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Cited by 117Antifungal resistance and susceptibilityImmune Response and InflammationNeutrophil, Myeloperoxidase and Oxidative Mechanisms

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Role of Dectin-2 for Host Defense against Systemic Infection with Candida glabrata

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Ifrim, Daniela C., Bain, Judith M., Reid, Delyth M., Oosting, Marije, Verschueren, Ineke, Gow, Neil A. R., van Krieken, J. Han, Brown, Gordon D., Kullberg, Bart-Jan, Joosten, Leo A. B., van der Meer, Jos W. M., Koentgen, Frank, Erwig, Lars P., Quintin, Jessica, Netea, Mihai G.·2014·Infection and Immunity
DOI 10.1128/iai.01189-13PMC PMC3957982
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Abstract

Although Candida glabrata is an important pathogenic Candida species, relatively little is known about its innate immune recognition. Here, we explore the potential role of Dectin-2 for host defense against C. glabrata. Dectin-2-deficient (Dectin-2(-/-)) mice were found to be more susceptible to C. glabrata infections, showing a defective fungal clearance in kidneys but not in the liver. The increased susceptibility to infection was accompanied by lower production of T helper 1 (Th1) and Th17-derived cytokines by splenocytes of Dectin-2(-/-) mice, while macrophage-derived cytokines were less affected. These defects were associated with a moderate yet significant decrease in phagocytosis of the fungus by the Dectin-2(-/-) macrophages and neutrophils. Neutrophils of Dectin-2(-/-) mice also displayed lower production of reactive oxygen species (ROS) upon challenge with opsonized C. glabrata or C. albicans. This study suggests that Dectin-2 is important in host defense against C. glabrata and provides new insights into the host defense mechanisms against this important fungal pathogen.

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FIG 1 Greater C. glabrata loads in the kidneys of mice during systemic infection. (A and B) Quantification of Candida colonies from liver (A) and kidneys (B) of wild-type (WT) and Dectin-2−/− mice at days 3, 7, and 14 postinfection is shown. Wild-type and Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. After 3, 7, and 14 days, organs were collected and serial dilutions were plated on Sabouraud solid medium. Results are means ± SEM (n = 10 to 14 mice per group from 3 independent experiments). Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; ***, P < 0.001. (C) Fungal burdens in the kidneys of wild-type and Dectin-2−/− mice provided by Y. Iwakura. Wild-type or Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. After 7 days, kidneys were collected and serial dilutions were plated on Sabouraud agar medium. Results are means ± SEM (n = 12 mice per group from two independent experiments). Significance was determined with the Mann-Whitney U test. **, P < 0.01.
FIG 1 Greater C. glabrata loads in the kidneys of mice during systemic infection. (A and B) Quantification of Candida colonies from liver (A) and kidneys (B) of wild-type (WT) and Dectin-2−/− mice at days 3, 7, and 14 postinfection is shown. Wild-type and Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. After 3, 7, and 14 days, organs were collected and serial dilutions were plated on Sabouraud solid medium. Results are means ± SEM (n = 10 to 14 mice per group from 3 independent experiments). Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; ***, P < 0.001. (C) Fungal burdens in the kidneys of wild-type and Dectin-2−/− mice provided by Y. Iwakura. Wild-type or Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. After 7 days, kidneys were collected and serial dilutions were plated on Sabouraud agar medium. Results are means ± SEM (n = 12 mice per group from two independent experiments). Significance was determined with the Mann-Whitney U test. **, P < 0.01.CC BY · PubMed Central
FIG 2 Dectin-2 deficiency affects kidney histopathology during systemic infection with C. glabrata. Histopathological assessment of kidneys in uninfected Dectin-2−/− (A), infected wild-type (B), and infected Dectin-2−/− (C) (hematoxylin-and-eosin [H&E]-stained sections) and infected Dectin-2−/− (D and E) (periodic acid-Schiff [PAS]-stained sections) mice. Representative localized lesions and C. glabrata colonies in the kidneys of Dectin-2−/− mice are shown (C, D, and E). All observations of infected kidneys were performed at day 14 after intravenous injection with C. glabrata.
