Exploring innate immune responses to rhinovirus in allergic asthma

Exacerbations of asthma, especially those caused by rhinovirus (RV), account for a disproportionate burden on
healthcare resources for children and adults who have asthma and are allergic. Following the onset of an RV
infection, innate immune responses develop rapidly before symptoms peak. However, attempts to evaluate the
early, innate response stimulated by RV during the onset of a natural infection have been challenging. Several
investigations, predominantly ex vivo, have provided evidence that anti-viral innate responses (in particular the
expression of type I and type III interferons) may be impaired in the asthmatic airway. This has been proposed
as a mechanism that could increase viral burden leading to an asthma exacerbation. In our studies conducted
in vivo, however, the experimental RV infection model and cross-sectional studies of RV-infected children
experiencing an asthma exacerbation, have not revealed increased viral loads in the airway. To address this
conundrum, the experimental RV infection model has advantages because it allows investigators to examine
the kinetics of the asthmatic response to RV following virus inoculation before symptoms peak. The
investigators collaborating in this research have long-standing experience and expertise using this model
which also permits frequent monitoring of subjects early in the infection when innate immune responses are at
play. For this reason, we will evaluate existing data sets and samples from our recently completed and
published experimental RV challenges to test our central hypothesis that, during an RV infection, allergic
asthmatics do not experience an increased viral load, but do generate augmented, pro- inflammatory type 2
immune responses, including eosinophilic inflammation, that begin early in the infection. We also speculate
that this early response will control viral load – but at the expense of increasing airway inflammation that in turn
drives the exacerbation. A rich set of data has been collected and is available from subjects who participated in
these trials. These data also include results from a subset of asthmatics treated with omalizumab to block
allergic, IgE-mediated pathways. The assessments in these trials were focused on viral load in nasal washes in
relation to upper and lower respiratory tract symptoms, lung function measurements, blood cell counts, and
immune responses in samples collected frequently from the upper airway where RV infects and replicates
vigorously. In Aim 1, nasal wash specimens are available for a comprehensive and detailed evaluation of
mediators, as well as type 1/3 and type 2 cytokines and chemokines that will be measured using Luminex and
highly sensitive proximity extension assays. In Aim 2, the results will be integrated with our existing clinical and
immune data sets. Combining the results will permit a systems biology approach that will employ discriminant
analyses and directed acyclic graphs focused on viral load as the primary analytic component to test the main
hypothesis. The results generated are expected to increase our understanding of the pathogenesis of asthma
exacerbations stimulated by RV and guide the development of new approaches to ameliorate symptom flares.

Grant Number: 1R03AI185854-01A1
NIH Institute/Center: NIH
Principal Investigator: LARRY BORISH