Vitamin D Deficiency Causes Defective Resistance to Aspergillus fumigatus in Mice via Aggravated and Sustained Inflammation

Li, Pei; Xu, Xiaoyong; Cao, E-Hong; Yu, Bo; Li, Wanchun; Fan, Min; Huang, Mei‐Rong; Shi, Lingen; Zeng, Rong; Su, Xin; Shi, Yi

doi:10.1371/journal.pone.0099805

Cited by 26 publications

(27 citation statements)

References 54 publications

(64 reference statements)

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“…Moreover, an investigation conducted in monocytes from type 2 diabetic patients showed that 1,25‐dihydroxyvitamin D (3) was able to downregulate the expression of TNF‐α, IL‐6, IL‐1, and IL‐8 (Giulietti et al., ). Vitamin D deficiency has been proved to be involved in enhanced expression of TNF‐α in mice (Li et al., ), while another observational investigation conducted in 957 old individuals showed that there was no association between vitamin D and TNF‐α levels. More studies are needed to fully evaluate the relationship between TNF‐α system and vitamin D in stroke patients.…”

Section: Discussionmentioning

confidence: 99%

Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients

et al. 2018

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IntroductionLow serum vitamin D levels are associated with the development of poststroke depression (PSD). Inflammatory markers play an important role in pathophysiology of PSD. The relationship between vitamin D levels and inflammatory markers has been discussed in nonstroke individuals. The purposes of this study were to explore the relationship between vitamin D levels and inflammatory markers in acute stroke patients and examine the effect of vitamin D and inflammatory markers on PSD.MethodsA total of 152 acute stroke patients were recruited. Serum levels of 25‐hydroxyvitamin D and inflammatory markers were measured by standardized laboratory methods. Depression symptoms were assessed with the 17‐item Hamilton Depression Scale (HAMD‐17). Patients with the HAMD‐17 scores ≥7 were identified to have depression symptoms.ResultsSerum vitamin D levels were negatively correlated with serum levels of interleukin‐6 and high‐sensitivity C‐reactive protein (hsCRP) (r = −.244, p = .002; r = −.231, p = .004). Multiple regression analysis showed that interleukin‐6 and hsCRP levels were associated with vitamin D levels (B = −0.355, p = .003; B = −2.085, p = .006), whereas age, height, weight, leukocyte count, neutrophil ratio, and lymphocyte rate could be omitted without changing the results. In multivariate analyses, the serum levels of vitamin D and interleukin‐6 were associated with the development of PSD after adjusted possible variables (OR = 0.976, 95% CI: 0.958–0.994, p = .009; OR = 1.029, 95% CI: 1.003–1.055, p = .027).ConclusionsSerum vitamin D levels are inversely associated with the levels of interleukin‐6 and hsCRP, suggesting a potential anti‐inflammatory role for vitamin D in stroke individuals.

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Section: Discussionmentioning

confidence: 99%

Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients

et al. 2018

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“…In a hamster model, the application of VitD leads to reduced neutrophil recruitment and blunted inflammation (32,37). VitD deficiency resulted in an impairment of host defense and increased inflammation after challenge with Aspergillus fumigatus compared to mice with elevated VitD levels (38). Also, recent studies in mice show that VitD depletion leads to structural changes in the developing lung (18), increased susceptibility to cigarette smoke-induced emphysema (27), and decreased muscle function after cigarette smoke exposure (26).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

et al. 2016

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bVitamin D (VitD) has a role in the regulation of calcium and phosphate metabolism and in addition impacts the activity of the immune system. VitD deficiency might be linked to increased susceptibility to respiratory tract infection. The aim of the present study was to characterize the impact of VitD deficiency on the susceptibility to bacterial infection in murine models. C57BL/6N mice were fed a diet with or without VitD for 10 weeks. The VitD-deficient or -sufficient mice were infected with Pseudomonas aeruginosa or Streptococcus pneumoniae. The colonization and inflammatory response in the lung were analyzed at defined time points. The serum 25-hydroxy-VitD concentration was significantly lower in mice on the VitD-deficient diet. In infection experiments with Pseudomonas aeruginosa or Streptococcus pneumoniae, no differences could be observed in the numbers of viable bacteria or in differential cell counts in the bronchoalveolar lavage fluids. Measurements of inflammatory cytokines (KC and interleukin-1␤ [IL-1␤]) did not show significant differences between the groups. In conclusion, VitD-deficient animals did not show significantly increased susceptibility to infection or an altered course of infection. The immune systems of humans and mice likely respond differently to VitD. Murine models are likely not appropriate for drawing conclusions on the role of VitD in human pulmonary host defense.

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“…Total ergosterol was analyzed using high-performance liquid chromatograph (HPLC) (Agilent Technologies) and detected at 282 nm on an AQ-C18 column (250 mm by 4.6 mm, 5 m) with a flow rate of 1 ml/min. (43,44). Briefly, 6-to 8-week-old male mice (ICR) were immunosuppressed on days Ϫ3 and Ϫ1 with cyclophosphamide (150 mg/kg) and on day Ϫ1 with hydrocortisone acetate (40 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

Long

Zeng

et al. 2017

Appl Environ Microbiol

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Ergosterol, a fungus-specific sterol enriched in cell plasma membranes, is an effective antifungal drug target. However, current knowledge of the ergosterol biosynthesis process in the saprophytic human fungal pathogen Aspergillus fumigatus remains limited. In this study, we found that two endoplasmic reticulumlocalized sterol C-24 reductases encoded by both erg4A and erg4B homologs are required to catalyze the reaction during the final step of ergosterol biosynthesis. Loss of one homolog of Erg4 induces the overexpression of the other one, accompanied by almost normal ergosterol synthesis and wild-type colony growth. However, double deletions of erg4A and erg4B completely block the last step of ergosterol synthesis, resulting in the accumulation of ergosta-5,7,22,24(28)-tetraenol, a precursor compound of ergosterol. Further studies indicate that erg4A and erg4B are required for conidiation but not for hyphal growth. Importantly, the Δerg4A Δerg4B mutant still demonstrates wild-type virulence in a compromised mouse model but displays remarkable increased susceptibility to antifungal azoles. Our data suggest that inhibitors of Erg4A and Erg4B may serve as effective candidates for adjunct antifungal agents with azoles.IMPORTANCE Knowledge of the ergosterol biosynthesis pathway in the human opportunistic pathogen A. fumigatus is useful for designing and finding new antifungal drugs. In this study, we demonstrated that the endoplasmic reticulum-localized sterol C-24 reductases Erg4A and Erg4B are required for conidiation via regulation of ergosterol biosynthesis. Moreover, inactivation of both Erg4A and Erg4B results in hypersensitivity to the clinical guideline-recommended antifungal drugs itraconazole and voriconazole. Therefore, our finding indicates that inhibition of Erg4A and Erg4B might be an effective approach for alleviating A. fumigatus infection.

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Vitamin D Deficiency Causes Defective Resistance to Aspergillus fumigatus in Mice via Aggravated and Sustained Inflammation

Cited by 26 publications

References 54 publications

Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients

Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients

Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

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