Inactivation of respiratory syncytial virus by zinc finger reactive compounds

<p>Abstract</p> <p>Background</p> <p>Infectivity of retroviruses such as HIV-1 and MuLV can be abrogated by compounds targeting zinc finger motif in viral nucleocapsid protein (NC), involved in controlling the processivity of reverse transcription and virus infectivity. Although a member of a different viral family (<it>Pneumoviridae</it>), respiratory syncytial virus (RSV) contains a zinc finger protein M2-1 also involved in control of viral polymerase processivity. Given the functional similarity between the two proteins, it was possible that zinc finger-reactive compounds inactivating retroviruses would have a similar effect against RSV by targeting RSV M2-1 protein. Moreover, inactivation of RSV through modification of an internal protein could yield a safer whole virus vaccine than that produced by RSV inactivation with formalin which modifies surface proteins.</p> <p>Results</p> <p>Three compounds were evaluated for their ability to reduce RSV infectivity: 2,2'-dithiodipyridine (AT-2), tetraethylthiuram disulfide and tetramethylthiuram disulfide. All three were capable of inactivating RSV, with AT-2 being the most potent. The mechanism of action of AT-2 was analyzed and it was found that AT-2 treatment indeed results in the modification of RSV M2-1. Altered intramolecular disulfide bond formation in M2-1 protein of AT-2-treated RSV virions might have been responsible for abrogation of RSV infectivity. AT-2-inactivated RSV was found to be moderately immunogenic in the cotton rats <it>S.hispidus </it>and did not cause a vaccine-enhancement seen in animals vaccinated with formalin-inactivated RSV. Increasing immunogenicity of AT-2-inactivated RSV by adjuvant (Ribi), however, led to vaccine-enhanced disease.</p> <p>Conclusions</p> <p>This work presents evidence that compounds that inactivate retroviruses by targeting the zinc finger motif in their nucleocapsid proteins are also effective against RSV. AT-2-inactivated RSV vaccine is not strongly immunogenic in the absence of adjuvants. In the adjuvanted form, however, vaccine induces immunopathologic response. The mere preservation of surface antigens of RSV, therefore may not be sufficient to produce a highly-efficacious inactivated virus vaccine that does not lead to an atypical disease.</p

A highly attenuated recombinant human respiratory syncytial virus lacking the G protein induces long-lasting protection in cotton rats

<p>Abstract</p> <p>Background</p> <p>Respiratory syncytial virus (RSV) is a primary cause of serious lower respiratory tract illness for which there is still no safe and effective vaccine available. Using reverse genetics, recombinant (r)RSV and an rRSV lacking the G gene (ΔG) were constructed based on a clinical RSV isolate (strain 98-25147-X).</p> <p>Results</p> <p>Growth of both recombinant viruses was equivalent to that of wild type virus in Vero cells, but was reduced in human epithelial cells like Hep-2. Replication in cotton rat lungs could not be detected for ΔG, while rRSV was 100-fold attenuated compared to wild type virus. Upon single dose intranasal administration in cotton rats, both recombinant viruses developed high levels of neutralizing antibodies and conferred comparable long-lasting protection against RSV challenge; protection against replication in the lungs lasted at least 147 days and protection against pulmonary inflammation lasted at least 75 days.</p> <p>Conclusion</p> <p>Collectively, the data indicate that a single dose immunization with the highly attenuated ΔG as well as the attenuated rRSV conferred long term protection in the cotton rat against subsequent RSV challenge, without inducing vaccine enhanced pathology. Since ΔG is not likely to revert to a less attenuated phenotype, we plan to evaluate this deletion mutant further and to investigate its potential as a vaccine candidate against RSV infection.</p

Comparison of airway measurements during influenza-induced tachypnea in infant and adult cotton rats

