The broad objectives of this K08 proposal are two-fold: (1) to foster the development of essential scientific and professional skills that will allow the candidate, Dr. Bria Coates, to achieve her long-term goal of becoming an independent physician-scientist concentrating on the development of acute lung injury in children with viral respiratory infections and seeking solutions that could be translated for therapeutic benefit to critically ill children, and (2) to investigate mechanisms that regulate the immune response to influenza A virus (IAV) and contribute to increased morbidity and mortality in the pediatric patient population. Through laboratory experience, didactic coursework, and the collaborative process, Dr. Coates will gain expertise in experimental design, laboratory procedures, data analysis, and scientific communication. Dr. Coates and her mentor, Dr. Karen Ridge, have designed a specific training plan that will afford Dr. Coates new knowledge and research skills in the pathophysiology of acute lung inflammation and acute respiratory distress syndrome (ARDS), which is a lung condition that causes tremendous morbidity and mortality in young patients with viral respiratory infections. Importantly, recent clinical data thwart the long-standing dogma that children with influenza have increased morbidity and mortality due to impaired viral clearance. Our preliminary data identify an altered innate immune response in IAV-infected juvenile mice as a critical parameter in disease progression. Specifically, we show that increased lung injury in IAV-infected juvenile mice is associated with robust activation of the NOD-like receptor (NLR) proteins NOD2 and the NLRP3, resulting in increased IFN?/? and IL-1?/18 levels, respectively, that persist beyond viral elimination. In addition, juvenile lungs produce more MCP-1 and recruit more inflammatory monocytes during IAV infection, which then perpetuates NOD2 and NLRP3 activation. We observe that juvenile recruited monocytes are uniquely inflammatory, and prevention of their recruitment during IAV infection protects juvenile mice from IAV-mediated lung injury. We hypothesize that age-specific, cell autonomous differences in the innate immune response to IAV contribute to the robust and sustained activation of NLR proteins and exacerbate IAV-induced lung injury in juvenile mice. We have formulated three interrelated specific aims to study the regulation of monocyte recruitment and NLR signaling in both in vivo and in vitro models of juvenile IAV-induced lung injury.
Specific Aim 1 : Investigate the age-specific mechanisms that modulate the activation of NLR proteins in response to IAV infection and contribute to IAV-induced acute lung injury.
Specific Aim 2 : Determine whether recruited monocytes are required for IAV-mediated acute lung injury in juvenile mice.
Specific Aim 3 : Identify cell autonomous differences in juvenile IAV infection that may drive age-specific inflammatory responses. Completion of these aims will provide a rigorous training program for Dr. Coates and uncover mechanisms driving acute lung injury in children with viral respiratory infections.

Public Health Relevance

Influenza A virus (IAV) is a highly contagious virus that causes life-threatening pneumonia in healthy children. Excessive recruitment of inflammatory monocytes and dysregulated activation of NOD-like receptor proteins can exacerbate lung injury in children infected with influenza. We aim to identify mechanisms underlying monocyte recruitment and NOD-like receptor activation that will lead to new therapeutic options for children infected with IAV.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL143127-01
Application #
9583737
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Natarajan, Aruna R
Project Start
2018-08-06
Project End
2022-06-30
Budget Start
2018-08-06
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611