicken, and from the hyperthermophile Pyrococcus furiosus. The three enzymes share similar packing, burial of nonpolar surface area, and main-chain hydrogen bonding. However, both psychrophilic and hyperthermophilic citrate synthases contain more charged residues, salt bridges, and salt-bridge networks than the mesophile. The electrostatic free-energy contributions toward protein stability by individual charged residues show greater variabilities in the psychrophilic citrate synthase than in the hyperthermophilic enzyme. The charged residues in the active-site regions of the psychrophile are more destabilizing than those in the active-site regions of the hyperthermophile. In the hyperthermophilic enzyme, salt bridges and their networks largely cluster in the active-site regions and at the dimer interface. In contrast, in the psychrophile, they are more dispersed throughout the structure. On average, salt bridges and their networks provide greater electrostatic stabilization to the thermophilic citrate synthase at 100 degrees C than to the psychrophilic enzyme at 0 degrees C. Electrostatics appears to play an important role in both heat and cold adaptation of citrate synthase. However, remarkably, the role may be different in the two types of enzyme: In the hyperthermophile, it may contribute to the integrity of both the protein dimer and the active site by possibly countering conformational disorder at high temperatures. On the other hand, in the psychrophile at low temperatures, electrostatics may contribute to enhance protein solvation and to ensure active-site flexibility.

Adaptation, Physiological↗

PubMed1990

[The effect of cooling on the characteristics of a single skeletal muscle contraction in cold-adapted rats].

The time parameters and amplitude of the m. gastrocnemius twitch contractions were studied in control and in cold-adapted rats at optimal muscle temperature (29-30 degrees C) and after cooling the muscle to 24-25 degrees C. A decrease of the twitch contraction force and an increase of the time of the contraction to the maximum, occurred in cold-adapted rats. The cooling of muscle decreased the velocity of the twitch contraction in both groups of animals.

Adaptation, Physiological↗

PubMed1982

Attenuated ts-recombinants of influenza A/USSR/77 (H1N1) virus obtained by crossing with the cold-adapted donor A/Leningrad/134/57 (H2N2) virus.

Conditions of obtaining attenuated influenza virus recombinants by crossing of a cold-adapted donor with A (H1N1) influenza virus that reappeared in 1977 were studied. Temperature-sensitive recombinants suitable for intranasal immunization of adults with low titres of anti-haemagglutinin and anti-neuraminidase antibodies, and possessing sufficiently high immunogenicity were obtained by crossing of native parent strains and cross-reactivation techniques. It was confirmed that the cold-adapted A/Leningrad/134/17/57 (H2N2) influenza virus variant is a prospective donor of attenuation for obtaining recombinants--candidates for live influenza vaccine strains.

Adolescent↗

PubMed1994

Evaluation of the genetic stability of the temperature-sensitive PB2 gene mutation of the influenza A/Ann Arbor/6/60 cold-adapted vaccine virus.

A single-gene reassortant bearing the PB2 gene of the A/Ann Arbor/6/60 cold-adapted virus in the background of the A/Korea/82 (H3N2) wild-type virus is a temperature-sensitive (ts) virus with an in vitro shutoff temperature of 38 degrees C. A single mutation at amino acid (aa) at 265 (Asp-Ser) of the PB2 protein is responsible for the ts phenotype. This ts single-gene PB2 reassortant virus was serially passaged at elevated temperatures in Madin-Darby canine kidney cells to generate ts+ phenotypic revertant viruses. Four ts+ phenotypically revertant viruses were derived independently, and each possessed a shutoff temperature for replication in vitro of > 40 degrees C. Each of the four phenotypically revertant viruses replicated efficiently in the upper and lower respiratory tracts of mice and hamsters, unlike the PB2 single-gene reassortant virus, confirming that the ts phenotype was responsible for the attenuation of this virus in rodents. Mating the ts+ revertants with wild-type virus yielded ts progeny in high frequency, indicating that the loss of ts phenotype was due to a suppressor mutation which was mapped to the PA gene in each of the four independently derived ts phenotypic revertants. Nucleotide sequence analysis confirmed the absence of new mutations on the PB2 gene and the presence of predicted amino acid changes in the PA proteins of the revertant viruses. These studies suggest that single amino acid changes at aa 245 (Glu-Lys) or 347 (Asp-Asn) of the PA protein can completely suppress the ts and attenuation phenotypes specified by the Asp-Ser mutation at aa 265 of the PB2 protein of the A/Ann Arbor/6/60 cold-adapted virus.

Amino Acid Sequence↗

PubMed1992

Reduced infectivity of cold-adapted influenza A H1N1 viruses in the elderly: correlation with serum and local antibodies.

