Inducible epithelial resistance protects mice against leukemia-associated pneumonia

Abstract

Key Points Survival of acute myelogenous leukemia is frequently limited by pneumonia, due to disease- and therapy-associated immune defects. Inducible epithelial resistance protects neutropenic, leukemic mice against lethal pneumonia without impacting AML cell proliferation.

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

“…[123][124][125][126] In a mouse model of chemotherapy-induced neutropenia, treatment of mice with an inhaled synergic combination of TLR2, 6 and 9 agonists induced protection against A. fumigatus, by enhancing mucosal and epithelial cell responses. 28 Similar protection was observed against other pathogens including Pseudomonas aeruginosa, suggesting that enhancing epithelial cell resistance to infection may be a useful strategy to reduce mortality due to opportunistic pneumonia in the HSCT population.…”

“…24,25 Mouse models of acute leukemia and GVHD have been developed but have not been used for the study of IA. [26][27][28] Despite these limitations, studies with these experimental models have begun to shed light on the pathogenesis of IA in HSCT patients. In this review, we will examine a selection of experimental studies that highlight key factors governing the host-pathogen interaction in IA, with a focus on fungal factors that play a distinct role in neutropenic vs. non-neutropenic hosts and host factors that have been directly linked to IA susceptibility in patients undergoing HSCT.…”

Bacterial Pneumonia in Patients with Cancer

“…Lung epithelial cells are long lived and relatively resistant to chemotherapy [141, 142]. Beyond their well-known barrier function, these cells also demonstrate a substantial capacity to detect pathogens, to modulate local immune responses and to generate directly bactericidal responses through the production of antimicrobial peptides and reactive species [26, 143].…”

“…Advances in the understanding of the molecular mechanisms involved in recognition and signal transduction have allowed development of inhaled therapeutics that induce protective innate immune responses from the lung epithelium in animals. In animal models of pneumonia, this provides protection from lethal pathogens even when there is concurrent neutropenia [142, 144, 145]. Preclinical animal studies of one such treatment, PUL-042, demonstrate protection against Gram-positive, Gram-negative, fungal and viral pneumonias, and clinical trials are ongoing [142, 145, 146].…”

“…In animal models of pneumonia, this provides protection from lethal pathogens even when there is concurrent neutropenia [142, 144, 145]. Preclinical animal studies of one such treatment, PUL-042, demonstrate protection against Gram-positive, Gram-negative, fungal and viral pneumonias, and clinical trials are ongoing [142, 145, 146]. Augmentation of innate immune responses offer several hypothetical advantages in terms of rapidity of effect, breadth of pathogen specificity, and lack of known antimicrobial resistance, but efficacy has not been established in humans.…”