Chronic diseases are the leading cause of death worldwide with increasing prevalence in all age groups, genders, and ethnicities. Most chronic disease deaths occur in middle-to low-income countries ...but are also a significant health problem in developed nations. Multiple chronic diseases now affect children and adolescents as well as adults. Being physically inactive is associated with increased chronic disease risk. Global societies are being negatively impacted by the increasing prevalence of chronic disease which is directly related to rising healthcare expenditures, workforce complications regarding attendance and productivity, military personnel recruitment, and academic success. However, increased physical activity (PA) and exercise are associated with reduced chronic disease risk. Most physiologic systems in the body benefit positively from PA and exercise by primary disease prevention and secondary disease prevention/treatment. The purpose of this brief review is to describe the significant global problem of chronic diseases for adults and children, and how PA and exercise can provide a non-invasive means for added prevention and treatment.
Early-life severe respiratory syncytial virus (RSV) infection has been associated with the onset of childhood wheezing illnesses. However, the relationship between RSV infection during infancy and ...the development of childhood asthma is unclear. We aimed to assess the association between RSV infection during infancy and childhood asthma.
INSPIRE is a large, population-based, birth cohort of healthy infants with non-low birthweight born at term between June and December, 2012, or between June and December, 2013. Infants were recruited from 11 paediatric practices across middle Tennessee, USA. We ascertained RSV infection status (no infection vs infection) in the first year of life using a combination of passive and active surveillance with viral identification through molecular and serological techniques. Children were then followed up prospectively for the primary outcome of 5-year current asthma, which we analysed in all participants who completed 5-year follow-up. Statistical models, which were done for children with available data, were adjusted for child's sex, race and ethnicity, any breastfeeding, day-care attendance during infancy, exposure to second-hand smoke in utero or during early infancy, and maternal asthma.
Of 1946 eligible children who were enrolled in the study, 1741 (89%) had available data to assess RSV infection status in the first year of life. The proportion of children with RSV infection during infancy was 944 (54%; 95% CI 52–57) of 1741 children. The proportion of children with 5-year current asthma was lower among those without RSV infection during infancy (91 16% of 587) than those with RSV infection during infancy (139 21% of 670; p=0·016). Not being infected with RSV during infancy was associated with a 26% lower risk of 5-year current asthma than being infected with RSV during infancy (adjusted RR 0·74, 95% CI 0·58–0·94, p=0·014). The estimated proportion of 5-year current asthma cases that could be prevented by avoiding RSV infection during infancy was 15% (95% CI 2·2–26·8).
Among healthy children born at term, not being infected with RSV in the first year of life was associated with a substantially reduced risk of developing childhood asthma. Our findings show an age-dependent association between RSV infection during infancy and childhood asthma. However, to definitively establish causality, the effect of interventions that prevent, delay, or decrease the severity of the initial RSV infection on childhood asthma will need to be studied.
US National Institutes of Health.
The newly emerged human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic of respiratory illness. Current evidence suggests that severe cases of ...SARS-CoV-2 are associated with a dysregulated immune response. However, little is known about how the innate immune system responds to SARS-CoV-2. In this study, we modeled SARS-CoV-2 infection using primary human airway epithelial (pHAE) cultures, which are maintained in an air-liquid interface. We found that SARS-CoV-2 infects and replicates in pHAE cultures and is directionally released on the apical, but not basolateral, surface. Transcriptional profiling studies found that infected pHAE cultures had a molecular signature dominated by proinflammatory cytokines and chemokine induction, including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and CXCL8, and identified NF-κB and ATF-4 as key drivers of this proinflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III interferon (IFN) response to SARS-CoV-2 infection. However, pretreatment and posttreatment with type I and III IFNs significantly reduced virus replication in pHAE cultures that correlated with upregulation of antiviral effector genes. Combined, our findings demonstrate that SARS-CoV-2 does not trigger an IFN response but is sensitive to the effects of type I and III IFNs. Our studies demonstrate the utility of pHAE cultures to model SARS-CoV-2 infection and that both type I and III IFNs can serve as therapeutic options to treat COVID-19 patients.
The current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. Our research identifies an excellent system to model SARS-CoV-2 infection of the human airways that can be used to test various treatments. Analysis of infection in this model system found that human airway epithelial cell cultures induce a strong proinflammatory cytokine response yet block the production of type I and III IFNs to SARS-CoV-2. However, treatment of airway cultures with the immune molecules type I or type III interferon (IFN) was able to inhibit SARS-CoV-2 infection. Thus, our model system identified type I or type III IFN as potential antiviral treatments for COVID-19 patients.
