Inducible innate resistance of lung epithelium to infection

Abstract

Most studies of innate immunity have focused on leukocytes such as neutrophils, macrophages, and natural killer cells. However, epithelial cells play key roles in innate defenses that include providing a mechanical barrier to microbial entry, signaling to leukocytes, and directly killing pathogens. Importantly, all these defenses are highly inducible in response to the sensing of microbial and host products. In healthy lungs, the level of innate immune epithelial function is low at baseline. This is indicated by low levels of spontaneous microbial killing and cytokine release, reflecting low constitutive stimulation in the nearly sterile lower respiratory tract when mucociliary clearance mechanisms are functioning effectively. This contrasts with the colon, where bacteria are continuously present and epithelial cells are constitutively activated. Although the surface area of the lungs presents a large target for microbial invasion, activated lung epithelial cells that are closely apposed to deposited pathogens are ideally positioned for microbial killing.

Figure 1. Time Course of Induced Innate Resistance in the Lungs

A. Host survival. Mice were pretreated in groups of 6 with an aerosolized lysate of the bacterium non-typeable H. influenzae (NTHi) to stimulate innate immunity, then challenged as a single group with live aerosolized S. pneumoniae (Spn) (6.1 × 10¹⁰ CFU/ml for 60 min). Survival at 7 days is shown as a function of the interval between treatment and challenge (* p = 0.015, ^† p = 0.002, treated vs. untreated). B. Bacterial Counts in the Lungs. Mice were pretreated in groups of 4 with an aerosolized NTHi lysate at various time points, then challenged as a single group with live aerosolized Spn (2.1 × 10¹⁰ CFU/ml for 60 min). Lungs were removed immediately after the aerosol challenge, homogenized, and plated for bacterial culture (mean ± SEM, * p < 0.05 for treated vs untreated). From Clement et al., Am J Respir Crit Care Med, 2008.

Figure 2. Architecture and Innate Immune Tone of Mucosal Surfaces

A. Architecture of Colon and Lung. The architecture of the mouse colon on the top, showing the epithelium with intracellular mucin (intense green), extracellular mucin (faint green), and overlying bacteria (red). The mucus gel layer is thick (up to 500 μm), and is adherent to the epithelium. From Johansson MEV, PNAS 2008, 105:15064. The architecture of the airway is illustrated on the bottom, showing a thin mucus layer (5 μm in distal airways to 50 μm in proximal airways) overlying a periciliary liquid layer ∼7 μm in depth. Aspirated microbes become entrapped in the mucus gel layer and are rapidly swept out of the lungs by ciliary action, keeping the lungs nearly sterile. B. Baseline Innate Immune Tone of Mucosal Surfaces. The epithelial resistance of mucosal surfaces of the mammalian body are postulated to be related to exposure to microbial products. The tone of the lung and gut are illustrated in relative terms with regard to each other and to the minimal and maximal points of the scale; the tone of all other surfaces is speculative.