Localization of Human Rhinovirus Replication in the Upper Respiratory Tract by In Situ Hybridization

Arruda, Eurico; Boyle, Timothy R.; Winther, Birgit; Pevear, Daniel C.; Gwaltney, Jack M.; Hayden, Frederick G.

doi:10.1093/infdis/171.5.1329

Cited by 156 publications

(117 citation statements)

References 8 publications

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“…However, we have shown viral replication and IFN responses in response to RV infection. Also, we believe the distinct nature of human RV infection, which causes minimal cytotoxicity (36,37) and infects relatively few cells in the airway compared with other respiratory viruses (38)(39)(40), argues in favor of the RV model despite the relatively low levels of replication. Another potential concern relates to its dependence on minor group viruses.…”

Section: Original Researchmentioning

confidence: 93%

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Chung¹,

Hong

Lei³

et al. 2015

Am J Respir Cell Mol Biol

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Rhinovirus (RV) causes asthma exacerbations. Previously, we showed that adherent bronchoalveolar cells from allergen-treated mice produce IL-13 when stimulated with RV ex vivo, implicating cells of the monocyte/macrophage lineage in viral-induced airway inflammation. In this study, we hypothesized that RV infection of allergen-treated mice results in IL-13 production by CD11b1 exudative macrophages in vivo. We sensitized and challenged BALB/c mice with ovalbumin (OVA), after which mice were inoculated with RV or sham HeLa cell lysate. After 1 day, lungs were harvested, and cell suspensions were analyzed by flow cytometry. We repeated this process in IL-13 reporter mice, CD11b-DTR mice in which diphtheria toxin selectively depletes CD11b1 cells, and chemokine receptor 2 (CCR2) null mice. We found that lungs of mice infected with RV alone showed increases in CD451, CD681, F4/801, Ly6C1, and CD11b high cells, indicating an influx of inflammatory monocytes and exudative macrophages. The combination of OVA and RV had synergistic effects on the exudative macrophage number. However, CD11b1 cells from OVA-treated, RV-infected mice showed M2 polarization, including expression of CD206 and CD301 and production of IL-13. Similar results were obtained in IL-13 reporter mice. Diphtheria toxin depleted CD11b1, IL-13-producing cells in OVA-treated, RV-infected, CD11b-DTR mice, decreasing airway inflammation and responsiveness. CD11b1, Ly6C1 cells were reduced in CCR2 knockout mice. We conclude that, in contrast to naive mice, RV infection of mice with allergic airways disease induces an influx of IL-13-producing CD11b1 exudative macrophages bearing M2 macrophage markers. This finding further implicates alternatively activated macrophages in RV-induced asthma exacerbations.

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Section: Original Researchmentioning

confidence: 93%

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Chung¹,

Hong

Lei³

et al. 2015

Am J Respir Cell Mol Biol

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“…With viruses such as HRV that infect relatively few cells in the airway (1,81), inflammatory responses contribute to respiratory symptoms. The majority of the cells recruited to the airway during acute colds are neutrophils, with smaller numbers of mononuclear cells and, in some studies, eosinophils.…”

