Chloroquine Modulates the Fungal Immune Response in Phagocytic Cells From Patients With Chronic Granulomatous Disease

Henriet, Stefanie; Jans, Jop; Simonetti, Elles; Kwon‐Chung, Kyung J.; Rijs, Antonius J. M. M.; Hermans, Peter W. M.; Holland, Steve; Jonge, Marien I. de; Warris, Adilia

doi:10.1093/infdis/jit103

Cited by 38 publications

(20 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…11 CQ interferes with the formation of autolysosome by increasing the pH in the cells. Previous studies have shown that pH also affect the growth of A. fumigatus, 39 which may be the cause of decreased fungal loads in our study. These three interventions are not specific to autophagy and may affect the fungal load through other pathways.…”

Section: Discussionsupporting

confidence: 47%

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

Cui

Lin

et al. 2020

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Li C, Li C, Lin J, et al. The role of autophagy in the innate immune response to fungal keratitis caused by Aspergillus fumigatus infection. Invest Ophthalmol Vis Sci. 2020;61(2):25. https://doi.org/10.1167/iovs.61.2.25 PURPOSE.To determine the role of autophagy in the innate immune response to fungal keratitis (FK) caused by Aspergillus fumigatus infection. METHODS.Corneal samples obtained from patients and mice with FK were visualized via transmission electron microscopy (TEM). Autophagy-related proteins LC3B-II, Beclin-1, LAMP-1, and p62 in A. fumigatus-infected corneas of C57BL/6 mice were tested by Western blot. After treatment with autophagy inhibitors 3-methyladenine (3-MA), chloroquine (CQ), or inducer rapamycin, autophagy-related proteins were detected by Western blot. Corneas were photographed with slit lamp microscopy and pathological changes were observed by hematoxylin and eosin staining. Polymorphonuclear neutrophilic leukocytes (PMNs) were assessed by immunofluorescent staining and observed under TEM. The levels of CXCL-1, IL-1β, HMGB1, IL-18, TNF-α, and IL-10 were tested by reverse transcription polymerase chain reaction and Western blot. The quantification of fungal loads was detected and photographed. RESULTS.The accumulation of autophagosomes in corneas of patients and mice with FK was observed with TEM. The expression of LC3B-II, Beclin-1, and LAMP-1 was elevated in corneas after fungal infection, whereas p62 was reduced. Treatment with 3-MA or CQ upregulated clinical scores, pathological changes, and the expression of CXCL-1, IL-1β, HMGB1, IL-18, and TNF-α except IL-10. The morphology of PMNs was changed and PMN recruitment was increased in mice corneas treated with 3-MA or CQ, whereas rapamycin reduced the inflammatory response to keratitis. These results were statistically significant. CONCLUSIONS. A. fumigatus infection increases the expression of autophagy in corneas.Autophagy plays an anti-inflammatory role in the innate immune response to A. fumigatus keratitis.

show abstract

Section: Discussionsupporting

confidence: 47%

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

Cui

Lin

et al. 2020

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…In addition to the antimalarial and antibacterial effects, HCQ also exhibits antifungal activities. Henriet et al, conducting an in vivo study with Aspergillus fumigatus and Aspergillus nidulans, demonstrated that chloroquine may increase the antifungal activity of leucocytes isolated in those with chronic granulomatous disease (CGD) at a low concentration through regulating the production of interleukin-1β and tumor necrosis factor-α [16]. Another in vitro study also found the synergistic effect of chloroquine and fluconazole against fluconazole-resistant Candida spp.…”

Section: Discussionmentioning

confidence: 99%

Hydroxychloroquine may reduce risk of Pneumocystis pneumonia in lupus patients: a Nationwide, population-based case-control study

