Innate and adaptive immune factors in the acquisition, expulsion and transmission of influenza virus infection

SUMMARY - Project 2 Understanding how the immune system senses and responds to infection is essential to elucidating the fundamental biology underlying influenza virus transmission and needed for designing vaccines that would interrupt viral spread. The immune system will shape transmission both by modulating viral load within an infected individual and by defining the susceptibility of exposed individuals to infection. However, the specific immunological mechanisms that act within donor and recipient hosts to mediate these effects are poorly understood and likely to be complex. Despite great progress in understanding the mechanisms of innate and adaptive immunity against influenza infection in mice, knowledge of such mechanisms in humans is sparse. Most immunological analysis of influenza in humans focuses on responses to vaccination, which is highly distinct from infection. Among those examining infection, most evaluate responses in the blood, with few relating the information obtained to responses active at the site of infection. Importantly, most prior studies in humans examine individuals with naturally acquired infection. In this context, the precise timing of infection typically cannot be determined and sampling prior to and early after infection is often not possible. These limitations have left important gaps in knowledge: 1. What is the role of innate immune memory in regulating antiviral immune responses? 2. How are systemic and local innate immune responses related? 3. What is the interplay between innate responses and recall adaptive immune responses? 4. What are the implications of the levels of pre-existing antibody in the mucosa for viral load dynamics? 5. How are levels of serum and mucosal antibody related pre-challenge and post-challenge? 6. Does the rapidity/magnitude of the CD8 T cell response correlate with faster viral clearance? 7. Do stalk-reactive antibodies help control viral replication in H3N2 infections as they do for H1N1 viruses? 8. Does influenza infection induce more durable bone marrow plasma cells, and therefore more persistent systemic antibody responses, compared to vaccination? The proposed P01 Program will examine participants challenged experimentally with influenza virus and followed up for both systemic and mucosal sampling at multiple acute and memory time points, presenting an extremely valuable opportunity to address each of these knowledge gaps. To obtain an holistic view of responses to infection, we will apply both functional immunological assays specific to the pathogen of interest and systems biology approaches designed to capture detailed molecular information in a broad and unbiased fashion. We propose two Specific Aims: 1. To define innate responses to influenza infection in high resolution and with well- defined temporal information and 2. To evaluate the role of adaptive immune responses in controlling influenza virus replication and transmission.