Long-term immunoprophylaxis by TLR9 ligand mediates macrophage-ILC cross-talk against respiratory viral infection
11 affiliations
- 1Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- 2Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
- 3International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- 4Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- 5Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan.
- 6Leprosy Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo, Japan.
- 7Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- 8The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), University of Tokyo, Tokyo, Japan.
- 9Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
- 10Department of Immunology, Hyogo Medical University School of Medicine, Nishinomiya, Hyogo, Japan.
- 11Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Hokkaido, Japan.
Abstract
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.
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BibTeX
@article{tobuse2026longterm,
title = {{Long-term immunoprophylaxis by TLR9 ligand mediates macrophage-ILC cross-talk against respiratory viral infection}},
author = {Asuka Joy Tobuse and Kouji Kobiyama and Jun Tsuchida and Masamitsu N. Asaka and Daichi Utsumi and Mariana Silva Almeida and Yaeko Nakajima-Takagi and Motohiko Oshima and Tomoya Hayashi and Burcu Temizoz and Etsushi Kuroda and Cevayir Coban and Yasuhiro Yasutomi and Atsushi Iwama and Ken J. Ishii},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh6480},
url = {https://www.science.org/doi/10.1126/sciadv.aeh6480},
note = {CC BY},
}
RIS
TY - JOUR
TI - Long-term immunoprophylaxis by TLR9 ligand mediates macrophage-ILC cross-talk against respiratory viral infection
AU - Asuka Joy Tobuse
AU - Kouji Kobiyama
AU - Jun Tsuchida
AU - Masamitsu N. Asaka
AU - Daichi Utsumi
AU - Mariana Silva Almeida
AU - Yaeko Nakajima-Takagi
AU - Motohiko Oshima
AU - Tomoya Hayashi
AU - Burcu Temizoz
AU - Etsushi Kuroda
AU - Cevayir Coban
AU - Yasuhiro Yasutomi
AU - Atsushi Iwama
AU - Ken J. Ishii
PY - 2026
DA - 2026/10/09
JO - Science Advances
DO - 10.1126/sciadv.aeh6480
UR - https://www.science.org/doi/10.1126/sciadv.aeh6480
AB - 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.
SN - 2375-2548
ER -