Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Bochkov, Yury A.; Watters, Kelly; Ashraf, Shamaila; Griggs, Theodor F.; Devries, Mark K.; Jackson, Daniel J.; Palmenberg, Ann C.; Gern, James E.

doi:10.1073/pnas.1421178112

Cited by 361 publications

(365 citation statements)

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“…However, we hypothesize that the murine cells we used in these studies have a low level or lack of receptors and/or coreceptors needed for replication. Many viruses, including enteroviruses, replicate well in vivo but fail to replicate in cell culture (37,38) and have been found to use a variety of coreceptors for cell entry (39). Additionally, the slight viral replication seen in the murine cell lines tested could be due to partial binding to a nonspecific receptor.…”

Section: Figmentioning

confidence: 99%

“…Additionally, the slight viral replication seen in the murine cell lines tested could be due to partial binding to a nonspecific receptor. For example, rhinovirus C was recently found through sequence analysis, even though rhinoviruses A and B have been known for decades (38). The failure of rhinovirus C to cause CPE on cell culture delayed its discovery.…”

Section: Figmentioning

confidence: 99%

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A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

Caine

Moncla

Ronderos

et al. 2016

J Virol

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Hand, foot, and mouth disease (HFMD) has spread throughout the Asia-Pacific region, affecting millions of young children, who develop symptoms ranging from painful blisters around their mouths and hands to neurological complications. Many members of the genus Enterovirus (family Picornaviridae) cause HFMD. Enterovirus 71 (EV71) is one of the primary causative agents and has been linked to severe disease. Vaccine efficacy and pathogenesis studies for EV71 have been limited because there is a lack of suitable animal models. Previously, we generated a mouse-adapted EV71 (mEV71) capable of infecting 12-week-old interferon receptor-deficient AG129 mice and used the model to evaluate the efficacy of candidate HFMD vaccines. Here, we present data investigating the genetic correlates of EV71 adaptation and characterize the virus's tissue tropism in mice. Using reverse genetics, a VP1 mutation (K244E) was shown to be necessary for mEV71 virulence in adult mice. Another VP1 mutation (H37R) was required for mEV71 recovery on rhabdomyosarcoma (RD) cells. Viral loads determined by real-time reverse transcription (RT)-PCR confirmed the presence of mEV71 in the sera and multiple organs of mice. Histological analysis revealed signs of meningitis and encephalitis, characteristic of severe human disease. The further description of this model has provided insight into EV71 pathogenesis and demonstrates the importance of the VP1 region in facilitating mEV71 adaptation. IMPORTANCEEV71 is a reemerging pathogen, and little is known about the genetic determinants involved in its pathogenesis. The absence of animal models has contributed to this lack of knowledge. The data presented here improve upon the existing animal models by characterizing a mouse-adapted strain of EV71. We determined that a VP1 mutation (K244E) was needed for EV71 virulence in adult AG129 mice. While this mutation was found previously for EV71 adaptation in 5-day-old BALB/c mice, neurotropic disease did not develop. Using interferon-deficient mice, we raised the age of susceptibility beyond 6 weeks and provided clear evidence that our model mimics severe human infections. The model can be exploited to identify determinants of EV71 virulence and to reveal molecular mechanisms that control the virus-host interaction, especially those associated with neurotropic disease. Furthermore, these data provide useful information regarding the importance of VP1, specifically position 244, in host adaptation and tissue dissemination. O ver the past decade, enterovirus 71 (EV71) (family Picornaviridae) was identified as one of the main causative agents responsible for large outbreaks of hand, foot, and mouth disease (HFMD) across the Asia-Pacific region. Other members of the genus Enterovirus cause HFMD, including coxsackieviruses A16, A6, A5, A7, A9, A10, B2, and B5, but EV71 has been linked to severe complications, including brainstem encephalitis, aseptic meningitis, and pulmonary edema (1-3). Picornaviruses, including the enteroviruses, have positive-sense, single-s...

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Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

Caine

Moncla

Ronderos

et al. 2016

J Virol

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“…The major group of RVs (e.g., RV-B14) use intercellular adhesion molecule 1 (ICAM-1), an Ig-like molecule, as a receptor, and the minor group RVs (e.g., RV-A2) use low-density lipoprotein receptor as a receptor. In contrast, members of the recently identified RV-C species use cadherin-related family member 3 as a cellular receptor (5).…”

mentioning

confidence: 92%

Antibody-induced uncoating of human rhinovirus B14

Dong

Liu

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Rhinoviruses (RVs) are the major causes of common colds in humans. They have a nonenveloped, icosahedral capsid surrounding a positive-strand RNA genome. Here we report that the antigenbinding (Fab) fragment of a neutralizing antibody (C5) can trigger genome release from RV-B14 to form emptied particles and neutralize virus infection. Using cryo-electron microscopy, structures of the C5 Fab in complex with the full and emptied particles have been determined at 2.3 Å and 3.0 Å resolution, respectively. Each of the 60 Fab molecules binds primarily to a region on viral protein 3 (VP3). Binding of the C5 Fabs to RV-B14 results in significant conformational changes around holes in the capsid through which the viral RNA might exit. These results are so far the highest resolution view of an antibody-virus complex and elucidate a mechanism whereby antibodies neutralize RVs and related viruses by inducing virus uncoating.rhinovirus | antibody | cryo-electron microscopy | genome release | atomic structure

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“…welve of the genus A human rhinoviruses (HRV-As; the minor group) bind members of the low-density lipoprotein receptor (LDLR) family, whereas the remaining 90 A and B types (the major group) bind intercellular adhesion molecule-1 (ICAM-1) (1, 2); the HRV-C receptor was recently identified as CDHR3, a protein only marginally expressed in established tissue culture cells (3). The A and B types investigated so far are taken up by receptormediated endocytosis (4).…”

mentioning

confidence: 99%

ICAM-1 Binding Rhinoviruses A89 and B14 Uncoat in Different Endosomal Compartments

Conzemius

Ganjian

Blaas

et al. 2016

J Virol

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Human rhinovirus A89 (HRV-A89) and HRV-B14 bind to and are internalized by intercellular adhesion molecule 1 (ICAM-1); as demonstrated earlier, the RNA genome of HRV-B14 penetrates into the cytoplasm from endosomal compartments of the lysosomal pathway. Here, we show by immunofluorescence microscopy that HRV-A89 but not HRV-B14 colocalizes with transferrin in the endocytic recycling compartment (ERC). Applying drugs differentially interfering with endosomal recycling and with the pathway to lysosomes, we demonstrate that these two major-group HRVs productively uncoat in distinct endosomal compartments. Overexpression of constitutively active (Rab11-GTP) and dominant negative (Rab11-GDP) mutants revealed that uncoating of HRV-A89 depends on functional Rab11. Thus, two ICAM-1 binding HRVs are routed into distinct endosomal compartments for productive uncoating. IMPORTANCEBased on similarity of their RNA genomic sequences, the more than 150 currently known common cold virus serotypes were classified as species A, B, and C. The majority of HRV-A viruses and all HRV-B viruses use ICAM-1 for cell attachment and entry. Our results highlight important differences of two ICAM-1 binding HRVs with respect to their intracellular trafficking and productive uncoating; they demonstrate that serotypes belonging to species A and B, but entering the cell via the same receptors, direct the endocytosis machinery to ferry them along distinct pathways toward different endocytic compartments for uncoating.

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Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Cited by 361 publications

References 41 publications

A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

Antibody-induced uncoating of human rhinovirus B14

ICAM-1 Binding Rhinoviruses A89 and B14 Uncoat in Different Endosomal Compartments

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