Immunomodulatory effects of interferon lambda on infant neutrophils

Project Abstract:
The mortality rate from influenza viral (IV) infection is highest in infants less than age six months, currently an
age group not eligible for the available influenza vaccine, but the mechanisms for this clinical observation are
not well understood. Vulnerability to respiratory viruses during infancy is likely manifested by both immature lung
and immune systems. To understand these age-specific differences of immune and pulmonary function at the
air-blood interface in the developing lung, an age-appropriate pre-clinical neonatal murine IV infection model is
employed. Previously, we demonstrated that murine neonates are exceptionally susceptible to IV infection, with
an early loss of viral control indicating an aberrant neonatal pulmonary innate immune response. Both Type I
interferons (IFN-I, IFNα and IFNβ) and type III interferons (IFN-III, IFNλ) are critical components of this innate
immune response. In adults, IFNs promote antiviral states following IV infection, but can also prolong lung repair.
In infants, there is a gap in knowledge about the age-specific role of IFN-I and IFN-III in IV response. To address
this knowledge gap, experiments with IFN receptor transgenic mice demonstrate 5 key findings. First, neonatal
mice with a defective IFN-I receptor (Ifnar1-/-) infected with PR-8 IV had an improved survival rate of 80%,
compared to the WT survival rate of 15%, despite having similar viral loads. In direct contrast, murine neonates
with deletion of the IFN-III receptor (Ifnlr1-/-), similarly infected with IV, all succumbed to infection. Moreover, in
vivo IFNβ treatment after IV infection accelerated death in murine neonates. To determine potential mechanisms
of IFN-I toxicity, we demonstrated that IFNβ directly led to increased ROS production in neonatal alveolar
epithelial and immune cells, but not in the adult. Finally, depletion of neutrophils, one of the primary producers
of ROS, protected murine neonates. Therefore, the neonatal propensity to produce ROS in response to
respiratory virus, coupled with a global antioxidant deficiency in the neonate, creates an oxidative stress
imbalance. Our overarching hypothesis is that in the IV-infected developing lung, IFN-III modulates neutrophils
to control pro-inflammatory cytokine and ROS production. Through a previously established collaboration,
the goal of this exploratory project is to identify the molecular pathways of developmental differences in the
neonatal neutrophil response to IFN-I and IFN-III. Furthermore, we will determine the impact of IFNλ on
neutrophil reactive oxygen and nitrogen species production, in vitro and in vivo. Using a unique neonatal murine
pre-clinical model of IV infection, coupled with an established bioinformatics pipeline, we will identify key
molecular pathways in the neonatal neutrophil response to respiratory viruses and how IFN-III can potentially
modulate these pathways, by impacting ROS/RNS production and tempering the pathogenic neutrophil response
in neonatal IV infection. Our studies will bring forth new understanding of infant mucosal immunity to develop
targeted therapeutics for the infant population.

Grant Number: 1R21AI188946-01
NIH Institute/Center: NIH
Principal Investigator: Alison Carey