Surfactant Protein D-Mediated Aggregation ofPneumocystis cariniiImpairs Phagocytosis by Alveolar Macrophages

Abstract

Pneumocystis carinii pneumonia remains an important, lifethreatening opportunistic infection in immunocompromised patients. It is particularly prevalent among those with AIDS, hematologic or solid malignancies, or transplanted organs and among patients receiving chronic immunosuppressive therapies, particularly corticosteroids (23,25,35,39,59). Histologically, P. carinii pneumonia is characterized by filling of the alveolar space with distinctive protein-rich frothy exudates containing prominent aggregates of organisms (32). The exact chemical nature of the proteinaceous alveolar exudates is not known, but prior studies have shown that these exudates are particularly rich in surfactant proteins A and D (SP-A and SP-D), fibronectin, and vitronectin (54). Interactions of these host components, particularly the surfactant-associated proteins, with P. carinii has been an area of intensive investigation (37,47,53,58,60).Pulmonary surfactant is a complex mixture of lipids and proteins synthesized by alveolar type II cells and secreted into the alveolar spaces. This surfactant exerts multiple functions including reduction of alveolar surface tension and modulation of host defense and inflammatory responses (20,29). It contains at least four associated proteins, of which two, SP-B and SP-C, are hydrophobic and two, SP-A and SP-D, are hydrophilic. SP-A and SP-D have been demonstrated to accumulate during P. carinii pneumonia, while SP-B and SP-C are suppressed during this infection (3,42,44). These surfactantassociated proteins have further been shown to modulate the interaction of P. carinii with host cells and to regulate host inflammatory responses to the organism (26,30,42,57).SP-D is a soluble, collagenous protein synthesized and secreted by type II pneumocytes and nonciliated bronchiolar cells (43). Structurally, it belongs to the group III, mammalian C-type lectin family that includes SP-A, mannose binding protein, and bovine conglutinin (21). SP-D is composed of 43-kDa monomers, each consisting of four major domains: a short cysteine-containing amino-terminal region, a triple helical collagenous domain, a trimeric coiled neck region, and a globular carboxy-terminal carbohydrate recognition domain (CRD) (11). These monomers are assembled into triple helical trimers, which form a single collagenous "arm" displaying the CRDs on the end. Four trimeric subunits undergo disulfide cross-linking within their amino-terminal domains to form a cruciform dodecameric structure (10). Although rat SP-D is assembled as dodecamers, human SP-D appears to consist of a complex of dodecamers and variable proportions of higherorder multimers and trimers (11). In addition, the extent of SP-D binding to P. carinii ligands appears to correlate with the number of CRDs in higher-order multimers of the molecule (55).Recent

Eosinophil-Associated Lung Diseases. A Cry for Surfactant Proteins A and D Help?

“…However, in some instances, pathogens are able to subvert the normal phagocyte clearance machinery and utilize the protective environment of the phagocyte. In these rare cases, enhanced SP-A/-D binding may be a risk factor contributing to worsening of disease and increased pathogen burden (16)(17)(18)(19). As an example, SP-D-deficient mice infected with the fungus Cryptococcus neoformans (CN) have decreased pulmonary eosinophils and lower IL-5 levels in lung lavage fluid compared with control wild-type (WT) mice.…”

“…In addition, reactive oxygen and nitrogen species may also affect posttranslational modifications of SP-D that alter its structure and function at sites of inflammation (39,113). For example, NO, produced locally by airway epithelial cells and increased in asthma (114), has been shown to S-nitrosylate two free Cys thiols in the N-terminus of dodecameric SP-D (Cys- [15][16][17][18][19][20] and to affect dissociation into SP-D trimers (115). Consequences of this structural perturbation include the activation of SP-D proinflammatory chemoattractant function and the loss of control TLR4 blockade (39).…”

Pneumocystis carinii Exhibits a Conserved Meiotic Control Pathway

“…Isolates with significant contamination of other microorganisms were discarded (28). The isolates were examined for P. carinii nuclei as described for Diff-Quick-stained smears, and P. carinii trophic forms represented greater than 99% of the material on Diff-Quick-stained smears (35). For experiments requiring separation of the cysts and trophic forms, differential filtration through a 3-m filter was performed as we previously reported (16).…”

Surfactant Protein D Is Present in Human Tear Fluid and the Cornea and Inhibits Epithelial Cell Invasion byPseudomonas aeruginosa

“…However, these antimicrobial effects vary between different microbial genera, species, or strains. For example, SP-D can also reduce microbial phagocytosis by immune cells for Mycobacterium tuberculosis (9) and Pneumocystis carinii (40), and the aggregative and growth inhibitory actions of SP-D are strain dependent (5,39). However, SP-D-deficient animals are more susceptible to lung infection by Haemophilus influenzae (25) and exhibit delayed clearance of P. carinii (3) and respiratory syncytial virus (24) from the airways.…”