# Development of neonatal innate lung defenses is dependent on gastrointestinal commensal bacteria

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $417,648

## Abstract

PROJECT SUMMARY:
Bacterial pneumonia kills more than 1 million newborns each year. Increased neonatal susceptibility to
pneumonia is directly linked to immature infant lung mucosal defenses. Colonization by intestinal commensal
bacteria, which begins immediately at birth, is hypothesized to be critical for postnatal development of neonate’s
immune system, but the underlying mechanisms remain unclear. The premise of this proposal is that early life
exposure to commensal bacteria promotes resistance to pneumonia in neonates by accelerating the immune
cell development. Modern childbirth practices like increased use of antibiotics to treat preterm labor and cesarean
deliveries alter the pattern of intestinal commensal colonization in the newborn and are associated with increased
risk of pneumonia. Therefore, understanding this relationship has translational impact.
This proposal is based on our recent publications, demonstrating that a rare population of sentinel immune cells-
group 3 innate lymphoid cells (ILC3), are critical in defense against bacterial pneumonia in the newborn. A wave
of ILC3 populates the murine and human lung in the postnatal period. ILC3 confer protection against bacterial
pneumonia in newborn mice. Chemokine receptor, CCR4 was important for lung-specific trafficking of ILC3. This
crosstalk was mediated by mucosal dendritic cells (DC), which capture the signals from intestinal commensal
bacteria. Disruption of intestinal commensal bacteria with antibiotics abolished the expression of CCR4,
interrupted the trafficking of ILC3 into the newborn’s lungs and rendered the antibiotic-treated neonatal mice
susceptible to pneumonia in an interleukin (IL)-22 dependent fashion. These findings challenge the current
paradigm that commensal bacteria-directed ILC3 development is locally restricted to the small intestine and
support the hypothesis that postnatal colonization by intestinal commensal bacteria promotes resistance to
pneumonia in neonates by accelerating the development of ILC3 in the newborn lung.
The proposed experiments are designed to answer the following fundamental questions regarding the acquisition
of pulmonary innate defenses in the newborn. 1) What is the migratory program of lung ILC3 in the newborns?
2) How do intestinal commensal bacteria instruct the migration of ILC3? 3) How do newly migrated ILC3 direct
the neonatal pulmonary mucosal defenses against bacterial pneumonia?
The proposed studies provide two conceptual advances regarding the development of pulmonary defense in the
newborn. First, intestinal colonization by commensal bacteria is necessary for expansion of ILC3 in the newborn
lung. Second, the newly expanded pool of ILC3 support lung epithelial stem cell proliferation and regulates
pulmonary alveolar repair after pneumonia. These concepts could potentially suggest an alteration to the current
practice of empiric broad-spectrum antibiotics in neonates. Our use of developmentally appropriate and clinically
...

## Key facts

- **NIH application ID:** 10000987
- **Project number:** 5R01HL142708-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Hitesh Deshmukh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,648
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000987

## Citation

> US National Institutes of Health, RePORTER application 10000987, Development of neonatal innate lung defenses is dependent on gastrointestinal commensal bacteria (5R01HL142708-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000987. Licensed CC0.

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