# Glycan-Lectin Receptor Regulation of Macrophage Maturation and Lung Innate Defenses in the Fetus and Newborn Infant

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $438,633

## Abstract

Summary
The fetal and neonatal immune systems maintain a state of tolerance during pregnancy. However the moment
that infants are born, their immature immune system must defend against the sudden onslaught of microbial
pathogens present in the environment. Unfortunately for many, the transition from tolerance to protection is slow,
providing windows of opportunity for specific infectious organisms. This susceptibility is best illustrated by group
B Streptococcus (GBS), which is the most common pathogen in neonates but rarely leads to disease in healthy
adults. Neonates are first exposed to GBS around delivery, as GBS frequently colonizes the birth canal. Despite
efforts around screening and maternal treatment, GBS continues to be the major cause of neonatal pneumonia
and early onset sepsis. To discover the mechanisms of GBS infection and immunity in the immature lung, we
developed a novel mouse GBS pneumonia model. Adult mice clear GBS within 24 h, quickly resolve the initial
lung inflammation, and universally survive GBS infection. However, neonatal mice fail to efficiently kill GBS,
develop persistent lung inflammation and injury, and can die from GBS infection. Macrophages, the first line of
defense in adult lungs, are immature in neonates making them vulnerable to inhaled and aspirated bacteria
including GBS. Our preliminary studies show that immature neonatal lung macrophages fail to mount a normal
immune response against GBS or kill phagocytosed bacteria. GBS avoids detection in the neonatal lung by
expressing a capsule coated with sialic acid, mimicking “self” antigens in the host. Neonatal lung macrophages
express very low levels of sialoadhesin, which facilitates recognition of sialic acid in the GBS capsule and
bacterial killing in adults. However neonatal lung macrophages do express Siglec-E, which suppresses
inflammatory signaling upon sialic acid binding. This appears to represent a fetal tolerance mechanism, as the
amniotic fluid is rich in the sialic acid modified Tamm-Horsfall Protein (THP). We hypothesize that THP and sialic
acid maintain immune tolerance in the fetal lung through interactions with macrophage inhibitory Siglecs. For
maturation of lung macrophages, THP-sialic acid-Siglec interactions must give way to the ability to detect and
kill pathogens. GBS uses its sialic acid rich capsule to mimic the effects of THP, suppressing immune activation
in newborn lungs. This proposal will use novel, state of the art approaches to further investigate the molecular
mechanisms regulating both immune tolerance in fetal lungs and neonatal immunity against GBS. By bringing
together outstanding expertise in the Principal Investigators’ laboratories, state of the art approaches
investigating development of lung immunity and mechanisms of host-microbe interactions will shed important
new light on the ongoing battle between immunity and microbes around the time of birth. Collectively the aims
in this proposal will identify unique molecular...

## Key facts

- **NIH application ID:** 9979752
- **Project number:** 5R01AI142864-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Victor Nizet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,633
- **Award type:** 5
- **Project period:** 2019-07-17 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979752

## Citation

> US National Institutes of Health, RePORTER application 9979752, Glycan-Lectin Receptor Regulation of Macrophage Maturation and Lung Innate Defenses in the Fetus and Newborn Infant (5R01AI142864-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979752. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*