FIG 2 Dectin-2 deficiency affects kidney histopathology during systemic infection with C. glabrata. Histopathological assessment of kidneys in uninfected Dectin-2−/− (A), infected wild-type (B), and infected Dectin-2−/− (C) (hematoxylin-and-eosin [H&E]-stained sections) and infected Dectin-2−/− (D and E) (periodic acid-Schiff [PAS]-stained sections) mice. Representative localized lesions and C. glabrata colonies in the kidneys of Dectin-2−/− mice are shown (C, D, and E). All observations of infected kidneys were performed at day 14 after intravenous injection with C. glabrata.CC BY · PubMed Central
FIG 3 Cytokine profile from naive mice. Cells from naive mice were stimulated for 24 h (peritoneal macrophages) (A) or for 48 h and 5 days (splenocytes) (B) with heat-killed (HK) or live C. glabrata (Cg), heat-killed C. albicans yeast (Cay) or hyphae (Cah), and live C. albicans (Ca). Levels of TNF-α, IL-6, KC, IL-1α, IL-1β, IL-10, IFN-γ, and IL-17 accumulation were measured by ELISA. Results are means ± SEM (n = 8 mice per group). Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; **, P < 0.01.
FIG 3 Cytokine profile from naive mice. Cells from naive mice were stimulated for 24 h (peritoneal macrophages) (A) or for 48 h and 5 days (splenocytes) (B) with heat-killed (HK) or live C. glabrata (Cg), heat-killed C. albicans yeast (Cay) or hyphae (Cah), and live C. albicans (Ca). Levels of TNF-α, IL-6, KC, IL-1α, IL-1β, IL-10, IFN-γ, and IL-17 accumulation were measured by ELISA. Results are means ± SEM (n = 8 mice per group). Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; **, P < 0.01.CC BY · PubMed Central
FIG 4 Dectin-2 is required during systemic C. glabrata infection for subsequent splenocyte recall responses. Wild-type or Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. (A) After 3, 7, and 14 days, peritoneal macrophages were restimulated ex vivo with heat-killed C. glabrata (Cg), heat-killed C. albicans yeast (Cay), or hyphae (Cah) for 24 h. Levels of TNF-α accumulation in the supernatants were measured by ELISA. Results are means ± SEM (n = 9 or 10 mice per group) from 2 independent experiments. Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05. (B and C) Wild-type or Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. After 3, 7, and 14 days, splenocytes were restimulated ex vivo with either heat-killed C. glabrata (B) or heat-killed C. albicans yeast (C) for 48 h and 5 days. Levels of accumulation of TNF-α, IL-10, and IFN-γ (48 h) and of IL-17 and IL-22 (5 days) in the supernatants were measured by ELISA. Results are means ± SEM (n = 14 or 15 mice per group) from 3 independent experiments. Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
FIG 4 Dectin-2 is required during systemic C. glabrata infection for subsequent splenocyte recall responses. Wild-type or Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. (A) After 3, 7, and 14 days, peritoneal macrophages were restimulated ex vivo with heat-killed C. glabrata (Cg), heat-killed C. albicans yeast (Cay), or hyphae (Cah) for 24 h. Levels of TNF-α accumulation in the supernatants were measured by ELISA. Results are means ± SEM (n = 9 or 10 mice per group) from 2 independent experiments. Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05. (B and C) Wild-type or Dectin-2−/− mice received 107 CFU of C. glabrata per mouse intravenously. After 3, 7, and 14 days, splenocytes were restimulated ex vivo with either heat-killed C. glabrata (B) or heat-killed C. albicans yeast (C) for 48 h and 5 days. Levels of accumulation of TNF-α, IL-10, and IFN-γ (48 h) and of IL-17 and IL-22 (5 days) in the supernatants were measured by ELISA. Results are means ± SEM (n = 14 or 15 mice per group) from 3 independent experiments. Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; **, P < 0.01; ***, P < 0.001.CC BY · PubMed Central
