Distinct Roles for Lung Collectins in Pulmonary Host Defense

It has long been recognized that the lung contains resident components of the innate immune system that provide a first-line defense against infectious challenge. Recent studies have provided considerable evidence that two surfactant associated proteins, surfactant protein (SP)-A and SP-D, play important roles in pulmonary host defense (1). SP-A and SP-D are members of a larger family of proteins known as collectins (collagenous C-type lectins), which also includes the serum collectins mannose-binding lectin (MBL) and conglutinin (2). Members of this family are characterized by common N-terminal collagen-like domains and C-terminal carbohydrate recognition domains (CRD). They have the capacity to bind a variety of macromolecules, including carbohydrates, phospholipids, and proteins. Numerous in vitro and in vivo studies during the past decade have supported the hypothesis that SP-A and SP-D contribute to the containment of infections caused by a wide variety of respiratory pathogens, including bacteria, viruses, and fungi, through modulation of pathogen clearance, immune cell function, and lung inflammation (reviewed in Refs. 1–5). Similar effects have been noted for SP-A and SP-D in the innate immune response. However, specific differences in function have suggested that each collectin may play a very specific role in defense against different microbial pathogens. Although both SP-A and SP-D can bind to, aggregate, and/or promote uptake of certain pathogens by immune cells in the airway (summarized in Table 1), each collectin behaves in a very specific manner, which may define the outcome of infection. For example, SP-A has been shown to function as an efficient opsonin for a variety of bacteria such as Pseudomonas aeruginosa and mycobacteria (Table 1; reviewed in Refs. 3–7), and promote uptake of the complexes by alveolar macrophages. In contrast, SP-D is not a very effective opsonin, and only moderately enhances the phagocytosis of P. aeurginosa by alveolar macrophages (8), and inhibits phagocytosis of Mycobacterium tuberculosis (9). SP-A also enhances the phagocytic capacity of macrophages (10), and increases ingestion of nonopsonized bacteria such as M. tuberculosis (11) and Klebsiella (12). Although SP-A has been reported to promote aggregation of certain viruses and bacteria, SP-D forms large aggregates compared with the microscopic aggregates in the presence of SP-A. These large SP-D-associated aggregates may promote airway mucociliary clearance as well as internalization by pulmonary phagocytic cells (3). The differences in the oligomeric structures of these collectins may contribute to their interaction with various microbial pathogens. SP-A and SP-D are both assembled as oligomers of trimeric subunits (1, 3). Each subunit contains a short amino-terminal disulfide crosslinking domain, a triple helical collagen domain, a short trimeric coiled-coil linking domain, and a C-terminal CRD. SP-A exists predominantly as octadecamers in “bouquet-like” oligomers, with closely spaced CRDs. SP-D is assembled as dodecamers with long crosslinking domains, resulting in more widely spaced CRDs. Because the separation of CRDs in SP-D is fivefold greater than for SP-A (100 nm versus 20 nm), SP-D has a greater capacity to link interactions between binding sites on different particulate ligands, potentially contributing to the higher levels of aggregation of microbial ligands seen with SP-D. Key recent studies using mice deficient in SP-A or SP-D support a role for these collectins in pulmonary host defense (summarized in Table 2). Work from several groups using SP-A / mice has shown increased bacterial load following infection with group B streptococcus (13), and defective clearance of Hemophilus influenzae (14), P. aeruginosa (15), and Mycoplasma pulmonis (16). SP-A / mice also show increased susceptibility to challenge with respiratory syncyticial virus (RSV) (17). In most instances, the decreased microbial clearance can be reversed by addition of exogenous SP-A. Because these mice show normal respiratory function and surfactant lipid metabolism (20), the defects in microbial defense appear to be primarily attributable to SP-A. Mice lacking SP-A also show variable increases in proinflammatory mediators and decreases in anti-inflammatory cytokines, with an overall net proinflammatory environment. In contrast, evaluation of the role of SP-D using SP-D–deficient mice has been complicated by abnormal surfactant homeostasis and altered alveolar macrophage function (21). Nevertheless, in the absence of SP-D, several studies have examined infection of SP-D / mice with bacterial and viral pathogens, including group B streptococcus (14), H. influenzae (14), and influenza A virus (IAV) (19). Several differences in response to in vivo challenges with these microbes by SP-A / and SP-D / mice have been reported. First, SP-D / mice show no change in bacterial load following group B streptococcus and H. influenzae challenge compared with reduced clearance in SP-A–deficient mice (14). Second, whereas production of reactive oxygen species (ROS) by alveolar macrophages ( Received in original form January 7, 2002 )