OBJECTIVE: To compare young and elderly adults in terms of their immune responses and rates of infection following intranasal vaccination with a live attenuated influenza virus. DESIGN: Time series, comparing outcomes in young and elderly convenience sample. METHOD: Retrospective laboratory analysis of serum and nasal wash specimens collected during prior studies in which young or elderly volunteers had been inoculated with cold-adapted influenza A/Kawasaki/86 (H1N1) reassortant virus. SETTING: Johns Hopkins Center for Immunization Research. PARTICIPANTS: Healthy young and elderly adults with pre-vaccination serum hemagglutination inhibition (HAI) antibody titers less than or equal to 1:8. OUTCOME MEASUREMENTS: Antibody responses in serum and nasal washes. MAIN RESULTS: The proportion of vaccinees who developed any serum or local antibody response was higher in young compared with elderly subjects (20/20 vs 5/14, P less than 0.0005). Resistance to infection with cold-adapted virus correlated with pre-vaccination levels of serum immunoglobulin G (IgG), serum IgA, and nasal wash IgA antibody to whole virus antigen. Age was highly correlated with a lack of response to vaccine by simple regression, but not when data were adjusted for pre-existing antibody levels. CONCLUSIONS: Cold-adapted reassortant influenza A H1N1 viruses achieve lower rates of infection in elderly than young adults, primarily due to age-related differences in preexisting levels of immunity which may not be reflected by HAI titer.

Administration, Intranasal↗

PubMed2006

A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine.

BACKGROUND: Live attenuated influenza vaccine (LAIV; FluMist) is a trivalent vaccine containing cold-adapted influenza vaccine viruses that infect and replicate in cells lining the nasopharynx to induce immunity. Recovery of viruses (shedding) is measured by culture of nasal specimens. Shedding of vaccine viruses is not equated with transmission because transmission requires more virus than is detected in many nasal swabs. Previous studies with LAIV did not detect transmission to close contacts. The primary objective of this study was to estimate the probability of transmission to placebo contacts in a day care setting. METHODS: One hundred ninety-seven healthy children aged 9 to 36 months attending day care were randomized to receive vaccine or placebo. Postvaccination viral shedding, safety, genotype and phenotype of shed viruses and probability of transmission were assessed. RESULTS: Eighty percent of 98 vaccine recipients shed at least one vaccine strain. No clinically significant differences in solicited adverse events attributable to vaccine occurred; safety profiles were similar in both groups. Vaccine virus isolates retained their phenotypic characteristics (cold adaptation and temperature sensitivity) and did not revert at nucleotides known to confer an attenuating phenotype. There was one confirmed transmission of a vaccine strain to a single placebo recipient. According to the Reed-Frost model, the calculated probability of transmission to a child after contact with a single vaccinated child was 0.58% (95% confidence interval, 0-1.7%). There was no increased reactogenicity or other safety concerns in the recipient child. CONCLUSIONS: Young children in a day care setting had a high rate of shedding and a low rate of transmission. No clinically significant illness occurred among children who received vaccine or placebo or in the child to whom the vaccine virus was transmitted.

Child Day Care Centers↗

PubMed1996

Detyrosination of tubulin is not correlated to cold-adaptation of microtubules in cultured cells from the Atlantic cod (Gadus morhua).

Isolated cod brain microtubules from the cold-adapted Atlantic cod (Gadus morhua) have previously been shown to be highly detyrosinated, a post-translational modification of tubulin usually found in stable subsets of microtubules. In this study we found this was not restricted only to isolated brain microtubules. Microtubules in primary cultures of brain and skin cells were composed of both tyrosinated (Tyr)- and detyrosinated (Glu)-tubulin seen by immunocytochemistry. Immunoelectron microscopy of isolated microtubules showed that individual microtubules were composed of a mixture of Tyr- and Glu-tubulin. Leukocytes with extending lamellopodia contained only microtubules stained with the antibody against Tyr-tubulin, and isolated heart tubulin lacked both Tyr- and Glu-tubulin, suggesting that a relative high level of detyrosination is a characteristic of most, but not all, cod microtubules. Brain cell microtubules were more resistant to mitotic inhibitors than skin cell microtubules, but this was not correlated to a difference in detyrosination. Brain and skin cell microtubules were only partially disassembled when incubated at 0 degrees C. Upon reassembly of microtubules at 12 degrees C, microtubules were still made of mixtures of Tyr- and Glu-tubulin, indicating that detyrosination of assembled microtubules is rapid and/or that in cod cells in contrast to mammalian cells, Glu-tubulin can reassemble to microtubules. Our data show that most cod microtubules are highly detyrosinated, but this is not the cause of their cold adaptation or drug stability.

Animals↗

PubMed2005

Cold adaptation and thyroid hormone metabolism.

