Abstract
Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ~90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.
Author Summary
Viruses exploit receptors on the host cell to cause infection. Therapies aimed at blocking virus-receptor interactions have the potential to prevent viral disease. Cellular receptors are also important for normal host cell function. Therefore, new therapies targeting these receptors to block viral infection may also inadvertently alter the physiology of the host cell. Viral pathogens, such as the cold virus (rhinovirus), are believed to be the major cause of asthma attacks and exacerbations in chronic obstructive pulmonary disease (COPD). In this study, we show that it is possible to identify novel therapeutic antibodies that block infection with rhinovirus without impairing the receptors' main function of cell adhesion. We then use animal models that show that an antibody can inhibit virus-induced lung inflammation and disease. Moreover, we show that this antibody can also inhibit a virally induced asthma exacerbation. This work is relevant in that it shows that antibodies can be tailored to distinct regions of viral receptors to block infection without inhibiting the receptors' normal cellular function. This is important for the development of new treatments that will prevent diseases caused by infection with rhinovirus, such as exacerbations of asthma and COPD.
Author Summary
Viruses exploit receptors on the host cell to cause infection. Therapies aimed at blocking virus-receptor interactions have the potential to prevent viral disease. Cellular receptors are also important for normal host cell function. Therefore, new therapies targeting these receptors to block viral infection may also inadvertently alter the physiology of the host cell. Viral pathogens, such as the cold virus (rhinovirus), are believed to be the major cause of asthma attacks and exacerbations in chronic obstructive pulmonary disease (COPD). In this study, we show that it is possible to identify novel therapeutic antibodies that block infection with rhinovirus without impairing the receptors' main function of cell adhesion. We then use animal models that show that an antibody can inhibit virus-induced lung inflammation and disease. Moreover, we show that this antibody can also inhibit a virally induced asthma exacerbation. This work is relevant in that it shows that antibodies can be tailored to distinct regions of viral receptors to block infection without inhibiting the receptors' normal cellular function. This is important for the development of new treatments that will prevent diseases caused by infection with rhinovirus, such as exacerbations of asthma and COPD.
Citation: Traub S, Nikonova A, Carruthers A, Dunmore R, Vousden KA, et al. (2013) An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation. PLoS Pathog 9(8): e1003520. doi:10.1371/journal.ppat.1003520
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Editor: Andrew Pekosz, Johns Hopkins University - Bloomberg School of Public Health, United States of America
Received: October 4, 2012; Accepted: May 29, 2013; Published: August 1, 2013
Copyright: © 2013 Traub et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by AstraZeneca and MedImmune and by a Chair from Asthma UK (CH11SJ), MRC Centre Grant G1000758, ERC FP7 Advanced grant 233015, Predicta FP7 Collaborative Project grant 260895 and the Wellcome Trust sponsored Centre for Respiratory Infection (CRI). AN is a recipient of an EAACI & GA2LEN Exchange Research Fellowship 2009 and European Respiratory Society Fellowship (number 682). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The following authors (AC, RD, KAV, WH, QZ, AH, RK, MAS, KB, MD, TW, AJL) are full time employees of MedImmune Ltd. or MedImmune LLC, wholly owned subsidiaries of Astrazeneca PLC. As employees they also receive shares and share options in the Astrazeneca Group. During the course of the study the following authors (AJL, TW) were employees of Astrazeneca PLC and received shares and share options. Astrazeneca is a global pharmaceutical company that conducts basic research and clinical trials in respiratory diseases such as severe asthma and chronic obstructive pulmonary disease. This work was in part funded by MedImmune and Astrazeneca PLC. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.
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