Section: Hrv Pathogenesismentioning

confidence: 99%

The ABCs of Rhinoviruses, Wheezing, and Asthma

Gern

2010

J Virol

235

226

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Human rhinoviruses (HRVs) were discovered as common cold pathogens over 50 years ago. Recent advances in molecular viral diagnostics have led to an appreciation of their role in more-significant respiratory illnesses, including bronchiolitis in infancy, childhood pneumonia, and acute exacerbations of chronic respiratory diseases such as asthma, chronic obstructive lung disease, and cystic fibrosis. Until a few years ago, only two groups of HRVs (A and B) had been recognized. However, full and partial sequencing of HRVs led to the discovery of a third species of HRV (HRV-C) that has distinct structural and biologic features. Risk factors and pathogenic mechanisms for more-severe HRV infections are being defined, and yet fundamental questions persist about mechanisms relating this common pathogen to allergic diseases and asthma. The close relationship between HRV infections and asthma suggests that antiviral treatments could have a major impact on the morbidity associated with this chronic respiratory disease.Virology and clinical textbooks and virtually all web-based information sources generally describe human rhinoviruses (HRVs) as the most frequent cause of the common cold. In this light, HRVs are important pathogens because common colds are so widespread and annoying, and from an economic perspective, supplying symptomatic-relief medications is a huge industry. A 2003 study estimated that expenditures on common cold medications in the United States exceeded 4 billion dollars, including 1.1 billion dollars spent on inappropriate prescriptions for antibiotics (18). Finding a cure for the common cold has been a much-publicized goal ever since HRVs were first discovered in the 1950s and 1960s. The basic biology of the replication cycle was soon described, and most HRVs were found to replicate best at 33°to 35°C (88, 99), which is consistent with their role as upper airway pathogens. HRVs were found to have tremendous diversity, and approximately 100 serotypes in two groups (A and B) had been identified by 1990, when it was presumed that all, or nearly all, HRVs had been identified. These HRVs were found to bind to one of two main receptors: ICAM-1 (major group) (30) and the low-density-lipoprotein receptor (most of the minor group) (35). Despite advances in understanding HRV genetics and the picornavirus replication cycle, efforts toward developing specific antivirals have fallen short due to modest efficacy, side effects, drug interactions, and economic considerations (16). Consequently, enthusiasm for pursuing a common cold cure has waned, and the pharmaceutical industry has refocused attention on viruses that cause more-significant illnesses. This failure is a bit embarrassing. As summarized by White and Fenner, "In this era of organ transplantation, genetic engineering, and other dramatic demonstrations of the wonders of medical science, the man in the street perceives a certain irony in the inability of modern medicine to make the slightest impact on that most trivial of all human ailments, the common cold" ...

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“…Of these viruses, rhinoviruses (RV) are the most common pathogen detected during an asthma or COPD exacerbation, with at least half of viral triggered episodes being associated with RV (4,8,9). The major group of RV including the RV16 strain uses the intercellular adhesion molecule (ICAM-1) as a receptor to infect the respiratory epithelium (11). Because rhinovirus is not itself cytopathic, the intensity of inflammation during the host immune response is thought to be a critical determinant of exacerbation severity (2).…”

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Signaling to Erk1/2 and STATs Control the Intensity of the Epithelial Inflammatory Responses to Rhinovirus Infection

Liu¹,

Gualano²,

Hibbs

et al. 2008

Journal of Biological Chemistry

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Rhinovirus infection is the most common cause of acute exacerbations of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease, where it provokes steroid refractory and abnormally intense neutrophilic inflammation that can be life threatening. Epidermal growth factor receptor (EGFR) expression correlates with disease severity and neutrophil infiltration in these conditions. However, the role of EGFR signaling in rhinovirus infection is unknown. We measured the key determinants of neutrophilic inflammation interleukin (IL)-8 and ICAM-1 in rhinovirus (RV16 serotype)-infected bronchial epithelial cells, BEAS-2B. RV16 infection stimulated IL-8 and ICAM-1 expression, which was further elevated (2-fold) by transient up-regulation of EGFR levels. Detection of viral RNA by quantitative real time PCR confirmed that enhanced expression was not associated with increased viral replication. EGFR ligands (epiregulin, amphiregulin, and heparin-binding epidermal growth factor) were induced by RV16 infection, and inhibition of metalloproteases responsible for ligand shedding partially suppressed this response. The EGFR inhibitor AG1478, completely blocked IL-8 and ICAM-1 expression to basal levels, as did the specific Erk1/2 inhibitor U0126. The p38 mitogen-activated protein kinase inhibitor SB203580 blocked IL-8 secretion but not ICAM-1 expression, whereas the PI3K inhibitor wortmannin was ineffective in both responses. Kinase inactive K721R EGFR, which is selectively deficient in STAT signaling, reversed RV16 responses associated with EGFR overexpression. In conclusion, RV16 infection rapidly promotes induction of EGFR ligands and utilizes EGFR signaling to increase IL-8 and ICAM-1 levels. These results suggest that targeting EGFR may provide a selective therapy that dampens neutrophil-driven inflammation without compromising essential antiviral pathways mediated by pathogen recognition receptors such as TLR3.

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Localization of Human Rhinovirus Replication in the Upper Respiratory Tract by In Situ Hybridization

Cited by 156 publications

References 8 publications

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

The ABCs of Rhinoviruses, Wheezing, and Asthma

Epidermal Growth Factor Receptor Signaling to Erk1/2 and STATs Control the Intensity of the Epithelial Inflammatory Responses to Rhinovirus Infection

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