Pneumocystis carinii enhancessoluble mannose receptor production by macrophages

Fraser, Iain P.; Takahashi, Kazue; Koziel, Henry; Fardin, Babak; Harmsen, Allen G.; Ezekowitz, R. A. B.

doi:10.1016/s1286-4579(00)01283-1

Cited by 53 publications

(35 citation statements)

References 22 publications

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“…HIV infection was sufficient to impair RhoGTPase activation in response to Pneumocystis. Impaired Rho GTPase activation may in part be attributed to reduced mannose receptor surface expression, based on reduced mRNA (Koziel et al, 1998a) or through increased release of the mannose receptor ectodomain (Fraser et al, 2000). Alternatively, impaired RhoGTPase activation may be due to direct influence by HIV gene products that can influence cellular receptor expression and signal transduction pathways (Emerman and Malim, 1998).…”

Section: Discussionmentioning

confidence: 99%

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Zhang

Zhu

et al. 2005

MBoC

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Human alveolar macrophages (AMs) phagocytose Pneumocystis (Pc) organisms predominantly through mannose receptors, although the molecular mechanism mediating this opsonin-independent process is not known. In this study, using AMs from healthy individuals, Pc phagocytosis was associated with focal F-actin polymerization and Cdc42, Rac1, and Rho activation in a time-dependent manner. Phagocytosis was primarily dependent on Cdc42 and RhoB activation (as determined by AM transfection with Cdc42 and RhoB dominant-negative alleles) and mediated predominantly through mannose receptors (as determined by siRNA gene silencing of AM mannose receptors). Pc also promoted PAK-1 phosphorylation, which was also dependent on RhoGTPase activation. HIV infection of AMs (as a model for reduced mannose receptor expression and function) was associated with impaired F-actin polymerization, reduced Cdc42 and Rho activation, and markedly reduced PAK-1 phosphorylation in response to Pc organisms. In healthy AMs, Pc phagocytosis was partially dependent on PAK activation, but dependent on the Rho effector molecule ROCK. These data provide a molecular mechanism for AM mannose receptor-mediated phagocytosis of unopsonized Pc organisms that appears distinct from opsonin-dependent phagocytic receptors. Reduced AM mannose receptor-mediated Cdc42 and Rho activation in the context of HIV infection may represent a mechanism that contributes to the pathogenesis of opportunistic pneumonia.

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Section: Discussionmentioning

confidence: 99%

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Zhang

Zhu

et al. 2005

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“…The interaction of Pneumocystis with the host mannose receptor (MR) on AMs was first reported by Ezekowitz et al, and the importance of this mechanism of uptake was revealed in studies of the interaction of Pneumocystis with AMs from HIV-infected patients, where phagocytosis of Pneumocystis was significantly diminished compared to that with cells from healthy controls (78,162). Subsequent studies revealed that Pneumocystis induced shedding of MR from AMs, and coating of Pneumocystis with soluble MR inhibited phagocytosis in experimental murine models (87). Interestingly, in vivo studies in normal mice did not reveal a downregulation of surface MR in response to Pneumocystis infection, and MR knockout mice depleted of CD4 ϩ T cells did not have a fungal burden significantly different from that of wild-type mice (284).…”

Section: Macrophagesmentioning

confidence: 98%

Colonization by Pneumocystis jirovecii and Its Role in Disease

2012

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SUMMARY Although the incidence of Pneumocystis pneumonia (PCP) has decreased since the introduction of combination antiretroviral therapy, it remains an important cause of disease in both HIV-infected and non-HIV-infected immunosuppressed populations. The epidemiology of PCP has shifted over the course of the HIV epidemic both from changes in HIV and PCP treatment and prevention and from changes in critical care medicine. Although less common in non-HIV-infected immunosuppressed patients, PCP is now more frequently seen due to the increasing numbers of organ transplants and development of novel immunotherapies. New diagnostic and treatment modalities are under investigation. The immune response is critical in preventing this disease but also results in lung damage, and future work may offer potential areas for vaccine development or immunomodulatory therapy. Colonization with Pneumocystis is an area of increasing clinical and research interest and may be important in development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss current clinical and research topics in the study of Pneumocystis and highlight areas for future research.

