a b s t r a c t Background: Coronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. Longacting muscarinic antagonists and b 2 -agonists and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including Please cite this article as: Yamaya M et al., Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells, Respiratory Investigation, https:// Available online xxx Keywords: Airway epithelial cells HCoV-229E CD13 Long-acting b 2 agonist Long-acting muscarinic antagonist HCoV-229E. However, the effects of these drugs on HCoV-229E replication and infectioninduced inflammation in the human airway are unknown. Methods: Primary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E. Results: Pretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-b.Treatment of the cells with the CD13 inhibitor 2 0 2 0 -dipyridyl decreased viral titers.Pretreatment of the cells with a combination of three drugs (glycopyrronium, formoterol, and budesonide) exerted additive inhibitory effects on viral titers and cytokine production.Pretreatment of HNE cells with glycopyrronium or formoterol reduced the susceptibility to infection, and pretreatment with the three drugs inhibited activation of nuclear factorkappa B p50 and p65 proteins. Pretreatment with formoterol increased cAMP levels and treatment with cAMP decreased viral titers, CD13 expression, and the fluorescence intensity of acidic endosomes.Conclusions: These findings suggest that glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibit HCoV-229E replication partly by inhibiting receptor expression and/or endosomal function and that these drugs modulate infection-induced inflammation in the airway.
Human coronavirus NL63 recently found in The Netherlands has been detected in Japan with a reverse transcription-polymerase chain reaction technique in clinical specimens from pediatric patients with respiratory symptoms. Of 419 specimens that were negative for common respiratory viruses, 5 were positive for human coronavirus NL63, and these specimens were all collected in the first 3 months of 2003.
Human coronavirus (HCoV) is a causative agent of the common cold. Although HCoV is highly prevalent in the world, studies of the genomic and antigenic details of circulating HCoV strains have been limited. In this study, we compared four Japanese isolates with the standard HCoV-229E strain obtained from ATCC (ATCC-VR740) by focusing on the spike (S) protein, a major determinant of neutralizing antigen and pathogenicity. The isolates were found to have nucleotide deletions and a number of sequence differences in the S1 region of the S protein. We compared two of the Japanese isolates with the ATCC-VR740 strain by using virus-neutralizing assays consisting of infectious HCoV-229E particles and vesicular stomatitis virus (VSV)-pseudotyped virus carrying the HCoV-229E S protein. The two clinical isolates (Sendai-H/1121/04 and Niigata/01/08) did not react with antiserum to the ATCC-VR740 strain via the neutralizing test. We then constructed a pseudotype VSV-harboured chimeric S protein with the ATCC S1 and Sendai S2 regions or that with Sendai S1 and ATCC S2 regions and compared them by a neutralization test. The results revealed that the difference in the neutralizing antigenicity depends on the S1 region. This different antigenic phenotype was also confirmed by a neutralizing test with clinically isolated human sera. These results suggest that the HCoV-229E viruses prevalent in Japan are quite different from the laboratory strain ATCC-VR740 in terms of the S sequence and neutralization antigenicity, which is attributed to the difference in the S1 region. INTRODUCTIONThe coronavirus (CoV) is an enveloped virus with a singlestranded, positive RNA genome of about 30 kb. Moreover, the virion is approximately 80-120 nm in diameter (Lai, 1990;Lai & Cavanagh, 1997) and is characterized in electron micrographs by its crown-like appearance of spikes protruding from the virion envelope (Lai, 1990;Lai & Cavanagh, 1997). A variety of virus species that infect domestic animals, as well as pets, are classified as CoVs. Some CoVs are highly pathogenic while others exhibit low virulence. Before severe acute respiratory syndrome (SARS)-CoV was reported in 2003(Peiris et al., 2004, only low-virulence human CoVs (HCoVs), such as 229E or OC43, were known to exist. After the SARS outbreak, more virulent HCoVs, such as HKU1 (Woo et al., 2005) and NL63 (van der Hoek et al., 2004), were isolated from humans with respiratory diseases.HCoV-229E, which was first reported in 1966 (Hamre & Procknow, 1966), is a prototype of HCoV and belongs to the genus Alphacoronavirus, together with HCoV-NL63. Both cause respiratory diseases in human infants (van der Hoek et al., 2004). Dijkman et al. (2008) reported that 75 and 65 % of the children between the age of 2.5 and 3.5 years were seropositive for NL63 and HCoV-229E, respectively, and most of the children seroconverted against both viruses by the age of six. This may mean that most people experience acute infection by these HCoVs during their childhood. However, while HCoV is highly A supplementar...
Respiratory viruses were detected in 360 of 1092 NPS specimens, including 157 isolates of respiratory syncytial virus and 88 of influenza virus. Among 1092 MEF specimens, 102 were virus-positive, including 43 for respiratory syncytial virus and 29 for influenza virus. In 75 children, respiratory viruses were only detected in MEF. The viral detection rate was higher in children with fever at an early stage of their illness. The tympanic membrane changes associated with viral infection tended to be less severe, while changes were more severe in cases with bacterial infection, especially co-infection with bacteria and viruses.
Nasal and middle ear specimens collected from children with acute otitis media were subjected to viral isolation and bacteria culture. All virus-negative specimens underwent reverse transcription polymerase chain reaction to detect human metapneumovirus. Three of 126 middle ear specimens were positive by this assay.
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