Surfactant protein a promotes attachment of Mycobacterium tuberculosis to alveolar macrophages during infection with human immunodeficiency virus.

101

Collectins, including surfactant proteins A (SP-A) and D (SP-D) and mannose binding lectin (MBL), are the important constituents of the innate immune system. Mycobacterium avium, a facultative intracellular pathogen, has developed numerous mechanisms for entering mononuclear phagocytes. In this study, we investigated the interactions of collectins with M. avium and the effects of these lectins on phagocytosis of M. avium by macrophages. SP-A, SP-D, and MBL exhibited a concentration-dependent binding to M. avium. The binding of SP-A to M. avium was Ca2+-dependent but that of SP-D and MBL was Ca2+-independent. SP-A and SP-D but not MBL enhanced the phagocytosis of FITC-labeled M. avium by rat alveolar macrophages and human monocyte-derived macrophages. Excess mannan, zymosan, and lipoarabinomannan derived from the M. avium-intracellular complex, significantly decreased the collectin-stimulated phagocytosis of M. avium. Enhanced phagocytosis was not affected by the presence of cycloheximide or chelation of Ca2+. The mutated collectin, SP-AE195Q, R197D exhibited decreased binding to M. avium but stimulated phagocytosis to a level comparable to wild-type SP-A. Enhanced phagocytosis by cells persisted even after preincubation and removal of SP-A or SP-D. Rat alveolar macrophages that had been incubated with SP-A or SP-D also exhibited enhanced uptake of 125I-mannosylated BSA. Analysis by confocal microscopy and flow cytometry revealed that the lung collectins up-regulated the cell surface expression of mannose receptor on monocyte-derived macrophages. These results provide compelling evidence that SP-A and SP-D enhance mannose receptor-mediated phagocytosis of M. avium by macrophages.

Section: Discussionsupporting

confidence: 60%

Pulmonary Collectins Enhance Phagocytosis of Mycobacterium avium through Increased Activity of Mannose Receptor

Kudo

Sano²,

Takahashi

et al. 2004

101

“…Levels in BAL fluids are ϳ2.82 g/ml (40), whereas concentrations in situ in the lung in association with lung surfactant are considerably higher. SP-A levels have also been shown to be elevated to 6 g/ml in HIV-infected BAL (41) and have been shown to be as high as 24 g/ml in amniotic fluid at term (42), when SP-A acts as signal for parturition (43). Levels of SP-A in the vaginal tract have yet to be definitively determined, and the collectin likely makes up only a part of the milieu of defense proteins that include human ␤-defensins, lysozyme, lactoferrin, and human neutrophil peptides which have already been shown to inhibit HIV infection (44).…”

Section: Discussionmentioning

confidence: 99%

Surfactant Protein A Binds to HIV and Inhibits Direct Infection of CD4+ Cells, but Enhances Dendritic Cell-Mediated Viral Transfer

Gaiha

Dong

Palaniyar

et al. 2008

The identification of surfactant protein A (SP-A) as an important innate immune factor of the lungs, amniotic fluid, and the vaginal tract suggests that it could play an important role during various stages of HIV disease progression and transmission. Therefore, we examined whether SP-A could bind to HIV and also had any effect on viral infectivity. Our data demonstrate that SP-A binds to HIV in a calcium-dependent manner that is inhibitable by mannose and EDTA. Affinity capture of the HIV viral lysate reveals that SP-A targets the envelope glycoprotein of HIV (gp120), which was confirmed by ELISA using recombinant gp120. Digestion of gp120 with endoglycosidase H abrogates the binding of SP-A, indicating that the high mannose structures on gp120 are the target of the collectin. Infectivity studies reveal that SP-A inhibits the infection of CD4+ T cells by two strains of HIV (BaL, IIIB) by >80%. Competition assays with CD4 and mAbs F105 and b12 suggest that SP-A inhibits infectivity by occlusion of the CD4-binding site. Studies with dendritic cells (DCs) demonstrate that SP-A enhances the binding of gp120 to DCs, the uptake of viral particles, and the transfer of virus from DCs to CD4+ T cells by >5-fold at a pH representative of the vaginal tract. Collectively, these results suggest that SP-A acts as a dual modulator of HIV infection by protecting CD4+ T cells from direct infection but enhancing the transfer of infection to CD4+ T cells mediated by DCs.

“…Binding of mycobacteria to AM is mediated by complement receptors binding to complement components fixed to mycobacteria (32,47) and by mannose receptors (48) under the participation of surfactant protein A (48,49), CD14 (50), and sialoglycoprotein CD43 (51). These molecules serve as pattern recognition receptors that bind conserved bacterial structures (50,52).…”

Section: Discussionmentioning

confidence: 99%

Induction of TNF in Human Alveolar Macrophages As a Potential Evasion Mechanism of VirulentMycobacterium tuberculosis

Engele

Stössel

Castiglione

et al. 2002

123

100

The ability of macrophages to release cytokines is crucial to the host response to intracellular infection. In particular, macrophage-derived TNF plays an important role in the host response to infection with the intracellular pathogen Mycobacterium tuberculosis. In mice, TNF is indispensable for the formation of tuberculous granulomas, which serve to demarcate the virulent bacterium. TNF is also implicated in many of the immunopathological features of tuberculosis. To investigate the role of TNF in the local immune response, we infected human alveolar macrophages with virulent and attenuated mycobacteria. Infection with virulent strains induced the secretion of significantly higher levels of bioactive TNF than attenuated strains correlating with their ability to multiply intracellularly. Treatment of infected macrophages with neutralizing anti-TNF Abs reduced the growth rate of intracellular bacteria, whereas bacterial replication was augmented by addition of exogenous TNF. Infected and uninfected macrophages contributed to cytokine production as determined by double-staining of M. tuberculosis and intracellular TNF. The induction of TNF by human alveolar macrophages at the site of infection permits the multiplication of intracellular bacteria and may therefore present an evasion mechanism of human pathogens.