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CCR5-mediated Recruitment of NK Cells to the Kidney Is a Critical Step for Host Defense to Systemic Candida albicans
Nu Z N Nguyen1, Vuvi G Tran1, Saerom Lee2
1BK21 Integrated Immunometabolism Education and Research Team, School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea.
Abstract:
C-C chemokine receptor type 5 (CCR5) regulates the trafficking of various immune cells to sites of infection. In this study, we showed that expression of CCR5 and its ligands was rapidly increased in the kidney after systemic Candida albicans infection, and infected CCR5-/- mice exhibited increased mortality and morbidity, indicating that CCR5 contributes to an effective defense mechanism against systemic C. albicans infection. The susceptibility of CCR5-/- mice to C. albicans infection was due to impaired fungal clearance, which in turn resulted in exacerbated renal inflammation and damage. CCR5-mediated recruitment of NK cells to the kidney in response to C. albicans infection was necessary for the anti-microbial activity of neutrophils, the main fungicidal effector cells. Mechanistically, C. albicans induced expression of IL-23 by CD11c+ dendritic cells (DCs). IL-23 in turn augmented the fungicidal activity of neutrophils through GM-CSF production by NK cells. As GM-CSF potentiated production of IL-23 in response to C. albicans, a positive feedback loop formed between NK cells and DCs seemed to function as an amplification point for host defense. Taken together, our results suggest that CCR5-mediated recruitment of NK cells to the site of fungal infection is an important step that underlies innate resistance to systemic C. albicans infection.
Insights
C-C chemokine receptor type 5 (CCR5) is crucial for fighting systemic Candida albicans infections. Its absence impairs fungal clearance, leading to increased kidney damage and mortality, highlighting CCR5
Area of Science:
- Immunology
- Microbiology
- Renal Pathology
Background:
- C-C chemokine receptor type 5 (CCR5) controls immune cell movement to infection sites.
- Systemic Candida albicans infection impacts host defense mechanisms.
Purpose of the Study:
- To investigate the role of CCR5 in host defense against systemic Candida albicans infection.
- To elucidate the mechanisms underlying CCR5-mediated immunity.
Main Methods:
- Comparative analysis of wild-type and CCR5-deficient (CCR5-/-) mice infected with Candida albicans.
- Assessment of immune cell infiltration, fungal burden, renal inflammation, and survival rates.
- Investigation of cytokine and chemokine signaling pathways involving neutrophils, NK cells, and dendritic cells.
Main Results:
- CCR5 expression and ligand levels increased in kidneys during C. albicans infection.
- CCR5-/- mice showed higher mortality, impaired fungal clearance, and exacerbated renal damage.
- CCR5-mediated recruitment of NK cells to the kidney was essential for neutrophil anti-fungal activity.
- A positive feedback loop between NK cells and dendritic cells, involving IL-23 and GM-CSF, amplified host defense.
Conclusions:
- CCR5 plays a vital role in innate resistance against systemic Candida albicans infection.
- CCR5 facilitates the recruitment of NK cells, which are critical for enhancing neutrophil fungicidal activity.
- The CCR5-driven NK cell-DC interaction amplifies the immune response, improving fungal clearance and reducing renal pathology.
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