Follistatin-like 1 Mediated Host Defense in Bacterial Pneumonia

Pneumonia is the leading cause of death in children and the leading infectious cause of
death in the U.S, costing more than $17 billion. Antibiotic resistance (AR) increasingly
complicates pneumonia treatment and poses a national and worldwide public health crisis.
Klebsiella pneumoniae, a common pneumonia-causing AR pathogen, is an excellent tool for
preclinical modeling of pulmonary immunity. While immune modulation therapies have
transformed the fields of cancer and autoimmunity, immunotherapy is undeveloped for the
treatment of bacterial infections including pneumonia.
We identified that follistatin-like 1 (FSTL-1) as is a novel host-immune gene critical for
pulmonary host defense. The FSTL-1 mediated effect required expression of nuclear hormone
receptor 4A1 (Nr4a1), a newly recognized determinant of K. pneumoniae (Kp) pulmonary
immunity. However, the mechanism underlying FSTL-1- and Nr4a1-mediated lung host defense
are unknown. Published literature and our preliminary data lead to the hypothesis that FSTL-
1, through CD14-binding, promotes pulmonary innate immunity against K. pneumoniae
by 1) directing neutrophil recruitment to the lung and 2) enhancing neutrophil-intrinsic,
Nr4a1-dependent bacterial killing, which will be tested via three Aims.
Aim 1) will elucidate the constituents of FSTL-1 mediated neutrophil recruitment to the
lung during K. pneumoniae infection using the Kp pneumonia model, will test whether FSTL-
1 -dependent neutrophil recruitment is immune cell-intrinsic, whether rFSTL-1-driven neutrophil
recruitment is mediated by the receptor CD14 and the cellular requirements therein, as well as
the cell-specific contribution of Nr4a1 in FSTL-1-mediated pulmonary immunity. Aim 2) will
determine how FSTL-1 enhances neutrophil-intrinsic bactericidal function by testing
whether neutrophil-intrinsic FSTL-1 expression is required antibacterial effector function, FSTL-
1-dependent neutrophil effector function (phagocytosis, oxidative burst/ROS production,
NETosis and the requirement of CD14 on neutrophils for this effect. Aim 3) will define the
therapeutic potential of targeting Nr4a1 during K. pneumoniae infection. This will examine
if Nr4a1-deficiency impairs neutrophil effector functions and whether Nr4a1 stimulating
treatment can be used to improve bacterial pneumonia.
Cumulatively, the proposed work will focus on filling an existing gap in knowledge: the
cellular and molecular constituents of FSTL-1-mediated pulmonary host-defense.

Grant Number: 5R01HL158576-04
NIH Institute/Center: NIH
Principal Investigator: BRIAN CAMPFIELD