Pneumonia is the leading cause of death among patients with acute myeloid leukemia (AML). Despite constant exposure of an immense surface area of delicate tissue to the external environment, the lungs' intrinsic defenses clear most aspirated and inhaled pathogens before infections are established. These same mucosal defenses can be therapeutically stimulated using a novel inhalational therapy comprised of a non-intuitive Toll- like receptor (TLR) agonist combination. This inducible resistance is associated with rapid intrapulmonary pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by common AML- associated pathogens, even in the setting of severe chemotherapy-induced immunocompromise. The discovery that lung epithelial cells are principle effectors of the inducible response makes this approach particularly appealing for use in neutropenic AML patients. This application proposes to dissect the molecular mechanisms underlying this remarkable phenomenon to aid clinical translation of this technology for use in AML patients and to advance understanding of novel host-pathogen interactions.
Aim 1 will identify the lung epithelial cell populations required for inducible resistance against AML-associated pneumonia. Contributions will be established by comparing inducible killing of AML pathogens by primary mouse and human epithelial cells and by functional testing of mice cell-selectively deficient in TLR signaling.
Aim 2 will determine whethe inducible resistance is impaired by leukemia cells or by treatment with standard cytotoxic or hypomethylating AML regimens. This will be assessed in vivo and in vitro based on effects on survival, pathogen killing, epithelial vitality, cellular activation, antimicrobial effectors, and circulating leukocytes Aim 3 will dissect the molecular mechanisms of inducible resistance to determine whether protection can persist despite co-administration of modern targeted molecular AML treatments, and to facilitate discovery of novel epithelial stimuli. Mouse genetic manipulation and in vitro models will identify required signaling and effector molecules and are expected to provide insight into the unexplained TLR synergy observed. The proposed studies are expected to identify critical cells, signaling pathways, and effector molecules of inducible resistance, promote discovery of more efficacious inducers of resistance, explore unanticipated TLR interactions, assess interactions of inducible resistance with AML and its treatments, identify AML populations most likely to benefit from the treatment, and facilitate the rapid translation of this technology into the clinic, so that AML patients can be protected from lethal pneumonia during periods of peak vulnerability.

Public Health Relevance

Pneumonia is the leading cause of death among patients with acute myeloid leukemia (AML), so recent observations that lung mucosal immunity can be stimulated to protect against pneumonia without reliance on AML-impaired white blood cells is of potentially immense importance. This proposal investigates the specific populations of cells responsible for this striking protective phenomenon and uses genetic manipulation of immune signaling pathways, common AML chemotherapy regimens and a mouse model of AML to explore the molecular mechanisms of the robust protection. These studies are expected to identify the specific AML populations most likely to benefit from this technology, to promote discovery of even more efficacious immune stimuli, and to facilitate rapid translation of this technology into clinically-available treatments to protect AML patients from lethal pneumonias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL117976-05
Application #
9405909
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Caler, Elisabet V
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Kirkpatrick, Carson T; Wang, Yongxing; Leiva Juarez, Miguel M et al. (2018) Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections. MBio 9:
Leiva-Juarez, Miguel M; Kirkpatrick, Carson T; Gilbert, Brian E et al. (2018) Combined aerosolized Toll-like receptor ligands are an effective therapeutic agent against influenza pneumonia when co-administered with oseltamivir. Eur J Pharmacol 818:191-197
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Han, Xiang Y; Ihegword, Andrea; Evans, Scott E et al. (2015) Microbiological and Clinical Studies of Legionellosis in 33 Patients with Cancer. J Clin Microbiol 53:2180-7

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