Resting oxygen consumption and energy expenditure is sensitive to slight alterations in thyroid function. This means that timing and magnitude of cold adaptation would to some extent depend on thyroid function. Local thyroid hormone metabolism is important for energy expenditure and dissipation of heat in special tissues. Recruitment of brown adipocytes and upregulation of uncoupling protein 1 in mitochondria depends on high tissue T3 concentrations. Most of this T3 is derived from local 5' deiodination of T4. Brown fat is vital for cold exposed mice and rats, and may be important for temperature adaptation in human neonates. The role of thyroid hormone metabolism in adult human cold adaptation has not been finally clarified. Hypothetically, cold exposure may enhance T3 production by deiodination of T4 in skeletal muscle, which may enhance heat production in muscle via a change in muscle fiber type. Another hypothetical possibility is recruitment of brown adipocytes embedded in white adipose tissue in human adults. Understanding cold adaptation in human adults may lead to development of new drugs against obesity.

Acclimatization↗

PubMed1988

[Post-denervation changes in the membrane potentials of muscle fibers in cold-adapted rats].

In rats, the resting and active MPs of single muscle fibers of fast (m. gastrocnemius) and slow (m. soleus) denervated muscles were measured in cold-adapted and control animals. Electrophysiological characteristics of muscle fibers were studied within 10 days after dissection of the sciatic nerve. Postdenervation changes in the control group were less obvious in the fast fibers, whereas in cold-adapted rats they were lesser in the slow muscle fibers.

Adaptation, Physiological↗

PubMed2006

Lipolytic activity of Antarctic cold-adapted marine bacteria (Terra Nova Bay, Ross Sea).

AIMS: The aim of this study was to investigate the lipolytic activity of cold-adapted Antarctic marine bacteria and, furthermore, the combined effect of some environmental factors on this enzymatic process. METHODS AND RESULTS: Strains were assayed for lipolytic activity on a basal medium amended with seven individual fatty acid esters. A significant activity was observed for 148 isolates (95.5% of the total screened). The interactive effect of pH, temperature and NaCl concentration on the substrates was tested for six representative isolates, identified as Pseudoalteromonas, Psychrobacter and Vibrio. Differences between strains according to NaCl and pH tolerances were observed. Only one strain degraded the substrate more efficiently at 4 degrees C than at 15 degrees C. CONCLUSIONS: Our findings demonstrate that the lipolytic activity of Antarctic marine bacteria is rather variable, depending on culture conditions, and occurs in a wide range of salt concentration and pH. SIGNIFICANCE AND IMPACT OF THE STUDY: Isolation and characterization of bacteria that are able to efficiently remove lipids at low temperatures will provide insight into the possibility to use cold-adapted bacteria as a source of exploitable enzymes. Moreover, research on the interactive effects of salt concentration, pH and temperature will be useful to understand the true enzyme potentialities for industrial applications.

Adaptation, Physiological↗

PubMed1991

Dominant-negative mutants as antiviral agents: simultaneous infection with the cold-adapted live-virus vaccine for influenza A protects ferrets from disease produced by wild-type influenza A.

The attenuated cold-adapted strain of influenza A virus that is a candidate live-virus vaccine suppressed clinical disease in ferrets when given simultaneously with a virulent epidemic strain of influenza A virus. The cold-adapted virus effectively prevented disease, even when the epidemic strain was of a different subtype than the attenuated virus. In this case, ferrets given a mixed inoculum produced antibody to both subtypes in the absence of clinical disease, indicating that both viruses are replicating in the respiratory tract. These findings suggest the possibility of the development of a novel class of antivirals for influenza, namely a live virus that is a dominant-negative attenuated mutant that interferes with the replication of epidemic strains of virus.

Animals↗

PubMed1979

Changes induced by cold adaptation in the brown adipose tissue from several species of rodents, with special reference to the mitochondrial components.

(1) The effects of cold adaptation upon the brown adipose tissue have been studied in rats, hamsters, mice, and guinea pigs. (2) Striking effects were found for total tissue as well as at the mitochondrial level, e.g., increases in protein and phospholipid contents, changes in phospholipid fatty acid composition (a decrease in the percentage of palmitic and palmitoleic acids and an increase in stearic and linoleic acids), and a change in the mitochondrial polypeptide composition (a marked increase in a 32000 molecular weight polypeptide, except for hamsters). (3) In situations where animals exhibit a greatly enhanced capacity for nonshivering thermogenesis (cold adaptation for rats, mice, and guinea pigs, birth for guinea pigs, and hibernation ability for hamsters, dormice, and garden dormice), brown fat mitochondria are characterized by the occurrence of large amounts of the 32000 molecular weight polypeptide characteristic of these mitochondria.

Adaptation, Physiological↗

PubMed1989

[The effect of triiodothyronine and catecholamines on the stability of trace effects of cold adaptation in rats].