FIG 5 Impact of Dectin-2 deficiency on phagocytosis and killing of C. glabrata by peritoneal macrophages. (A) Phagocytosis and killing of C. glabrata cells by murine peritoneal macrophages. The results are represented as percentage of phagocytosis (the percentage of fungal cells engulfed by macrophages present in the well) and percentage of killing (the percentage of killed fungal cells among the phagocytosed yeasts). The C. glabrata/macrophage ratio was 10:1. Significance was determined with the Mann-Whitney U test. Values represent means ± SEM (n = 5 mice per group). (B) Migration of peritoneal macrophages was determined using live-cell video microscopy. Tracking diagrams illustrate the distances traveled and the directionality and velocity of macrophages exposed to C. glabrata at a fungal particle/macrophage ratio of 3:1. Due to the large number of macrophages tracked per video, the data were filtered to show only macrophages whose tracks lasted until 30 min to 60 min, as previous work has shown that migration activity is greater early on (25). Tracks represent the movement of individual macrophages relative to their starting position, symbols indicate the location of macrophages at 1-min intervals, and arrows represent directionality. (n = 7 control mice and n = 8 Dectin-2−/− mice for 4 independent experiments). (C and D) Percentage of uptake (C) and phagocytic index (D) determined using live-cell video microscopy. The percentage of macrophages that have ingested at least one C. glabrata and the number of C. glabrata per 100 macrophages are depicted. Significance was determined with the Mann-Whitney U test. Values represent means ± SEM. *, P < 0.05.
FIG 5 Impact of Dectin-2 deficiency on phagocytosis and killing of C. glabrata by peritoneal macrophages. (A) Phagocytosis and killing of C. glabrata cells by murine peritoneal macrophages. The results are represented as percentage of phagocytosis (the percentage of fungal cells engulfed by macrophages present in the well) and percentage of killing (the percentage of killed fungal cells among the phagocytosed yeasts). The C. glabrata/macrophage ratio was 10:1. Significance was determined with the Mann-Whitney U test. Values represent means ± SEM (n = 5 mice per group). (B) Migration of peritoneal macrophages was determined using live-cell video microscopy. Tracking diagrams illustrate the distances traveled and the directionality and velocity of macrophages exposed to C. glabrata at a fungal particle/macrophage ratio of 3:1. Due to the large number of macrophages tracked per video, the data were filtered to show only macrophages whose tracks lasted until 30 min to 60 min, as previous work has shown that migration activity is greater early on (25). Tracks represent the movement of individual macrophages relative to their starting position, symbols indicate the location of macrophages at 1-min intervals, and arrows represent directionality. (n = 7 control mice and n = 8 Dectin-2−/− mice for 4 independent experiments). (C and D) Percentage of uptake (C) and phagocytic index (D) determined using live-cell video microscopy. The percentage of macrophages that have ingested at least one C. glabrata and the number of C. glabrata per 100 macrophages are depicted. Significance was determined with the Mann-Whitney U test. Values represent means ± SEM. *, P < 0.05.CC BY · PubMed Central
FIG 6 Impact of Dectin-2 deficiency on phagocytosis and killing of C. glabrata by neutrophils. (A) Phagocytosis and killing of C. glabrata cells by murine neutrophils. The results are represented as percentage of phagocytosis (the percentage of fungal cells engulfed by neutrophils present in the well) and percentage of killing (the percentage of killed fungal cells among the phagocytosed yeast). The C. glabrata/neutrophil ratio was 10:1. Values represent means ± SEM (n = 10 mice per group) for 2 independent experiments. P values are for phagocytosis or killing induced by wild-type and Dectin-2−/− macrophages. *, P < 0.05. (B) Dectin-2−/− neutrophils cannot induce the respiratory burst to the same extent as the wild type. Dectin-2−/− or wild-type neutrophils were stimulated with RPMI, phorbol 12-myristate 13-acetate (PMA), live opsonized C. glabrata, or live opsonized C. albicans, and overall oxygen radical production (area under the curve after 60 min) was measured with luminol-enhanced chemiluminescence in isolated neutrophils. Data are represented as means ± SEM (n = 10 mice per group) for 2 independent experiments. Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; ***, P < 0.001.
