Rhinovirus protease cleavage of nucleoporins: perspective on implications for airway remodeling.

Human Rhinoviruses (RV) are a major cause of common colds and infections in early childhood and can lead to subsequent development of asthma via an as yet unknown mechanism. Asthma is a chronic inflammatory pulmonary disease characterized by significant airway remodeling. A key component of airway remodeling is the transdifferentiation of airway epithelial and fibroblast cells into cells with a more contractile phenotype. Interestingly, transforming growth factor-beta (TGF-ß), a well characterized inducer of transdifferentiation, is significantly higher in airways of asthmatics compared to non-asthmatics. RV infection induces TGF-ß signaling, at the same time nucleoporins (Nups), including Nup153, are cleaved by RV proteases disrupting nucleocytoplasmic transport. As Nup153 regulates nuclear export of SMAD2, a key intermediate in the TGF-ß transdifferentiation pathway, its loss of function would result in nuclear retention of SMAD2 and dysregulated TGF-ß signaling. We hypothesize that RV infection leads to increased nuclear SMAD2, resulting in sustained TGF-ß induced gene expression, priming the airway for subsequent development of asthma. Our hypothesis brings together disparate studies on RV, asthma and Nup153 with the aim to prompt new research into the role of RV infection in development of asthma.

Extra-Low-Frequency Pulse Stimulated Conformational Change in Blood-Cell Proteins and Consequent Immune Activity Transformation.

Objective: investigation of the extra-low-frequency (ELF) stimulation effect on blood-cell proteins, that causes variation in its electrostatic-state. A hypothesis that this results in the conformational change in the blood-cell proteins which could enhance immune activity is explored. Since HIV-1 and host-cell engage through charge-charge interactions, an electrical-pulse may cause charge redistribution, hypothetically resulting in host-cell proteins to be isolated from viral access. Methods: Buffy coat samples were exposed to ELF square waveform pulses of 5Hz, 10Hz and 1MHz, for 2-hours, and were then examined using immunofluorescence technique. The expression of glycoprotein CD4, and co-receptor protein CCR5, were investigated. Also, the binding activity of the N-terminal domain of CCR5 and the distribution of the nuclear-pore-complex (NPC) transport factor, FGNup153 were investigated. Comparison with control samples were carried out. Results: Increased CD4 count, which could enhance the immune system. In addition, the inability of N-terminus-specific antibody 3A9 to bind to CCR5 N-terminal, could be due to the interactions with the ELF electric-field, which may also hypothetically inhibit HIV-1 attachment. Furthermore, the electrostatic interactions between the ELF pulse and the FGNup153 induces redistribution in its disorder sequence and possibly causes conformational change. This could possibly prevent large virus particle transport through the NPC. Conclusion: Novel concept of ELF stimulation of blood cellular proteins has been developed leading to transformation of immune activity. Clinical-Impact: The translational aspect is the use of ELF as an avenue of electro-medicine and the results are a possible foundation for the clinical application of ELF stimulation in immune response.