Interferon lambda drives immunological maturation in the infant lung and protects against lethal Bordetella pertussis infection
- 1University of Maryland School of Medicine
Abstract
Serious pertussis infections disproportionately affect infants but the biological basis for this age-dependent susceptibility remains unclear. Infant mouse models recapitulate features of severe human infant pertussis. We investigated the role of interferon lambda (IFN-{lambda}), a key regulator of mucosal immunity, in Bordetella pertussis infection of infant mice. While infected adult mice upregulate lung IFN-{lambda}, infant mice inoculated at P7 fail to upregulate IFN-{lambda} and succumb to infection. We hypothesized that failure to produce IFN-{lambda} during infection represents a critical immunological deficit in infant mice, and that restoring IFN-{lambda} signaling would improve survival outcomes. Whereas wild-type mice gained complete protection from lethal B. pertussis infection by P10, mice lacking the IFN-{lambda} receptor component IFNLR1 did not achieve full protection until P21. Loss of IFNLR1 was associated with enhanced bacterial dissemination to systemic organs. Infant mice possessed a functional IFN-{lambda} receptor in the lungs but failed to upregulate IFN-{lambda} during infection, and supplementing IFN-{lambda} exogenously extended survival. RNA sequencing of lung tissue from infected and uninfected wild-type and IFNLR1-deficient mice inoculated at different ages identified an immune transcriptional framework distinguishing susceptible from resistant animals at a systems level and revealed IFN-{lambda} signaling as a critical driver of immunological maturation in the infant lung. Infected infant IFNLR1-deficient mice had dysregulated immune cell recruitment to the lungs, indicating a quantitatively expanded but qualitatively impaired response. These findings demonstrate that IFN-{lambda} affects immune maturation accounting for a critical window of age-dependent resistance to lethal pertussis with novel therapeutic possibilities for human infants with this disease.
Related
- Chemical Fatty Acylation Confers Hemolytic and Toxic Activities to Adenylate Cyclase Protoxin of Bordetella pertussis
- Dissecting Adult Peripheral Cellular Immunity to Bordetella pertussis: Innate-Associated IFN-γ Responses, Transient T-Cell Recall, and HLA-A*02-Associated CD8+ Reactivity
- Diagnostic accuracy of Mycobacterium tuberculosis antigen-induced interferon-γ-inducible protein 10 for latent tuberculosis infection among high-risk groups: a systematic review and meta-analysis
- Interferon-λ signaling to maternal dendritic cells protects against congenital Zika virus infection
- Immunological and metabolic profiles associated with active Giardia intestinalis infection in adults with metabolic disorders: an exploratory analysis
BibTeX
@misc{johnson2026interferon,
title = {{Interferon lambda drives immunological maturation in the infant lung and protects against lethal Bordetella pertussis infection}},
author = {D. Johnson and N. H. Carbonetti},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753444},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753444v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Interferon lambda drives immunological maturation in the infant lung and protects against lethal Bordetella pertussis infection
AU - D. Johnson
AU - N. H. Carbonetti
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753444
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753444v1
AB - Serious pertussis infections disproportionately affect infants but the biological basis for this age-dependent susceptibility remains unclear. Infant mouse models recapitulate features of severe human infant pertussis. We investigated the role of interferon lambda (IFN-{lambda}), a key regulator of mucosal immunity, in Bordetella pertussis infection of infant mice. While infected adult mice upregulate lung IFN-{lambda}, infant mice inoculated at P7 fail to upregulate IFN-{lambda} and succumb to infection. We hypothesized that failure to produce IFN-{lambda} during infection represents a critical immunological deficit in infant mice, and that restoring IFN-{lambda} signaling would improve survival outcomes. Whereas wild-type mice gained complete protection from lethal B. pertussis infection by P10, mice lacking the IFN-{lambda} receptor component IFNLR1 did not achieve full protection until P21. Loss of IFNLR1 was associated with enhanced bacterial dissemination to systemic organs. Infant mice possessed a functional IFN-{lambda} receptor in the lungs but failed to upregulate IFN-{lambda} during infection, and supplementing IFN-{lambda} exogenously extended survival. RNA sequencing of lung tissue from infected and uninfected wild-type and IFNLR1-deficient mice inoculated at different ages identified an immune transcriptional framework distinguishing susceptible from resistant animals at a systems level and revealed IFN-{lambda} signaling as a critical driver of immunological maturation in the infant lung. Infected infant IFNLR1-deficient mice had dysregulated immune cell recruitment to the lungs, indicating a quantitatively expanded but qualitatively impaired response. These findings demonstrate that IFN-{lambda} affects immune maturation accounting for a critical window of age-dependent resistance to lethal pertussis with novel therapeutic possibilities for human infants with this disease.
ER -