Yeo

Chen

et al. 2020

BMC Infect Dis

View full text Add to dashboard Cite

Background: Pneumocystis pneumonia (PCP) is increasingly being diagnosed in patients with systemic lupus erythematosus (SLE), and hydroxychloroquine (HCQ) has been found to possess antifungal activities. We hence aimed to investigate the association between HCQ and PCP risk among patients with SLE. Methods: Using the 1997-2013 nationwide claim data, we identified 24,343 newly-diagnosed SLE patients. We then identified 58 PCP cases and selected 348 non-PCP controls matching (1:6) by age, sex, disease duration and the year of PCP diagnosis date. The risk of PCP was assessed by determing odds ratios (ORs) with 95% confidence intervals (CIs) by using multivariable conditional logistic regression. Results: The risk of PCP was associated with moderate to severe renal disease (OR 6.73, 95% CI 1.98-22.92), higher doses of glucocorticoids (≤5 mg/day, reference; 5-10 mg/day, OR 25.88, 95% CI 2.97-225.33; > 10 mg/day, OR 286.58, 95% CI 28.58-> 999), higher 3-month cumulative dose of cyclophosphamide (not use, reference; ≤1.4 g, OR 0.64, 95% CI 0.14-3.01; > 1.4 g, OR 11.52, 95% CI 1.97-67.39) and use of mycophenolate mofetil/mycophenolic acid (OR 50.79, 95% CI 5.32-484.77), whereas 3-month cumulative dose of HCQ was associated with a reduced risk of PCP among patients with SLE (not use, reference; ≤14 g, OR 0.69, 95% CI 0.21-2.24; > 14 g, OR 0.20, 95% CI 0.05-0.71). Conclusions: This study demonstrated incident PCP was associated with mycophenolate mofetil/mycophenolic acid use and higher doses of cyclophosphamide or glucocorticoid, whereas the use of a higher dose of HCQ was associated with a reduced risk of PCP in lupus patients.

show abstract

“…NOX2 activation is accompanied by an influx of K + ions and a rise in pH, which, in turn, is linked to activation of primary granular proteases that are predicted to enhance intracellular killing [34]. In support of this model, chloroquine, a lysosomotropic agent that prevents endosomal acidification, increased the antifungal activity of neutrophils from CGD patients [35]. …”

Section: Activation Of Neutrophil Proteases and Neutrophil Extracellumentioning

confidence: 99%

NOX2-dependent regulation of inflammation

2016

View full text Add to dashboard Cite

NADPH oxidase (NOX) isoforms together have multiple functions that are important for normal physiology and have been implicated in the pathogenesis of a broad range of diseases, including atherosclerosis, cancer and neurodegenerative diseases. The phagocyte NADPH oxidase (NOX2) is critical for antimicrobial host defence. Chronic granulomatous disease (CGD) is an inherited disorder of NOX2 characterized by severe life-threatening bacterial and fungal infections and by excessive inflammation, including Crohn’s-like inflammatory bowel disease (IBD). NOX2 defends against microbes through the direct antimicrobial activity of reactive oxidants and through activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the breakdown of cell membranes and extracellular release of chromatin and neutrophil granular constituents that target extracellular pathogens. Although the immediate effects of oxidant generation and NETosis are predicted to be injurious, NOX2, in several contexts, limits inflammation and injury by modulation of key signalling pathways that affect neutrophil accumulation and clearance. NOX2 also plays a role in antigen presentation and regulation of adaptive immunity. Specific NOX2-activated pathways such as nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor that induces antioxidative and cytoprotective responses, may be important therapeutic targets for CGD and, more broadly, diseases associated with excessive inflammation and injury.

show abstract

Chloroquine Modulates the Fungal Immune Response in Phagocytic Cells From Patients With Chronic Granulomatous Disease

Cited by 38 publications

References 33 publications

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

The Role of Autophagy in the Innate Immune Response to Fungal Keratitis Caused by Aspergillus fumigatus Infection

Hydroxychloroquine may reduce risk of Pneumocystis pneumonia in lupus patients: a Nationwide, population-based case-control study

NOX2-dependent regulation of inflammation

Contact Info

Product

Resources

About