Asthma exacerbations are caused primarily by viral infections. Antisense and small interfering RNA (siRNA) technologies have gained attention as potential antiasthma and antiviral approaches. In this study we analyzed whether gene silencing of interleukin (IL)-4 expression and respiratory syncytial virus (RSV) replication by RNA interference is able to suppress allergen- and virus-induced responses in a mouse model of virus-induced asthma exacerbation. Knockdown efficacy of IL-4 siRNA molecules was analyzed in the human HEK293T cell line by cotransfection of six different siRNAs with a plasmid carrying mouse IL-4. The most potent siRNA was then used in a mouse model of RSV-induced asthma exacerbation. BALB/c mice were sensitized intraperitoneally with ovalbumin (OVA) and then infected 12 days later intranasally with RSV Long strain (1×10(6) TCID50/mouse), followed 1 day later by intranasal challenge with OVA for 3 days. Mice were pretreated intranasally three times with either siRNA to IL-4 or GFP control, 2 days before, and on the first two OVA challenge days. siRNAs to RSV or rhinovirus control were inoculated intranasally once, 3 hr before RSV infection. Combined anti-IL-4 and anti-RSV siRNAs were able to significantly reduce total cell counts and eosinophilia in bronchoalveolar lavage fluid, development of airway hyperresponsiveness, and airway inflammation and to downregulate IL-4 mRNA expression and RSV viral RNA, but to upregulate IFN-γ levels in lung tissues. We conclude that anti-helper T cells type 2 and antiviral siRNAs may constitute a new therapeutic approach for treatment of virus induced asthma exacerbations.
The European Virus Archive (EVA) was created in 2008 with funding from the FP7-EU Infrastructure Programme, in response to the need for a coordinated and readily accessible collection of viruses that could be made available to academia, public health organisations and industry. Within three years, it developed from a consortium of nine European laboratories to encompass associated partners in Africa, Russia, China, Turkey, Germany and Italy. In 2014, the H2020 Research and Innovation Framework Programme (INFRAS projects) provided support for the transformation of the EVA from a European to a global organization (EVAg). The EVAg now operates as a non-profit consortium, with 26 partners and 20 associated partners from 21 EU and non-EU countries. In this paper, we outline the structure, management and goals of the EVAg, to bring to the attention of researchers the wealth of products it can provide and to illustrate how end-users can gain access to these resources. Organisations or individuals who would like to be considered as contributors are invited to contact the EVAg coordinator, Jean-Louis Romette, at jean-louis.romette@univmed.fr.
Tuberculosis (TB) and HIV have profound effects on the immune system, which can lead to the activation of viral replication and negatively regulate the activation of T cells. Dysregulation in the production of cytokines necessary to fight HIV and M. tuberculosis may ultimately affect the results of the treatment and be important in the pathogenesis of HIV infection and TB. This work presents the results of a study of the expression of pro- and anti-inflammatory cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-1RA) in drug-naïve patients with dual infection of HIV/TB at the late stages of HIV-infection, with newly diagnosed HIV and TB, and previously untreated HIV in the process of receiving antiretroviral (ART) and TB treatment vs. a cohort of patients with HIV monoinfection and TB monoinfection. The study revealed that during a double HIV/TB infection, both Th1 and Th2 immune responses are suppressed, and a prolonged dysregulation of the immune response and an increased severity of the disease in pulmonary/extrapulmonary tuberculosis is observed in HIV/TB co-infection. Moreover, it was revealed that a double HIV/TB infection is characterized by delayed and incomplete recovery of immune activity. High levels of IL-6 were detected in patients with HIV/TB co-infection before initiation of dual therapy (2.1-fold increase vs. HIV), which persisted even after 6 months of treatment (8.96-fold increase vs. HIV), unlike other cytokines. The persistent enhanced expression of IL-6 in patients with dual HIV/TB co-infection allows the consideration of it as a potential marker of early detection of M. tuberculosis infection in HIV-infected individuals. The results of multivariate regression analysis showed a statistical trend towards an increase in the incidence of IRIS in patients with high IL-1Ra levels (in the range of 1550–2500 pg/mL): OR = 4.3 (95%CI 3.7–14.12, p = 0.53), which also allows IL-1Ra to be considered as a potential predictive biomarker of the development of TB-IRIS and treatment outcomes.
Stress adaptations often include a trade‐off of weakened performance in nonlocal conditions, resulting in divergent selection, and potentially, genetic differentiation and evolutionary adaptation. Results of a two‐phase (greenhouse and field) common garden experiment demonstrated adaptation of mountain birch (Betula pubescens subsp. czerepanovii) populations from industrially polluted areas of the Kola Peninsula, north‐western Russia, to heavy metals (HM), whereas no adaptations to wind or drought stress were detected in populations from wind‐exposed sites. HM‐adapted seedlings were maladapted to drought but less palatable (co‐resistant) to insect herbivores, even under background HM concentrations. The absence of adaptations to harsh microclimate and the generally high adaptive potential of mountain birch, a critical forest forming tree in subarctic Europe, need to be accounted for in models predicting consequences of human‐driven environmental changes, including the projected climate change.
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