Respiratory disorders
Lung infections and innate host defense

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Human lungs continuously handle various pollutants, microbes, and allergens. The pulmonary innate immune response eliminates most of these foreign particles while maintaining a sterile environment within the lung. This response is tightly regulated in order to minimize inflammation and protect the host. This review focuses on the major pulmonary innate immune components that respond to infectious agents, including alveolar macrophages and their major receptors and surfactant, and its ability to regulate the host response to certain infectious pathogens. Finally, potential therapeutic applications relevant to these innate immune determinants will be discussed.

Section editor:

Clay Braden Marsh – Department of Internal Medicine, Ohio State University, USA

Introduction

Human lungs move around 14,000 L of air every day. Thus significant amounts of organic and inorganic particulates and microbes inhaled from the environment and aspirated from the posterior pharynx can reach the 150 m2 of alveolar surface. The integrity of the thin alveolar membrane is essential to assure oxygen and CO2 gas exchange; therefore the recognition and handling of these particulates without causing excessive inflammation are extremely important. Specialized lung innate immune responses play a key role in this process. Recognition of particulates is broad and based on use of pattern recognition receptors (PRRs); however, the immune responses following recognition in the lung are unique enabling dampening of pro-inflammation and thereby limiting damage to the alveolar surface. Alveolar macrophages (AMs) and dendritic cells (DC) are the first cellular line of defense in the alveoli and their surfaces are rich in PRRs. Evidence is accumulating that soluble and cell-associated C-type (Ca2+-dependent) lectins play a key role in shaping the innate response in the lung. In addition to the established role for Toll-like receptors (TLRs) in this process, recent evidence indicates that NOD (nucleotide-binding oligomerization domain)-like proteins (NLR) also play an important role as intracellular sensors that regulate inflammatory responses. Here we will discuss these important cellular and soluble determinants of the lung innate immune response, provide examples of their roles in modifying the host response to specific infectious agents during disease pathogenesis and address potential therapeutic applications.

Section snippets

Surfactant proteins A and D

The alveolar space consists of flat lining cells or type I cells important in gas exchange and type II cells that produce and secrete a mixture of proteins and phospholipids that comprise surfactant. Surfactant proteins B and C have important biological properties that result in lowering surface tension and preventing the alveoli from collapsing. A deficiency of these proteins in premature infants leads to infant respiratory distress syndrome, for which administration of exogenous surfactant is

Alveolar macrophages

Because of its location at the alveolar air tissue interface, the alveolar macrophage (AM) is the first line of cellular defense against inhaled environmental particles and infectious microorganisms that enter the lungs. These cells express several immune receptors, including Fc-γ receptors and complement receptors (e.g. CR1, CR3 and CR4); and particularly high levels of pattern recognition receptors such as the MR, Dectin-1 (β-glucan receptor), scavenger receptors, Toll-like receptors and

The mannose receptor

The mannose receptor (MR) is a C-type lectin that is expressed on tissue macrophages, AMs and DCs but not monocytes [53, 54, 55]. The MR is a Type I transmembrane protein with a short cytoplasmic tail and an extracellular domain that shares homology with other C-type lectins. The extracellular domain is a PRR that binds with high affinity to mannose- and fucose-containing glycoconjugates frequently found on the surface of a variety of microbes referred to as pathogen-associated molecular

DC-SIGN

Dendritic cells are a diverse group of myeloid and lymphoid-origin cells that play a key role in the adaptive immune response. One way these cells can regulate this immune response is through the expression of major pattern recognition receptors [67]. The DC-specific ICAM-grabbing non-integrin (DC-SIGN, CD209) is a C-type lectin that binds to HIV gp120 [68, 69]. Like the MR, DC-SIGN has an extracellular CRD. Its cytoplasmatic domain is important for antigen internalization and signal

Dectin-1

This C-type lectin is expressed on macrophages, DCs and neutrophils and is primarily a PRR for fungal β-glucan [74, 78]. It contains an extracellular CRD and an intracellular immunoreceptor tyrosine-based activation motif (ITAM) required for interactions with TLR2 [74] and the cytoskeletal changes that occur after Dectin-1 mediated phagocytosis [79]. A unique feature of Dectin-1 is that it mediates the production of TNF-α in response to C. albicans and Streptomyces cerevisiae [80]. The

Toll-like receptors

Toll-like receptors are membrane-associated type I receptors that largely function to recognize PAMPs [83]. There are 11 mammalian TLRs which vary in function largely with respect to the ligands that they recognize [84]. The externalized amino terminus contains variable arrangements of leucine-rich repeats (LRRs) which serve to recognize the PAMPs. The cytosolic carboxy terminus of TLRs is highly homologous to the IL-1 receptor and contains a Toll/IL-1R (TIR) domain that forms the nidus for the

NOD proteins

Although surface PRRs such as TLRs are widely recognized regulators of immune responses, 23 cytosolic NOD-like receptors (NLRs) implicated in the innate recognition of intracellular pathogens have been recently described [87, 88, 89, 90, 91, 92]. They are composed of a C-terminal series of leucine-rich repeats similar to the extracellular domain of TLRs, a central nucleotide-oligomerization domain and an amino-terminal protein–protein interaction domain, such as caspase activation and

Mannose binding lectin (MBL)

The mannose binding lectin (MBL) is a soluble collectin present in serum [113]. Like other collectins, it serves as a PRR for microorganisms. There is increasing evidence that polymorphisms in the MBL are associated with different types of infections such as HIV, cryptosporidiosis, meningococcal disease and tuberculosis [114, 115, 116, 117].

M. tuberculosis

M. tuberculosis is an intracellular pathogen of mononuclear phagocytes and highly adapted to the human host. This bacterium enters macrophages by the phagocytic process using a defined subset of receptors, and subsequently multiplies within a unique phagosomal compartment. SP-A and SP-D regulate the early interaction between M. tuberculosis and macrophages. SP-A increases the phagocytosis of M. tuberculosis through a direct interaction of the protein with macrophages [118], which up-regulates

Future directions and therapeutic options

For more than 25 years surfactant therapy has been successfully used in neonates with respiratory distress syndrome with the purpose of facilitating alveolar gas interchange. Surfactant therapy has also been used in adults with acute respiratory distress syndrome (ARDS) without benefit [138]. However, surfactant replacement therapy has been based on the biomechanical properties of surfactant rather than its biological properties, and neither SP-A nor SP-D are components of artificial

Acknowledgment

Part of the research was supported by NIH Grants A1052458 and A1059639.

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