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Rhinoviruses are the major cause of the common cold and a trigger of acute asthma exacerbations. Whether these exacerbations result from direct infection of the lower airway or from indirect mechanisms consequent on infection of the upper airway alone is currently unknown. Lower respiratory infection was investigated in vitro by exposing primary human bronchial epithelial cells to rhinoviruses and in vivo after experimental upper respiratory infection of human volunteers. Bronchial infection was confirmed by both approaches. Furthermore, rhinoviruses induced production of interleukin-6, -8, and -16 and RANTES and were cytotoxic to cultured respiratory epithelium. This evidence strongly supports a direct lower respiratory epithelial reaction as the initial event in the induction of rhinovirus-mediated asthma exacerbations. The frequency of infection and the nature of the inflammatory response observed are similar to those of the upper respiratory tract, suggesting that rhinovirus infections may be one of the most important causes of lower in addition to upper respiratory disease.

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The epidemiological studies cited have indicated that viruses are commonly associated with wheezing illnesses in populations, in individuals, and in time, but, unlike bacteria, are rarely found during asymptomatic periods. Viruses have been identified in up to 50% of wheezing illnesses and asthma exacerbations occurring in childhood, and in up to 20% of those in adults. In childhood the predominant organisms identified have been rhinoviruses. RSV and parainfluenza viruses, but coronaviruses have not been studied adequately. Wheezing appears to be more common during rhinovirus and RSV than other virus infections in children spontaneously presenting with respiratory infections to medical care, but all virus groups have been incriminated, and in general, wheezing occurs in upwards of 50% of viral infections in asthmatics followed prospectively. The few adult studies available show little difference between viruses in identification rates during wheezing, or propensity to result in wheezing. The predominant viruses change with age, and children with asthma seem to be more prone to symptomatic virus infections than other children, although the presence of atopy alone does not appear to be important. There are important gaps in our knowledge of the epidemiology of virus-associated wheezing attacks, and further prospective studies are required, using early investigation and sensitive methods for identifying rhinoviruses and coronaviruses, to study severe asthma in children and adults. It is hoped that the use of nucleic acid hybridization and newer antigen-detection techniques will improve the ability to identify difficult viruses such as coronaviruses and rhinoviruses in the future. The ability to identify subclinical infections and compare the ratio of subclinical to clinical infections in normal and asthmatic children would be useful but would require intense monitoring of both groups for an extended period (minimum 12 months to cover seasonal variation) with full virological studies every 2-4 weeks-a difficult and expensive task. Another important line of study would be to prospectively document indoor aeroallergen exposure and virus infections in the same individuals, and compare their importance as precipitants of acute severe asthma attacks. With a clearer understanding of the groups at risk for asthma attacks, and the factors which put them at risk and precipitate their attacks, effective preventive strategies will become more feasible.

†These authors contributed equally to this publication.Dengue virus nonstructural protein 5 (NS5) is a large multifunctional protein with a central role in viral replication. We previously identified two nuclear localization sequences (NLSs) within the central region of dengue virus type-2 (DENV-2) NS5 ('aNLS' and 'bNLS') that are recognized by the importin a/b and importin b1 nuclear transporters, respectively. Here, we demonstrate the importance of the kinetics of NS5 nuclear localization to virus production for the first time and show that the aNLS is responsible. Site-specific mutations in the bipartitetype aNLS or bNLS region were introduced into a reporter plasmid encoding green fluorescent protein fused to the N-terminus of DENV-2 NS5, as well as into DENV-2 genomic length complementary DNA. Mutation of basic residues in the highly conserved region of the bNLS did not affect nuclear import of NS5. In contrast, mutations in either basic cluster of the aNLS decreased NS5 nuclear accumulation and reduced virus production, with the greatest reduction observed for mutation of the second cluster (K 387 K 388 K 389 ); mutagenesis of both clusters abolished NS5 nuclear import and DENV-2 virus production completely. The latter appeared to relate to the impaired ability of virus lacking nuclear-localizing NS5, as compared with wild-type virus expressing nuclear-localizing NS5, to reduce interleukin-8 production as part of the antiviral response. The results overall indicate that NS5 nuclear localization through the aNLS is integral to viral infection, with significant implications for other flaviviruses of medical importance, such as yellow fever and West Nile viruses.

Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

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