Identification of compounds that decrease numbers of <i>Mycobacteria</i> in human macrophages in the presence of serum amyloid P

Wang, Xiang; Cox, Nehemiah; Gomer, Richard H.

doi:10.1189/jlb.1a0317-118rr

Cited by 3 publications

(3 citation statements)

References 62 publications

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“…Phagocytosis of M. tuberculosis or Mycobacterium smegmatis in the presence of SAP also skews the macrophages toward the “tolerant” M2c cell type, and this skew can be reduced in the presence of small molecules that block SAP binding (36). Thus, in both microbes (M.…”

Section: Discussionmentioning

confidence: 99%

“…The phagocytosis of M. tuberculosis is similar to that of C. albicans , i.e., both are engulfed within a phagolysosome, the difference is that the bacteria persist in macrophages, whereas C. albicans is killed ( 34 ), or the fungus kills the macrophage after shifting to hyphal morphology ( 35 ). Phagocytosis of M. tuberculosis or Mycobacterium smegmatis in the presence of SAP also skews the macrophages toward the “tolerant” M2c cell type, and this skew can be reduced in the presence of small molecules that block SAP binding ( 36 ). Thus, in both microbes ( M. tuberculosis and C. albicans ), SAP may bind to amyloid-like structures and lead to increased microbe survival and propagation.…”

Section: Discussionmentioning

confidence: 99%

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Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines

Behrens

Lipke

Pilling

et al. 2019

mBio

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In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to Candida albicans dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid. In the absence of SAP, phagocytosis of fungi by human macrophages was potentiated by expression of amyloid on the fungi. SAP binding to fungi inhibited their phagocytosis by macrophages. Macrophages pretreated with SAP displayed reduced fungal phagocytosis, reduced secretion of inflammatory cytokines (IFN-γ, IL-6, and TNF-α), and increased secretion of the anti-inflammatory cytokine IL-10. SAP bound to fungi or added to the medium upregulated the expression of the anti-inflammatory receptor CD206 on macrophages. These findings suggest that SAP bound to amyloid-like structures on fungal cells dampens the host cellular immune response in fungal diseases such as invasive candidiasis. IMPORTANCE Macrophages are a key part of our innate immune system and are responsible for recognizing invading microbes, ingesting them, and sending appropriate signals to other immune cells. We have found that human macrophages can recognize invading yeast pathogens that have a specific molecular pattern of proteins on their surfaces: these proteins have structures similar to the structures of amyloid aggregates in neurodegenerative diseases like Alzheimer’s disease. However, this surface pattern also causes the fungi to bind a serum protein called serum amyloid P component (SAP). In turn, the SAP-coated yeasts are poorly recognized and seldom ingested by the macrophages, and the macrophages have a more tolerant and less inflammatory response in the presence of SAP. Therefore, we find that surface structures on the yeast can alter how the macrophages react to invading microbes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines

Behrens

Lipke

Pilling

et al. 2019

mBio

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“…Tuberculosis bacteria can live inside macrophages, where they also push the host macrophage away from a M1 phenotype to help the survival of the parasitic bacteria ( 169 ). To test the hypothesis that blocking SAP signaling to macrophages would reduce regulatory macrophages and increase M1 macrophages, we screened 3,000 compounds for the ability to inhibit the binding of SAP to FcγRI, and found 12 that reduced this binding ( 170 ). In support of the hypothesis, SAP potentiated the proliferation of Mycobacterium smegmatis and Mycobacterium tuberculosis in human macrophages, and in the presence of SAP, 2 of the compounds reduced the intra-macrophage proliferation of these bacteria ( 170 ).…”

Section: Blocking Sap Signaling As a Possible Therapeutic For Diseasementioning

confidence: 99%

The Development of Serum Amyloid P as a Possible Therapeutic

Pilling

2018

Front. Immunol.

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Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30–45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases.

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Blocking Serum Amyloid-P Component from Binding to Macrophages and Augmenting Fungal Functional Amyloid Increases Macrophage Phagocytosis of Candida albicans

2022

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Candida-macrophage interactions are important immune defense responses associated with disseminated and deep-seated candidiasis in humans. Cells of Candida spp. express functional amyloids on their surfaces during the pathogenesis of disseminated candidiasis. These amyloids become decorated with serum amyloid P-component (SAP) that binds to Candida cells and macrophages and downregulates the cellular and cytokine response to the fungi. In this report, further characterization of the interactions of SAP and fungal functional amyloid are demonstrated. Blocking the binding of SAP to macrophage FcγR1 receptors increases phagocytosis of yeast cells; seeding a pro-amyloid-forming peptide on the yeast cell surface also increases phagocytosis of yeasts by macrophages; and, lastly, miridesap, a small palindromic molecule, prevents binding of SAP to yeasts and removes SAP that is bound to C. albicans thus, potentially increasing phagocytosis of yeasts by macrophages. Some, or all, of these interventions may be useful in boosting the host immune response to disseminated candidiasis.

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Identification of compounds that decrease numbers of Mycobacteria in human macrophages in the presence of serum amyloid P

Cited by 3 publications

References 62 publications

Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines

Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines

The Development of Serum Amyloid P as a Possible Therapeutic

Blocking Serum Amyloid-P Component from Binding to Macrophages and Augmenting Fungal Functional Amyloid Increases Macrophage Phagocytosis of Candida albicans

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