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“…Furthermore, phagocytosis of Pneumocystis organisms by macrophages is reduced in human immunodeficiency virus patients with P. carinii pneumonia, and the expression of the macrophage mannose receptor is decreased in these patients (24). Previous results suggest that Pneumocystis organisms cause alveolar macrophages to shed mannose receptors (12). These findings indicate that alveolar macrophages from Pneumocystis-infected hosts are defective in phagocytosis of Pneumocystis organisms.…”

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confidence: 89%

Effect of Bronchoalveolar Lavage Fluid fromPneumocystis carinii- Infected Hosts on Phagocytic Activity of Alveolar Macrophages

et al. 2004

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Alveolar macrophages from Pneumocystis carinii-infected rats are defective in phagocytosis. To investigate whether this defect is due to a certain factor present in P. carinii-infected lungs, alveolar macrophages from uninfected rats were incubated with bronchoalveolar lavage (BAL) fluid samples from P. carinii-infected rats. Alveolar macrophages treated with these BAL fluid samples became defective in phagocytosis but remained normal when treated with BAL fluid samples from noninfected or Toxoplasma gondii-infected rats. The suppressive activity of the BAL fluid samples from P. carinii-infected rats on phagocytosis was retained when the BAL fluid samples were passed through a filter with a pore size of 0.45 m but was lost when the BAL fluid samples were digested with proteases such as trypsin, pepsin, papain, or endopeptidase Gly-C. Lipid fractions of these BAL fluid samples had no suppressive activity on phagocytosis. The suppressive activity of these BAL fluid samples was also lost when they were incubated with concanavalin A-agarose beads, suggesting that the inhibitor is a glycoprotein. The inhibitor was estimated to be larger than 100,000 Da by exclusion filtration. After binding to the concanavalin A-agarose beads, the inhibitor in BAL fluid samples and P. carinii lysate could be eluted with 200 mM methylmannose. Treatment of both the crude BAL fluid samples and P. carinii lysate and the 200 mM methylmannose eluate with antibody against the major surface glycoprotein of P. carinii eliminated their suppressive activity. These results suggest that the factor capable of suppressing the phagocytic activity of alveolar macrophages is P. carinii major surface glycoprotein or one or more of its derivatives.An important function of alveolar macrophages is to clear foreign particles and infectious agents from the lung. Their role in the defense against Pneumocystis carinii infection is demonstrated by the observation that transtracheally inoculated P. carinii organisms are not cleared in alveolar macrophage-depleted rats (31). Administration of granulocyte-macrophage colony-stimulating factor, which activates alveolar macrophages (40), decreases the severity of P. carinii pneumonia (34). This finding also indicates the importance of alveolar macrophages in the clearance of Pneumocystis organisms.The alveoli are constantly exposed to foreign material and microorganisms. The alveolar macrophage maintains a low level of activation to engulf and destroy these materials while inhibiting an overly reactive inflammatory reaction to foreign objects encountered. To accomplish this, alveolar macrophages inhibit antigen presentation by dendritic cells (20), limit the expansion of lymphocyte populations (38), and restrict pulmonary lymphocyte functions (19). When activated, alveolar macrophages become proinflammatory and produce interleukin-8, which attracts neutrophils and lymphocytes by chemotaxis, as well as interleukin-1␤, tumor necrosis factor alpha, interleukin-6, and granulocyte-macrophage colony-stimulating factor, wh...

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Pneumocystis carinii enhancessoluble mannose receptor production by macrophages

Cited by 53 publications

References 22 publications

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Colonization by Pneumocystis jirovecii and Its Role in Disease

Effect of Bronchoalveolar Lavage Fluid fromPneumocystis carinii- Infected Hosts on Phagocytic Activity of Alveolar Macrophages

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