FIG 6 Impact of Dectin-2 deficiency on phagocytosis and killing of C. glabrata by neutrophils. (A) Phagocytosis and killing of C. glabrata cells by murine neutrophils. The results are represented as percentage of phagocytosis (the percentage of fungal cells engulfed by neutrophils present in the well) and percentage of killing (the percentage of killed fungal cells among the phagocytosed yeast). The C. glabrata/neutrophil ratio was 10:1. Values represent means ± SEM (n = 10 mice per group) for 2 independent experiments. P values are for phagocytosis or killing induced by wild-type and Dectin-2−/− macrophages. *, P < 0.05. (B) Dectin-2−/− neutrophils cannot induce the respiratory burst to the same extent as the wild type. Dectin-2−/− or wild-type neutrophils were stimulated with RPMI, phorbol 12-myristate 13-acetate (PMA), live opsonized C. glabrata, or live opsonized C. albicans, and overall oxygen radical production (area under the curve after 60 min) was measured with luminol-enhanced chemiluminescence in isolated neutrophils. Data are represented as means ± SEM (n = 10 mice per group) for 2 independent experiments. Significance was determined with the Mann-Whitney U test. Statistically different groups are indicated as follows: *, P < 0.05; ***, P < 0.001.CC BY · PubMed Central

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Authors
Ifrim, D. C., Bain, J. M., Reid, D. M., Oosting, M., Verschueren, I., Gow, N. A. R., van Krieken, J. H., Brown, G. D., Kullberg, B.-J., Joosten, L. A. B., van der Meer, J. W. M., Koentgen, F., Erwig, L. P., Quintin, J., & Netea, M. G.
Affiliations
  • Radboud University Medical Center (NL)
  • University of Aberdeen (GB)
  • Radboud University Medical Center, Department of Pathology, Nijmegen, The Netherlands
  • Radboud University Medical Center, Department of Internal Medicine, Division of Experimental Internal Medicine, Nijmegen, The Netherlands
  • Ozgene Pty Ltd., Bentley, Australia
Corresponding author
Netea, Mihai G.
ORCID
Venue
Infection and Immunity
Publisher
American Society for Microbiology
Published
2014-03
Volume
82
Issue
3
Pages
1064-1073
ISSN
  • 0019-9567 (ISSN-L)
  • 1098-5522
DOI
10.1128/iai.01189-13
PMC
PMC3957982
OpenAlex
W2026106645
Cited by
117
References
46
Citations by year
2026: 6 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 6 · 2019: 10 · 2018: 13 · 2017: 18 · 2016: 12 · 2015: 11 · 2014: 7
FWCI
7.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Infection and Immunity (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • HAL (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Wellcome Trust (086558, 097377/Z/11/Z, 086827, 097377, 101873, 094847, 089930, 080088, 075470, 102705, 102705/Z/13/Z)
  • European Commission (FP7/2007, 260338)
  • University of Aberdeen
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
Dectin-2, Candida glabrata, innate immune recognition, host defense against fungi, Th1 cytokines, Th17 cytokines, macrophage phagocytosis, neutrophils, reactive oxygen species, Candida albicans, systemic fungal infection
MeSH terms
Animals, Candida albicans, Candidiasis, Female, Macrophages, Mice, Inbred C57BL, Neutrophils, Phagocytosis, Cytokines, Reactive Oxygen Species, Th1 Cells, Lectins, C-Type, Candida glabrata, Mice

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