<p>Abstract</p> <p>Background</p> <p>Increased respiratory rate (tachypnea) is frequently observed as a clinical sign of influenza pneumonia in pediatric patients admitted to the hospital. We previously demonstrated that influenza infection of adult cotton rats (<it>Sigmodon hispidus</it>) also results in tachypnea and wanted to establish whether this clinical sign was observed in infected infant cotton rats. We hypothesized that age-dependent differences in lung mechanics result in differences in ventilatory characteristics following influenza infection.</p> <p>Methods</p> <p>Lung tidal volume, dynamic elastance, resistance, and pleural pressure were measured in a resistance and compliance system on mechanically-ventilated anesthestized young (14–28 day old) and adult (6–12 week old) cotton rats. Animals at the same age were infected with influenza virus, and breathing rates and other respiratory measurements were recorded using a whole body flow plethysmograph.</p> <p>Results</p> <p>Adult cotton rats had significantly greater tidal volume (TV), and lower resistance and elastance than young animals. To evaluate the impact of this increased lung capacity and stiffening on respiratory disease, young and adult animals were infected intra-nasally with influenza A/Wuhan/359/95. Both age groups had increased respiratory rate and enhanced pause (<it>Penh</it>) during infection, suggesting lower airway obstruction. However, in spite of significant tachypnea, the infant (unlike the adult) cotton rats maintained the same tidal volume, resulting in an increased minute volume. In addition, the parameters that contribute to <it>Penh </it>were different: while relaxation time between breaths and time of expiration was decreased in both age groups, a disproportionate increase in peak inspiratory and expiratory flow contributed to the increase in <it>Penh </it>in infant animals.</p> <p>Conclusion</p> <p>While respiratory rate is increased in both adult and infant influenza-infected cotton rats, the volume of air exchanged per minute (minute volume) is increased in the infant animals only. This is likely to be a consequence of greater lung elastance in the very young animals. This model replicates many respiratory features of humans and consequently may be a useful tool to investigate new strategies to treat respiratory disease in influenza-infected infants.</p

Artificial Lighting as a Vector Attractant and Cause of Disease Diffusion

BACKGROUND: Traditionally, epidemiologists have considered electrification to be a positive factor. In fact, electrification and plumbing are typical initiatives that represent the integration of an isolated population into modern society, ensuring the control of pathogens and promoting public health. Nonetheless, electrification is always accompanied by night lighting that attracts insect vectors and changes people's behavior. Although this may lead to new modes of infection and increased transmission of insect-borne diseases, epidemiologists rarely consider the role of night lighting in their surveys. OBJECTIVE: We reviewed the epidemiological evidence concerning the role of lighting in the spread of vector-borne diseases to encourage other researchers to consider it in future studies. DISCUSSION: We present three infectious vector-borne diseases-Chagas, leishmaniasis, and malaria-and discuss evidence that suggests that the use of artificial lighting results in behavioral changes among human populations and changes in the prevalence of vector species and in the modes of transmission. CONCLUSION: Despite a surprising lack of studies, existing evidence supports our hypothesis that artificial lighting leads to a higher risk of infection from vector-borne diseases. We believe that this is related not only to the simple attraction of traditional vectors to light sources but also to changes in the behavior of both humans and insects that result in new modes of disease transmission. Considering the ongoing expansion of night lighting in developing countries, additional research on this subject is urgently needed.National Council for Scientific and Technological Development (CNPq), Brasilia, Brazi

From the Eye of the Albatrosses: A Bird-Borne Camera Shows an Association between Albatrosses and a Killer Whale in the Southern Ocean

Albatrosses fly many hundreds of kilometers across the open ocean to find and feed upon their prey. Despite the growing number of studies concerning their foraging behaviour, relatively little is known about how albatrosses actually locate their prey. Here, we present our results from the first deployments of a combined animal-borne camera and depth data logger on free-ranging black-browed albatrosses (Thalassarche melanophrys). The still images recorded from these cameras showed that some albatrosses actively followed a killer whale (Orcinus orca), possibly to feed on food scraps left by this diving predator. The camera images together with the depth profiles showed that the birds dived only occasionally, but that they actively dived when other birds or the killer whale were present. This association with diving predators or other birds may partially explain how albatrosses find their prey more efficiently in the apparently ‘featureless’ ocean, with a minimal requirement for energetically costly diving or landing activities

Investigation of the presence of human or bovine respiratory syncytial virus in the lungs of mink (Neovison vison) with hemorrhagic pneumonia due to Pseudomonas aeruginosa

<p>Abstract</p> <p>Background</p> <p>Hemorrhagic pneumonia is a disease of farmed mink (<it>Neovison vison</it>) caused by <it>Pseudomonas aeruginosa</it>. The disease is highly seasonal in Danish mink with outbreaks occurring almost exclusively in the autumn. Human respiratory syncytial virus (RSV) has been shown to augment infection with <it>P. aeruginosa</it> in mice and to promote adhesion of <it>P. aeruginosa</it> to human respiratory cells.</p> <p>Findings</p> <p>We tested 50 lung specimens from mink with hemorrhagic pneumonia for bovine RSV by reverse transcriptase polymerase chain reaction (PCR) and for human RSV by a commercial real-time PCR. RSV was not found.</p> <p>Conclusions</p> <p>This study indicates that human and bovine RSV is not a major co-factor for development of hemorrhagic pneumonia in Danish mink.</p

