Early-life heterologous rhinovirus infections induce an exaggerated asthma-like phenotype

Rajput, Charu; Han, Mingyuan; Ishikawa, Tomoko; Lei, Jing; Jazaeri, Seyedehzarifeh; Bentley, J. Kelley; Hershenson, Marc B.

doi:10.1016/j.jaci.2020.03.039

Cited by 21 publications

(26 citation statements)

References 41 publications

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“…We examined RV-C15-induced cytokine responses in ILC2deficient Rora fl/fl Il7r Cre mice and Rora fl/fl littermates. We previously found that six day-old Rora fl/fl Il7r Cre mice fail to show ILC2 expansion after RV-A1B infection despite a small increase in viral load, demonstrating the effectiveness of this knockout (48). RV-C15 infection increased airway eosinophilic inflammation (Figure 10A) and mRNA expression of IL-13, Muc5ac and Muc5b in Rora fl/fl mice but not Rora fl/fl Il7r Cre littermates (Figure 10B).…”

Section: Potential Contribution Of Ilc2s To Rv-c-induced Airway Inflammationmentioning

confidence: 83%

Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

et al. 2021

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Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.

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Section: Potential Contribution Of Ilc2s To Rv-c-induced Airway Inflammationmentioning

confidence: 83%

Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

et al. 2021

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“…Together, these results suggest that activation of lung ILC2 by IL-33 during early-life may "train" ILC2 within the lung that become long-lived resident cells that have stronger type 2 responses to challenges later in life. As indicated in the previous sections, early-life respiratory viral infections likely enhance disease associated "training" that can influence later disease phenotypes (41,43,44,46).…”

Section: Trained Ilc2 Immunity and Exacerbated Lung Disease Lasting Impact Of Activation Of Ilc2 In Lung Development And Viral Infectionsmentioning

confidence: 90%

“…In addition to RSV-driven immunopathology, ILC2 have also been implicated in pathologies related to early-life rhinovirus (RV) infection (40,42,(46)(47)(48). Similar to RSV studies, it was determined that rhinovirus infection in neonatal mice led to increased IL-13-producing ILC2 that was not seen in mature mice (47).…”

Section: Rhinovirusmentioning

confidence: 95%

“…This latter study determined that IL-13-producing ILC2 were activated through IL-33 production from alveolar macrophages following NLRP3-inflammasome activation by the influenza virus leading to airway hyperreactivity (AHR) (39). Further studies using animal modeling, have discovered that ILC2 are increased in the lungs following other respiratory virus infections, such as RSV and rhinovirus infection (11,(40)(41)(42)(43)(44)(45)(46)(47)(48). Also, of note, early in life males are more susceptible to severe disease caused by respiratory viruses compared to females.…”

Section: Role Of Ilc2 In Th2-induction During Respiratory Viral Infectionmentioning

confidence: 98%

“…Furthermore, a direct effect of IFN-g on ILC2 was suggested since there was a reduction in IL-13-producing ILC2 without altering the expression of IL-25, IL-33 or TSLP (48). Importantly, studies that limit ILC2 induction, utilizing an ROR-a inhibitor (SR3335) or genetic deletion of ROR-a, either using complete knockout mice (RORa sg/sg ) or conditional knockout mice to target only ILC2 (Rora/ Il7r Cre+ ), led to protection from severe disease induced by RV infection (42,46). Unlike RSV infection (43,45), RV infection did not drive IL-1b, and neonatal infection in mice lacking IL-1b signaling (NLRP3-/-mice or chemical inhibition of IL-1b) led to enhanced RV-induced Th2 cytokine expression and mucus metaplasia (62).…”

Section: Rhinovirusmentioning

confidence: 99%

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Role of ILC2 in Viral-Induced Lung Pathogenesis

et al. 2021

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Innate lymphoid type-2 cells (ILC2) are a population of innate cells of lymphoid origin that are known to drive strong Type 2 immunity. ILC2 play a key role in lung homeostasis, repair/remodeling of lung structures following injury, and initiation of inflammation as well as more complex roles during the immune response, including the transition from innate to adaptive immunity. Remarkably, dysregulation of this single population has been linked with chronic lung pathologies, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrotic diseases (IPF). Furthermore, ILC2 have been shown to increase following early-life respiratory viral infections, such as respiratory syncytial virus (RSV) and rhinovirus (RV), that may lead to long-term alterations of the lung environment. The detrimental roles of increased ILC2 following these infections may include pathogenic chronic inflammation and/or alterations of the structural, repair, and even developmental processes of the lung. Respiratory viral infections in older adults and patients with established chronic pulmonary diseases often lead to exacerbated responses, likely due to previous exposures that leave the lung in a dysregulated functional and structural state. This review will focus on the role of ILC2 during respiratory viral exposures and their effects on the induction and regulation of lung pathogenesis. We aim to provide insight into ILC2-driven mechanisms that may enhance lung-associated diseases throughout life. Understanding these mechanisms will help identify better treatment options to limit not only viral infection severity but also protect against the development and/or exacerbation of other lung pathologies linked to severe respiratory viral infections.

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Modeling Asthma in Mice Using Rhinovirus Infection

Bentley

2022

Methods in Molecular Biology

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Rhinovirus (RV) infection is linked to early life wheezing and exacerbation of adult asthma. RV infection can be modeled in adult and neonatal mice. This chapter outlines methods for the production of standardized human rhinovirus A1B and mouse infection. The chapter also describes methods to couple infections with allergen (ovalbumin and house dust mite) administrations. The production of the virus involves its amplification, purification, and concentration. In order to standardize the concentrated RV stock, a plaque assay on HeLa cells is outlined as a method of calibrating infectivity. Once the number of plaque-forming units is determined, the standardized virus is used for mouse infection.

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Early-life heterologous rhinovirus infections induce an exaggerated asthma-like phenotype

Cited by 21 publications

References 41 publications

Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

Role of ILC2 in Viral-Induced Lung Pathogenesis

Modeling Asthma in Mice Using Rhinovirus Infection

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