Influenza viruses are rapidly mutating RNA viruses and are the causative agent of about one billion annual
respiratory virus infections and 500,000 deaths worldwide. Influenza-related deaths are generally attributable to
viral or bacterial pneumonia (from secondary bacterial infections); excessive inflammation resulting in acute
respiratory distress syndrome; and severe lung immunopathology, leading to hypoxia and multi-organ failure.
Influenza viruses have significant pandemic potential, seasonal epidemics burden the human population, and
viral resistance has developed to all available treatment options. Much emphasis is placed on the humoral
immune response to influenza, as neutralizing antibodies are the desired vaccine outcome. However, B cell-
deficient mice and humans with hyper-IgM syndrome clear influenza virus infections, while T cell-deficient mice
do not. Thus, B cell-independent mechanisms protect against influenza virus-related mortality. However, the
immune response to influenza virus infection remains poorly understood, and much-needed therapeutics
augmenting the antiviral immune response while preventing harmful immunopathology remain to be developed.
To address this knowledge gap, we recently generated novel and compelling evidence that Influenza A virus
(IAV) infection triggers lung mast cells (MCs) to produce the anti-inflammatory cytokine IL-10 (MC-IL-10). In wild-
type (WT) and T- and B-cell deficient (Rag1-KO) mice, IAV/MC-IL-10 induces the expression of the IL-10 receptor
(IL-10R) and programmed cell death ligand 1 (PD-L1) on Natural Killer (NK) cells. Notably, in Rag1-KO mice,
where NK cells are the sole virus-fighting lymphocytes, PD-L1 blockade, but not PD-1, PD-L2, or CD80 blockade,
significantly reduces IAV-related lethality. The IAV/MC-IL10/NK-PD-L1 pathway is also conserved in humans, at
least in vitro: IAV infection of human-lung tissue-derived single-primary-cell suspensions or intact human lung
tissue slices elicit MC-IL-10 and NK cell-expressed IL-10R and PD-L1. In mice and humans, T cells also
upregulate the IL-10R, PD-1, and PD-L1 upon IAV infection. Further, IAV-infected IL-10-KO/Rag-WT mice,
whose NK and T cells do not upregulate IL-10R, PD-1, PD-L1, or PD-L2, and IAV-infected WT mice in which
PD-L1 is blocked, develop prolonged immune infiltration and immunopathology after IAV clearance. Our findings
are novel and surprising. The induction of the PD/PD-L pathway is generally associated with lymphocyte
exhaustion (via T cell-expressed PD-1) in cancer or chronic infection rather than the modulation of lymphocyte
function in response to an acute viral illness. We hypothesize that influenza virus-induced MC-IL-10 balances
helpful antiviral responses with harmful immunopathology through PDL1 signaling in NK cells, and PD-1 and/or
PD-L1 signaling in T cells. We propose identifying the mechanisms of IAV/MC/IL-10/PD-L1-mediated NK cell
and IAV/MC/IL-10/PD-1 and/or PD-L1-mediated T cell regulation and each pathway's contribution to viral
clearance vs. lung tissue damage. Our proposal is highly significant to human health, as it has great potential to
identify therapeutic targets for alleviating IAV immunopathology-associated mortality and morbidity.