Temporal High-Resolution Atlas of Human Blood Leukocyte Composition in Response to Respiratory Virus Inoculation

BackgroundViral respiratory infections are a significant global health burden. Human immune responses to infections caused by respiratory viruses are complex and dependent on the length of time the host has been infected. Human viral challenge studies provide a useful opportunity to understand the timing of human immune responses as samples can be obtained pre-inoculation and post-inoculation by defined virus inocula. Transcriptomic data is available from a large amount of publicly available viral challenge studies and genome-wide transcriptomic data is primarily derived from bulk samples containing mixed cell subpopulations. Traditional bulk transcriptomic analysis methods often utilize deconvolution techniques to study changes in cell proportions of major immune cell types. Methods and Principal FindingsIn this study, we digitally sorted the cellular diversity of 31 blood immune cell types over time in human challenge studies after inoculation by H3N2 influenza virus H1N1 influenza virus, and RSV using xCell, a digital cell separation method, on human bulk transcriptional repository data. We identified common inoculation-induced changes in cell subpopulations across studies of the three viruses with time kinetics. We observed a consistent elevation of myeloid cells and their subtypes post-inoculation across various viral inoculations. Lymphocytes and their subpopulations were reduced in symptomatic and infected (Sx/Inf) participants compared to asymptomatic and uninfected (Asx/Uninf) participants. H3N2 evoked the earliest transcriptional immune responses, followed by H1N1, RSV infection elicited a delayed transcriptional response compared to both influenza viruses likely due to slower replication kinetics. Our analysis also revealed unique immune cell composition changes caused by specific viruses. We found that pre-existing baseline memory T cells were associated with resistance to influenza viral infection and that the key cell type is effector memory (Tem) CD8 T cells. ConclusionThese findings identify specific target cell subpopulations which respond to respiratory virus inoculation over time, shedding light on mechanisms for eliciting a robust baseline level of immune memory against multiple viral strains. These studies highlight potential immune cell responses that can be utilized to enhance vaccine design.