Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages

Jenson Lim (Corresponding Author), Christopher J. Coates, Paula S Denicola, Mariam Garelnabi, Leanne M Smith, Pauline Monteith, Camille L Macleod, Claire Escaron, Gordon D Brown, Rebecca A Hall, Robin C May

Research output: Contribution to journalArticle

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Abstract

The pathogenic fungus Cryptococcus enters the human host via inhalation into the lung and is able to reside in a niche environment that is serum- (opsonin) limiting. Little is known about the mechanism by which nonopsonic phagocytosis occurs via phagocytes in such situations. Using a combination of soluble inhibitors of phagocytic receptors and macrophages derived from knockout mice and human volunteers, we show that uptake of nonopsonized Cryptococcus neoformans and C. gattii via the mannose receptor is dependent on macrophage activation by cytokines. However, although uptake of C. neoformans is via both dectin-1 and dectin-2, C. gattii uptake occurs largely via dectin-1. Interestingly, dectin inhibitors also blocked phagocytosis of unopsonized Cryptococci in wax moth (Galleria mellonella) larvae and partially protected the larvae from infection by both fungi, supporting a key role for host phagocytes in augmenting early disease establishment. Finally, we demonstrated that internalization of nonopsonized Cryptococci is not accompanied by the nuclear translocation of NF-κB or its concomitant production of proinflammatory cytokines such as TNF-α. Thus, nonopsonized Cryptococci are recognized by mammalian phagocytes in a manner that minimizes proinflammatory cytokine production and potentially facilitates fungal pathogenesis.

Original languageEnglish
Pages (from-to)3539-3546
JournalThe Journal of Immunology
Volume200
Issue number10
Early online date11 Apr 2018
DOIs
Publication statusPublished - 15 May 2018

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Cryptococcus
Phagocytes
Macrophages
Cryptococcus neoformans
Cytokines
Phagocytosis
Larva
Opsonin Proteins
Macrophage Activation
Moths
Mycoses
Waxes
Knockout Mice
Inhalation
Volunteers
Fungi
Lung
Serum
dectin 1

Keywords

  • syk
  • dectin
  • Cryptococcus neoformans
  • cCyptococcus gattii
  • phagocytes

Cite this

Lim, J., Coates, C. J., Denicola, P. S., Garelnabi, M., Smith, L. M., Monteith, P., ... May, R. C. (2018). Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages. The Journal of Immunology, 200(10), 3539-3546. https://doi.org/10.4049/jimmunol.1700790

Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages. / Lim, Jenson (Corresponding Author); Coates, Christopher J. ; Denicola, Paula S ; Garelnabi, Mariam ; Smith, Leanne M; Monteith, Pauline ; Macleod, Camille L ; Escaron, Claire ; Brown, Gordon D; Hall, Rebecca A; May, Robin C.

In: The Journal of Immunology, Vol. 200, No. 10, 15.05.2018, p. 3539-3546.

Research output: Contribution to journalArticle

Lim, J, Coates, CJ, Denicola, PS, Garelnabi, M, Smith, LM, Monteith, P, Macleod, CL, Escaron, C, Brown, GD, Hall, RA & May, RC 2018, 'Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages', The Journal of Immunology, vol. 200, no. 10, pp. 3539-3546. https://doi.org/10.4049/jimmunol.1700790
Lim J, Coates CJ, Denicola PS, Garelnabi M, Smith LM, Monteith P et al. Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages. The Journal of Immunology. 2018 May 15;200(10):3539-3546. https://doi.org/10.4049/jimmunol.1700790
Lim, Jenson ; Coates, Christopher J. ; Denicola, Paula S ; Garelnabi, Mariam ; Smith, Leanne M ; Monteith, Pauline ; Macleod, Camille L ; Escaron, Claire ; Brown, Gordon D ; Hall, Rebecca A ; May, Robin C. / Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages. In: The Journal of Immunology. 2018 ; Vol. 200, No. 10. pp. 3539-3546.
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abstract = "The pathogenic fungus Cryptococcus enters the human host via inhalation into the lung and is able to reside in a niche environment that is serum- (opsonin) limiting. Little is known about the mechanism by which nonopsonic phagocytosis occurs via phagocytes in such situations. Using a combination of soluble inhibitors of phagocytic receptors and macrophages derived from knockout mice and human volunteers, we show that uptake of nonopsonized Cryptococcus neoformans and C. gattii via the mannose receptor is dependent on macrophage activation by cytokines. However, although uptake of C. neoformans is via both dectin-1 and dectin-2, C. gattii uptake occurs largely via dectin-1. Interestingly, dectin inhibitors also blocked phagocytosis of unopsonized Cryptococci in wax moth (Galleria mellonella) larvae and partially protected the larvae from infection by both fungi, supporting a key role for host phagocytes in augmenting early disease establishment. Finally, we demonstrated that internalization of nonopsonized Cryptococci is not accompanied by the nuclear translocation of NF-κB or its concomitant production of proinflammatory cytokines such as TNF-α. Thus, nonopsonized Cryptococci are recognized by mammalian phagocytes in a manner that minimizes proinflammatory cytokine production and potentially facilitates fungal pathogenesis.",
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