Decoding Human Immune Programs in Sequential Rhinovirus Infections

About This Grant

SUMMARY Human rhinoviruses (RV) are a major cause of common cold and exacerbator of chronic lung diseases. The antigenic variability of RV across more than 160 different serotypes has hindered the design of interventions to cure or mitigate infection. Despite possessing memory T and B cells that cross-react with different RV strains, most individuals remain susceptible to re-infection. Moreover, neutralizing antibodies (nAb) induced by RV are strain-specific, wane over time, and do not reliably protect. Thus, there is a critical need to identify reliable and durable immune determinants that will inform novel therapeutic targets. Our work in human RV challenge models reveals variable infection profiles based on viral loads, kinetics of viral shedding, and the propensity to develop serum nAb. These differences likely reflect the degree of success or failure of viral control in the upper airways. Our data also indicate the influence of prior RV (and perhaps non-RV) exposures on the response to RV, as evidenced by the contributions of pre-existing innate and adaptive immunity to improved protection. These findings suggest a complex interplay between “memory” innate and adaptive elements in regulating immunity to RV. Nonetheless, significant knowledge gaps remain regarding the role of these components, and how their coordinated actions dictate the degree of protection to the same or different RV strain. To address this, our exploratory study will leverage existing specimens to perform a comprehensive analysis of immune cells and anti-viral mediators in the blood and nose during sequential homotypic and heterotypic RV challenges performed over a 30-week period. Advanced analytical pipelines designed to maximize discoveries will pinpoint a limited set of biologically relevant targets for follow-up studies. Two complementary and reinforcing aims will test the central hypothesis that distinct immune programs determine the degree of local viral control, and reflect immunity that is shaped by prior RV exposures. Aim 1 will address how the dynamics of innate and adaptive cells determine susceptibility to infection. This will be done using high-dimensional spectral flow cytometry in conjunction with machine learning methods, to identify and quantify the expansion or depletion of numerous cell types in the blood during each RV challenge, define their trajectories, and elucidate their relationships to infection outcomes. Aim 2 will answer whether distinct immune programs dictate protection versus infection, and how these programs are shaped by prior exposures. Here, a multi-modal integrative strategy will build immune programs by connecting large cytometric datasets in the blood to mediators in the nose. Interrogation of immune programs at each RV challenge, will provide an unprecedented view of the interplay between innate and adaptive elements in relation to local viral control versus failed viral containment with broader immune activation, and elucidate the impact of prior homotypic and heterotypic RV exposures on these programs. Outcomes will accelerate the discovery of potential innate and adaptive mechanisms for follow-up studies, while informing how to protect against other common respiratory viruses.