Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth

Sawada, Kyoko; Ariki, Shigeru; Kojima, Takashi; Saito, Atsushi; Yamazoe, Masami; Nishitani, Chiaki; Shimizu, Takeyuki; Takahashi, M.; Mitsuzawa, Hiroaki; Yokota, Shinichi; Sawada, Norimasa; Fujii, Nobuhiro; Takahashi, Hiroki; Kuroki, Yoshio

doi:10.1074/jbc.m109.074765

Cited by 39 publications

(31 citation statements)

References 46 publications

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“…These data support a previously hypothesized mechanism for the collectin-promoted lysosomal fusion with Legionella-containing phagosomes resulting in growth suppression of the pathogen (32). In that study, SP-A and SP-D significantly increased the number of Legionella pneumophila colocalized with LAMP-1 in THP-1 cells (32).…”

Section: Discussionsupporting

confidence: 77%

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Pulmonary Surfactant Protein A Enhances Endolysosomal Trafficking in Alveolar Macrophages through Regulation of Rab7

Sender

Moulakakis

Stamme

2011

The Journal of Immunology

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Surfactant protein A (SP-A), the most abundant pulmonary soluble collectin, modulates innate and adaptive immunity of the lung, partially via its direct effects on alveolar macrophages (AM), the most predominant intra-alveolar cells under physiological conditions. Enhanced phagocytosis and endocytosis are key functional consequences of AM/SP-A interaction, suggesting a SP-A–mediated modulation of small Rab (Ras related in brain) GTPases that are pivotal membrane organizers in both processes. In this article, we show that SP-A specifically and transiently enhances the protein expression of endogenous Rab7 and Rab7b, but not Rab5 and Rab11, in primary AM from rats and mice. SP-A–enhanced GTPases are functionally active as determined by increased interaction of Rab7 with its downstream effector Rab7 interacting lysosomal protein (RILP) and enhanced maturation of cathepsin-D, a function of Rab7b. In AM and RAW264.7 macrophages, the SP-A–enhanced lysosomal delivery of GFP-Escherichia coli is abolished by the inhibition of Rab7 and Rab7 small interfering RNA transfection, respectively. The constitutive expression of Rab7 in AM from SP-A−/− mice is significantly reduced compared with SP-A+/+ mice and is restored by SP-A. Rab7 blocking peptides antagonize SP-A–rescued lysosomal delivery of GFP-E. coli in AM from SP-A−/− mice. Activation of Rab7, but not Rab7b, by SP-A depends on the PI3K/Akt/protein kinase Cζ (PKCζ) signal transduction pathway in AM and RAW264.7 macrophages. SP-A induces a Rab7/PKCζ interaction in these cells, and the disruption of PKCζ by small interfering RNA knockdown abolishes the effect of SP-A on Rab7. The data demonstrate a novel role for SP-A in modulating endolysosomal trafficking via Rab7 in primary AM and define biochemical pathways involved.

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Section: Discussionsupporting

confidence: 77%

“…Furthermore, both SP-A and SP-D significantly increase the number of Legionella pneumophila colocalized with lysosome-associated membrane protein-1 (LAMP-1) in THP-1 cells (32). However, the option that SP-A influences membrane trafficking by directly modulating Rab GTPases has not been investigated so far.…”

mentioning

confidence: 97%

Pulmonary Surfactant Protein A Enhances Endolysosomal Trafficking in Alveolar Macrophages through Regulation of Rab7

Sender

Moulakakis

Stamme

2011

The Journal of Immunology

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“…Specifically, surfactant protein A (SP-A) and SP-D have been shown to opsonize and enhance the clearance of a number of microorganisms and allergens (14,18,23,36,43,49,50,52) and thereby characteristically have protective functions in the lung. The roles of surfactant proteins during fungal infections remain unclear, as a number of studies have reported conflicting results, and few investigations have been performed to evaluate the role of SPs in response to C. neoformans infection in vivo.…”

mentioning

confidence: 99%

Surfactant Protein D Facilitates Cryptococcus neoformans Infection

et al. 2012

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ABSTRACTConcurrent with the global escalation of the AIDS pandemic, cryptococcal infections are increasing and are of significant medical importance. Furthermore,Cryptococcus neoformanshas become a primary human pathogen, causing infection in seemingly healthy individuals. Although numerous studies have elucidated the virulence properties ofC. neoformans, less is understood regarding lung host immune factors during early stages of fungal infection. Based on our previous studies documenting that pulmonary surfactant protein D (SP-D) protectsC. neoformanscells against macrophage-mediated defense mechanismsin vitro(S. Geunes-Boyer et al., Infect. Immun. 77:2783–2794, 2009), we postulated that SP-D would facilitate fungal infectionin vivo. To test this hypothesis, we examined the role of SP-D in response toC. neoformansusing SP-D−/−mice. Here, we demonstrate that mice lacking SP-D were partially protected duringC. neoformansinfection; they displayed a longer mean time to death and decreased fungal burden at several time points postinfection than wild-type mice. This effect was reversed by the administration of exogenous SP-D. Furthermore, we show that SP-D bound to the surface of the yeast cells and protected the pathogenic microbes against macrophage-mediated defense mechanisms and hydrogen peroxide (H2O2)-induced oxidative stressin vitroandin vivo. These findings indicate thatC. neoformansis capable of coopting host SP-D to increase host susceptibility to the yeast. This study establishes a new paradigm for the role played by SP-D during host responses toC. neoformansand consequently imparts insight into potential future preventive and/or treatment strategies for cryptococcosis.

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“…Given the susceptibility of SP-A and SP-D KO mice to many viral, bacterial, and fungal pulmonary pathogens, this finding is particularly unexpected (3,24,26,27,35). Moreover, given the increased immune infiltration in the lungs of M. tuberculosis-infected SP-A and SP-A/-D KO mice, it is especially surprising to observe a lack of difference in bacterial titers (7,15,25).…”

Section: Cd4mentioning

confidence: 81%

Dispensability of Surfactant Proteins A and D in Immune Control ofMycobacterium tuberculosisInfection following Aerosol Challenge of Mice

2011

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Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth

Abstract: Pulmonary collectins, surfactant proteins A (SP-A

Cited by 39 publications

References 46 publications

Pulmonary Surfactant Protein A Enhances Endolysosomal Trafficking in Alveolar Macrophages through Regulation of Rab7

Pulmonary Surfactant Protein A Enhances Endolysosomal Trafficking in Alveolar Macrophages through Regulation of Rab7

Surfactant Protein D Facilitates Cryptococcus neoformans Infection

Dispensability of Surfactant Proteins A and D in Immune Control ofMycobacterium tuberculosisInfection following Aerosol Challenge of Mice

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