Long-term immunoprophylaxis by TLR9 ligand mediates macrophage-ILC cross-talk against respiratory viral infection.

Rapid development of host immunity is critical during the emergence of viral outbreaks when vaccines are not yet available. Here, we demonstrate that CpG oligodeoxynucleotide-schizophyllan complex (K3-SPG) induces antigen-independent, long-term protection against lethal respiratory virus infection. A single intranasal administration successfully enhanced host resistance to infection for as long as 100 days posttreatment. Mechanistically, we observed a lung-restricted biphasic innate activation of macrophages and innate lymphoid cells. Early protection was mediated by CD11b+CD11c+ macrophages (DP MΦ) and monocyte-derived interstitial macrophages (IMΦ). Late protection was mediated by innate lymphoid cells that were epigenetically reprogrammed, suggesting that two distinct innate immune subsets contribute to the maintenance of disease tolerance in the lung microenvironment. Deficiency of TLR9 or TNF-α abrogated innate activation and protective immunity. Collectively, these findings demonstrate that adjuvant-induced prophylaxis is a promising approach to enhancing host resistance against respiratory virus infection, involving the biphasic cooperation between innate immune cells in the local tissue.