Background The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives We sought to determine the ...effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Results Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Conclusions Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease in young children and a substantial contributor to respiratory tract disease throughout life and as such ...a high priority for vaccine development. However, after nearly 60 years of research no vaccine is yet available. The challenges to developing an RSV vaccine include the young age, 2-4 months of age, for the peak of disease, the enhanced RSV disease associated with the first RSV vaccine, formalin-inactivated RSV with an alum adjuvant (FI-RSV), and difficulty achieving protection as illustrated by repeat infections with disease that occur throughout life. Understanding the biology of infection and disease pathogenesis has and will continue to guide vaccine development. In this paper, we review the roles that RSV proteins play in the biology of infection and disease pathogenesis and the corresponding contribution to live attenuated and subunit RSV vaccines. Each of RSV's 11 proteins are in the design of one or more vaccines. The G protein's contribution to disease pathogenesis through altering host immune responses as well as its role in the biology of infection suggest it can make a unique contribution to an RSV vaccine, both live attenuated and subunit vaccines. One of G's potential unique contributions to a vaccine is the potential for anti-G immunity to have an anti-inflammatory effect independent of virus replication. Though an anti-viral effect is essential to an effective RSV vaccine, it is important to remember that the goal of a vaccine is to prevent disease. Thus, other effects of the infection, such as G's alteration of the host immune response may provide opportunities to induce responses that block this effect and improve an RSV vaccine. Keeping in mind the goal of a vaccine is to prevent disease and not virus replication may help identify new strategies for other vaccine challenges, such as improving influenza vaccines and developing HIV vaccines.
Assays that can characterize MSC immune potency need to be identified for use in advanced clinical trials. MSCs possess a number of putative regenerative and immunomodulatory properties, and an assay ...matrix approach may best capture involved effector pathways. We have tested two assay systems to measure the potency of MSCs derived from human subjects: MSC secretome analysis and a quantitative RNA-based array for genes specific to immunomodulatory and homing properties of MSCs. Secretome analysis identified a unique cytokine signature that is upregulated by MSCs or downregulated in responder PBMCs and correlated with T cell suppression. Use of interferon-γ as a surrogate for the action of activated PBMCs on MSCs served as an alternative for the use of human PBMCs as responder cells in a potency assay. Our approach and results define and simplify the multifunctional or matrix responses of MSCs and may serve as a platform for robust potency analysis.
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•T cell suppression by MSCs correlates with cytokine and morphogen expression•MSC and responder PBMC interactions are bidirectional•MSC potency affects the secretome and correlates with T cell suppression•The matrix response of MSCs to PBMCs is replicated by IFNγ stimulation
Assays that inform on mesenchymal stromal cell (MSC) immune potency need to be defined in advanced clinical trials. Chinnadurai et al. tested an in vitro assay matrix approach combining molecular genetic and secretome analysis, elements of which could be deployed to define MSC immune modulatory potency.
Respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections in children <5 years of age worldwide and repeated infections throughout life leading to serious ...disease in the elderly and persons with compromised immune, cardiac, and pulmonary systems. The disease burden has made it a high priority for vaccine and antiviral drug development but without success except for immune prophylaxis for certain young infants. Two RSV proteins are associated with protection, F and G, and F is most often pursued for vaccine and antiviral drug development. Several features of the G protein suggest it could also be an important to vaccine or antiviral drug target design. We review features of G that effect biology of infection, the host immune response, and disease associated with infection. Though it is not clear how to fit these together into an integrated picture, it is clear that G mediates cell surface binding and facilitates cellular infection, modulates host responses that affect both immunity and disease, and its CX3C aa motif contributes to many of these effects. These features of G and the ability to block the effects with antibody, suggest G has substantial potential in vaccine and antiviral drug design.
distinct lineage of influenza A virus from bats Tong, Suxiang; Li, Yan; Rivailler, Pierre ...
Proceedings of the National Academy of Sciences,
03/2012, Letnik:
109, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Influenza A virus reservoirs in animals have provided novel genetic elements leading to the emergence of global pandemics in humans. Most influenza A viruses circulate in waterfowl, but those that ...infect mammalian hosts are thought to pose the greatest risk for zoonotic spread to humans and the generation of pandemic or panzootic viruses. We have identified an influenza A virus from little yellow-shouldered bats captured at two locations in Guatemala. It is significantly divergent from known influenza A viruses. The HA of the bat virus was estimated to have diverged at roughly the same time as the known subtypes of HA and was designated as H17. The neuraminidase (NA) gene is highly divergent from all known influenza NAs, and the internal genes from the bat virus diverged from those of known influenza A viruses before the estimated divergence of the known influenza A internal gene lineages. Attempts to propagate this virus in cell cultures and chicken embryos were unsuccessful, suggesting distinct requirements compared with known influenza viruses. Despite its divergence from known influenza A viruses, the bat virus is compatible for genetic exchange with human influenza viruses in human cells, suggesting the potential capability for reassortment and contributions to new pandemic or panzootic influenza A viruses.
Ordered and Dynamic Assembly of Single Spliceosomes Hoskins, Aaron A; Friedman, Larry J; Gallagher, Sarah S ...
Science (American Association for the Advancement of Science),
03/2011, Letnik:
331, Številka:
6022
Journal Article
Recenzirano
Odprti dostop
The spliceosome is the complex macromolecular machine responsible for removing introns from precursors to messenger RNAs (pre-mRNAs). We combined yeast genetic engineering, chemical biology, and ...multiwavelength fluorescence microscopy to follow assembly of single spliceosomes in real time in whole-cell extracts. We find that individual spliceosomal subcomplexes associate with pre-mRNA sequentially via an ordered pathway to yield functional spliceosomes and that association of every subcomplex is reversible. Further, early subcomplex binding events do not fully commit a pre-mRNA to splicing; rather, commitment increases as assembly proceeds. These findings have important implications for the regulation of alternative splicing. This experimental strategy should prove widely useful for mechanistic analysis of other macromolecular machines in environments approaching the complexity of living cells.
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