The role of three-iodine-thyronine, noradrenaline (NA), adrenaline (A), reserpine and propranolol in extinguishing of trace-effects of the long-term cold adaptation was studied in rats. A possibility to control the process of the temperature disadaptation through administration of different hormonal drugs, was shown. Three-iodine-thyronine and NA proved to be the most effective in this respect. Weakening of sympathetic-adrenal effects by means of combined reserpine and propranolol during the disadaptation accelerated the process of extinguishing of practically all the trace-effects of the long-term cold adaptation.

Adaptation, Physiological↗

PubMed1978

Comparative measurements of in vitro thermogenesis of brown adipose tissue from control and cold adapted rats.

Heat output and oxygen uptake rates as well as caloric equivalents of O2 were measured in brown fat fragments from cold-adapted and control rats. Resting metabolic rate per unit wet weight was the same in both groups. Submaximal responses to noradrenaline were significantly lower in the cold-adapted than in the control group. Apparent maximal responses were the same for both groups. Caloric equivalents of O2 gave no evidence for anaerobic glycolysis even under conditions of oxygen limitation.

Acclimatization↗

PubMed2006

Mitochondrial mechanisms of cold adaptation in cod (Gadus morhua L.) populations from different climatic zones.

Adjustments in mitochondrial properties and capacities are crucial in acclimatization to seasonal cold as well as in evolutionary cold adaptation of marine ectotherms. To examine whether gene expression mechanisms contribute to different settings of aerobic capacities in populations of cod (Gadus morhua) along a latitudinal cline, maximum activities of key enzymes of mitochondrial metabolism and their respective mRNA levels were compared in white muscle and liver of cold (4 degrees C) and warm (10 degrees C) acclimated individuals from cod populations of the North Sea and the Barents Sea, respectively. In white muscle, cold acclimation caused a parallel increase in citrate synthase (CS) and in cytochrome c oxidase (COX) activities, but with a much larger effect in the cold eurythermal Arctic population. In liver, cold acclimation was accompanied by increments in CS activities, but differences between populations were minor. Overall COX activities in liver were not affected by cold acclimation, but were higher in the cold adapted population. In both populations increments in muscle CS capacities were tightly correlated with elevated mRNA levels, suggesting transcriptional control of citrate synthase levels in muscle. In liver, CS mRNA levels differed between populations but were not affected by cold acclimation, so that post-transcriptional control may contribute to elevated functional levels in this tissue. Mitochondrial-encoded COX2 mRNA levels were not limiting for functional activities in both tissues, in favour of post-transcriptional control or limitations by other transcripts of the COX complex. Altogether, the differentiation in gene expression between both populations was more strongly expressed at 4 degrees C. The comparison of functional levels and transcript levels may reflect genetic differentiation at functional sites, in line with genetic differences between the two populations previously established by non-coding genetic markers.

Acclimatization↗

PubMed1984

The mitochondrial uncoupling protein from guinea-pig brown adipose tissue. Synchronous increase in structural and functional parameters during cold-adaptation.

The time-course for the induction of the uncoupling pathway in the inner membrane of brown-fat mitochondria from cold-adapting guinea pigs was studied. The amount of the protein was quantified from the capacity for high-affinity binding of GDP to the intact mitochondria, and was compared with the functional parameters diagnostic of the protein, namely the nucleotide-sensitive proton conductance and the sensitivity to uncoupling by low concentrations of fatty acids. A monophasic increase in nucleotide titre was observed, with no evidence of an early 'unmasking' of preexisting nucleotide-binding sites. The nucleotide-sensitive conductance increased in precise synchrony with the nucleotide-binding capacity. Mitochondria from newborn animals, and those from acutely cold-adapted animals, showed anomalously low sensitivities to uncoupling by fatty acids.

Adaptation, Physiological↗

PubMed2004

Live cold-adapted influenza A vaccine produced in Vero cell line.

The African green monkey kidney (Vero) cell line was used as a substrate for the development of a live cold-adapted (ca) reassortant influenza vaccine. For that purpose, a new master strain was generated by an adaptation of the wild type (wt) A/Singapore/1/57 virus to growth at 25 degrees C in a Vero cell line. The resulting cold-adapted (ca) muster strain A/Singapore/1/57ca showed temperature sensitive (ts) phenotype and was attenuated in animal models and protective in the challenge experiments in ferrets. Two vaccine candidates of influenza A(H1N1) and A(H3N2) subtypes (6/2 reassortants) inheriting six genes coding internal proteins from the new master strain and the surface antigens hemagglutinin (HA) and neuraminidase (NA) from the epidemic viruses were obtained by a standard method of genetic reassortment. All steps of the vaccine preparation were done exclusively in Vero cells, including the isolation of the epidemic viruses. Both vaccine strains were used for immunization of young adult volunteers in a limited clinical trial and appeared to be safe, well tolerated and immunogenic after intranasal administration.

Adaptation, Physiological↗