Normative productivity of the global vegetation

<p>Abstract</p> <p>Background</p> <p>The biosphere models of terrestrial productivity are essential for projecting climate change and assessing mitigation and adaptation options. Many of them have been developed in connection to the International Geosphere-Biosphere Program (IGBP) that backs the work of the Intergovernmental Panel on Climate Change (IPCC). In the end of 1990s, IGBP sponsored release of a data set summarizing the model outputs and setting certain norms for estimates of terrestrial productivity. Since a number of new models and new versions of old models were developed during the past decade, these normative data require updating.</p> <p>Results</p> <p>Here, we provide the series of updates that reflects evolution of biosphere models and demonstrates evolutional stability of the global and regional estimates of terrestrial productivity. Most of them fit well the long-living Miami model. At the same time we call attention to the emerging alternative: the global potential for net primary production of biomass may be as high as 70 PgC y^-1, the productivity of larch forest zone may be comparable to the productivity of taiga zone, and the productivity of rain-green forest zone may be comparable to the productivity of tropical rainforest zone.</p> <p>Conclusion</p> <p>The departure from Miami model's worldview mentioned above cannot be simply ignored. It requires thorough examination using modern observational tools and techniques for model-data fusion. Stability of normative knowledge is not its ultimate goal – the norms for estimates of terrestrial productivity must be evidence-based.</p

No Association between Fish Intake and Depression in over 15,000 Older Adults from Seven Low and Middle Income Countries–The 10/66 Study

Background: Evidence on the association between fish consumption and depression is inconsistent and virtually nonexistent from low-and middle-income countries. Using a standard protocol, we aim to assess the association of fish consumption and late-life depression in seven low-and middle-income countries. Methodology/Findings: We used cross-sectional data from the 10/66 cohort study and applied two diagnostic criteria for late-life depression to assess the association between categories of weekly fish consumption and depression according to ICD-10 and the EURO-D depression symptoms scale scores, adjusting for relevant confounders. All-catchment area surveys were carried out in Cuba, Dominican Republic, Venezuela, Peru, Mexico, China, and India, and over 15,000 community-dwelling older adults (65+) were sampled. Using Poisson models the adjusted association between categories of fish consumption and ICD-10 depression was positive in India (p for trend = 0.001), inverse in Peru (p = 0.025), and not significant in all other countries. We found a linear inverse association between fish consumption categories and EURO-D scores only in Cuba (p for trend = 0.039) and China (p&lt;0.001); associations were not significant in all other countries. Between-country heterogeneity was marked for both ICD-10 (I-2&gt;61%) and EURO-D criteria (I-2&gt;66%). Conclusions: The associations of fish consumption with depression in large samples of older adults varied markedly across countries and by depression diagnosis and were explained by socio-demographic and lifestyle variables. Experimental studies in these settings are needed to confirm our findings.Multidisciplinary SciencesSCI(E)SSCI0ARTICLE6null

Immunogenicity and Protective Capacity of a Virosomal Respiratory Syncytial Virus Vaccine Adjuvanted with Monophosphoryl Lipid A in Mice

Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is also a significant problem in elderly and immuno-compromised adults. To date there is no efficacious and safe RSV vaccine, partially because of the outcome of a clinical trial in the 1960s with a formalin-inactivated RSV vaccine (FI-RSV). This vaccine caused enhanced respiratory disease upon exposure to the live virus, leading to increased morbidity and the death of two children. Subsequent analyses of this incident showed that FI-RSV induces a Th2-skewed immune response together with poorly neutralizing antibodies. As a new approach, we used reconstituted RSV viral envelopes, i.e. virosomes, with incorporated monophosphoryl lipid A (MPLA) adjuvant to enhance immunogenicity and to skew the immune response towards a Th1 phenotype. Incorporation of MPLA stimulated the overall immunogenicity of the virosomes compared to non-adjuvanted virosomes in mice. Intramuscular administration of the vaccine led to the induction of RSV-specific IgG2a levels similar to those induced by inoculation of the animals with live RSV. These antibodies were able to neutralize RSV in vitro. Furthermore, MPLA-adjuvanted RSV virosomes induced high amounts of IFNγ and low amounts of IL5 in both spleens and lungs of immunized and subsequently challenged animals, compared to levels of these cytokines in animals vaccinated with FI-RSV, indicating a Th1-skewed response. Mice vaccinated with RSV-MPLA virosomes were protected from live RSV challenge, clearing the inoculated virus without showing signs of lung pathology. Taken together, these data demonstrate that RSV-MPLA virosomes represent a safe and efficacious vaccine candidate which warrants further evaluation