Stimulated Innate Resistance of Lung Epithelium Protects Mice Broadly against Bacteria and Fungi

Abstract

Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and class A bioterror bacterial pathogens, and the fungal pathogen, Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kB, type I and II IFN, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly up-regulated. Taken together, stimulated innate resistance appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection.

Mechanisms of clearance of nontypeable Haemophilus influenzae from cigarette smoke-exposed mouse lungs

“…Taken together, the present findings suggest that the protective factor is an Ig, most probably IgA. This mode of protection appears to be distinct from the recently described protection conferred by bacterial lysate, which was mediated by the epithelial cells' innate antimicrobial defence pathways [31]. Mechanisms of accelerated clearance via NTHi-specific IgA probably involve opsonisation of bacteria and subsequent phagocytosis.…”

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

“…In this regard, despite the fact that airways ECs phagocytose Aspergillus conidia, 16,17 the ability of conidia to survive in ECs 17 was taken to indicate airways ECs as a possible fungus reservoir. More recently, ECs were found to respond to Aspergillus conidia via MyD88-dependent and -independent pathways 18 and by upregulating antimicrobial peptides 43,44 endowed with antifungal activity. 45 Thus, the production of IL-17A, known to induce antimicrobial peptides, 46 is of particular interest and worth of further investigation.…”

Inducible epithelial resistance protects mice against leukemia-associated pneumonia

“…As described, 19 Aspergillus fumigatus strain AF293 (American Type Culture Collection) was plated on yeast extract agar for 3 days and then collected by gentle agitation in 0.1% Tween-20 PBS. The suspension was filtered, centrifuged, washed, and resuspended in 10 mL PBS; 10 9 conidia/mL were nebulized for 60 minutes.…”

“…[18][19][20][21][22] Given the relative tolerance of lung epithelial cells to immunosuppressive therapies 23,24 and our observation that inducible resistance persists despite leukocyte depletion, [25][26][27] we hypothesized that this strategy could protect against pneumonia in the setting of leukemia and leukemia therapy. Here, we present evidence that inducible resistance persists in vitro and in vivo, despite exposure to leukemia and common antileukemia chemotherapy and propose this novel approach as a means to improve survival of patients with AML/MDS.…”