# Myeloid cell-specific type I interferon signaling mediates age-dependent inflammation and protection in Bordetella pertussis infection

## TL;DR

This study shows how type I interferon signaling in myeloid cells affects inflammation and protection during whooping cough in mice, with age-specific differences.

## Contribution

The study reveals a novel LPAR1-dependent pathway for IFN-λ induction in the absence of type I IFN signaling during B. pertussis infection.

## Key findings

- Myeloid cell-specific IFNAR1 deficiency reduces lung inflammation and cytokine production in adult mice.
- Infant mice lacking IFNAR1 in myeloid cells remain highly susceptible to B. pertussis infection through postnatal day 21.
- IFNAR1-deficient macrophages produce IFN-λ in response to B. pertussis, dependent on LPAR1.

## Abstract

Type I interferons (IFNs) play complex roles during bacterial infections. We previously found that type I IFNs were induced in Bordetella pertussis-infected adult mice but not in infant mice, a potentially relevant clinical dichotomy, since pertussis can be fatal in human infants. We investigated the role of type I IFNs and their cross-regulation with type III IFNs (IFN-λ) in B. pertussis infection across developmental stages. In contrast to global IFNAR1 knockout adult mice, in which lung inflammation was equivalent to that in wild-type mice, myeloid cell-specific deficiency of the type I IFN receptor protein IFNAR1 (LysMCreIFNAR1fl/fl) resulted in significantly reduced lung inflammation and pro-inflammatory cytokine production, despite elevated pulmonary IFN-λ levels. Mechanistically, we found that, in contrast to WT macrophages, IFNAR1-deficient macrophages produced IFN-λ in response to B. pertussis or pertussis toxin, a process dependent on the G protein-coupled receptor lysophosphatidic acid receptor 1 (LPAR1). IFNAR1 deficiency did not affect type I IFN expression or killing capacity by macrophages and neutrophils. In striking contrast to WT infant mice, which developed resistance to lethal B. pertussis infection by postnatal day 10 (P10), LysMCreIFNAR1fl/fl infant mice remained highly susceptible to lethal infection through P21, exhibiting increased lung bacterial burden and inflammation, as well as increased bacterial dissemination compared to WT infant mice. These findings reveal a critical age- and cell-specific interplay between type I and III IFNs during B. pertussis infection and highlight a novel LPAR1-dependent pathway for IFN-λ induction in the absence of type I IFN signaling.