scholarly journals Pathogenesis and host defence against Mucorales: the role of cytokines and interaction with antifungal drugs

Mycoses ◽  
2014 ◽  
Vol 57 ◽  
pp. 40-47 ◽  
Author(s):  
Emmanuel Roilides ◽  
Charalampos Antachopoulos ◽  
Maria Simitsopoulou
Keyword(s):  
Antifungal Drugs ◽  
Host Defence

scholarly journals GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Zhen-Zhen Liu ◽  
Yong-Jun Yang ◽  
Feng-Hua Zhou ◽  
Ke Ma ◽  
Xiao-Qi Lin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Skin Infection ◽  
Bacterial Colonization ◽  
Critical Role ◽  
Host Defence ◽  
Skin Damage ◽  
Microbial Infection ◽  
Caspase 1 ◽  
Deficient Mice

AbstractGasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1β secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1–Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1β production, the critical role of IL-1β was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1β production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus. Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1–Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1–Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.

scholarly journals Effects of LL-37 on Gingival Fibroblasts: A Role in Periodontal Tissue Remodeling?

Vaccines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 44 ◽  
Author(s):  
Maelíosa McCrudden ◽  
Katherine O’Donnell ◽  
Chris Irwin ◽  
Fionnuala Lundy
Keyword(s):  
Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Statistical Significance ◽  
Host Defence ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Gingival Fibroblasts ◽  
Periodontal Tissues ◽  
Hepatocyte Growth ◽  
Periodontal Tissue Remodeling

Mounting evidence suggests that the host defence peptide, LL-37, plays a role in both inflammation and in wound healing; however, the role of this peptide in the remodeling and maintenance of oral tissues is not yet fully understood. Fibroblasts are the most abundant cell type within the periodontal tissues, and gingival fibroblasts play an important role in maintaining and repairing the gingival tissues which are constantly exposed to external insults. In this study we examined the direct effects of LL-37 treatment on gingival fibroblasts and found that LL-37 significantly increased secretion of both interleukin 8 (IL-8) and IL-6 from these cells. LL-37 tended to decrease matrix metalloproteinase (MMP) activity in gingival fibroblasts, but this decrease did not reach statistical significance. LL-37 significantly increased tissue inhibitor of metalloproteinase-1 (TIMP-1) production by gingival fibroblasts, but had no significant effect on TIMP-2 levels. LL-37 was also shown to significantly increase production of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) in gingival fibroblasts. Taken together, these results suggest an important role for the host defence peptide, LL-37, in modulating the fibroblast response to remodeling in periodontal tissues.

scholarly journals Absent in melanoma 2 inflammasome is required for host defence against Streptococcus pneumoniae infection

2019 ◽  
Vol 25 (7) ◽  
pp. 412-419 ◽  
Author(s):  
Siwei Feng ◽  
Tingting Chen ◽  
Guihua Lei ◽  
Fengqing Hou ◽  
Jiali Jiang ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pneumococcal Infection ◽  
Host Defence ◽  
Mortality And Morbidity ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Increased Susceptibility

Streptococcus pneumoniae, a leading cause of invasive pneumococcal disease, is responsible for high mortality and morbidity worldwide. A previous study showed that the NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes are essential for caspase-1 activation and IL-1β production in the host response to S. pneumoniae infection. The function of NLRP3 in host innate immunity to S. pneumoniae was studied in vivo and in vitro. However, the role of AIM2 in host defence against S. pneumoniae remains unclear. Here, we show that AIM2-deficient (AIM2–/–) mice display increased susceptibility to intra-nasal infection with S. pneumoniae in comparison to wild type mice and that this susceptibility was associated with defective IL-1β production. Macrophages from AIM2–/– mice infected with S. pneumoniae showed impaired secretion of IL-1β as well as activation of the inflammasome, as determined by the oligomerisation of apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 activation. Taken together, these results indicate that the AIM2 inflammasome is essential for caspase-1-dependent cytokine IL-1β production and eventual protection from pneumococcal infection in mice.

scholarly journals Effects of Cytochrome P450 Inhibitors on Itraconazole and Fluconazole Induced Cytotoxicity in Hepatocytes

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Nhareet Somchit ◽  
Chong Sock Ngee ◽  
Azhar Yaakob ◽  
Zuraini Ahmad ◽  
Zainul Amiruddin Zakaria
Keyword(s):  
Cytochrome P450 ◽  
Liver Perfusion ◽  
Antifungal Drugs ◽  
Female Rats ◽  
Atp Levels ◽  
P450 Inhibitors ◽  
Hepatocyte Toxicity

Itraconazole and fluconazole have been reported to induce hepatotoxicity in patients. The present study was designed to investigate the role of cytochrome P450 inhibitors, SKF 525A, and curcumin pretreatment on the cytotoxicity of antifungal drugs fluconazole and itraconazole. For 3 consecutive days, female rats were administered daily SKF 525A or curcumin (5 and 25 mg/kg). Control rats received an equivalent amount of dosed vehicle. The animals were anaesthetized 24 hours after receiving the last dose for liver perfusion. Hepatocytes were then exposed to various concentrations of antifungal drugs. In vitro incubation of hepatocytes with itraconazole revealed significantly lower viability when compared to fluconazole as assessed by lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase activities. The cytotoxicity of itraconazole was enhanced when incubated with hepatocytes pretreated with SKF 525A. SKF 525A had no effects on the cytotoxicity of fluconazole. Curcumin failed to either increase or decrease the cytotoxicity of both antifungal drugs. ATP levels also showed significant decrease in both itraconazole and fluconazole incubated hepatocytes. However, SKF 525A pretreated hepatocytes had significantly lower ATP levels after itraconazole incubations. Collectively, these results confirm the involvement of cytochrome P450 in the cytoprotection in itraconazole induced hepatocyte toxicity. Differences of the effects of SKF 525A on the cytotoxicity induced by itraconazole and fluconazole may be due to the differences on the metabolism of each antifungal drug in vivo.

The role of Dectin-1 in the host defence against fungal infections

2011 ◽  
Vol 14 (4) ◽  
pp. 392-399 ◽  
Author(s):  
Rebecca A Drummond ◽  
Gordon D Brown
Keyword(s):  
Fungal Infections ◽  
Host Defence

scholarly journals A non-canonical RNAi pathway controls virulence and genome stability in Mucorales

2020 ◽  
Author(s):  
C. Pérez-Arques ◽  
M.I. Navarro-Mendoza ◽  
L. Murcia ◽  
E. Navarro ◽  
V. Garre ◽  
...  
Keyword(s):  
Genome Stability ◽  
Mucor Circinelloides ◽  
Antifungal Drugs ◽  
Regular Growth ◽  
Rnai Pathway ◽  
Ribonuclease Iii ◽  
Transcriptomic Response ◽  
Stressful Environment ◽  
Macrophage Phagocytosis

AbstractEpimutations in fungal pathogens are emerging as novel phenomena that could explain the fast-developing resistance to antifungal drugs and other stresses. These epimutations are generated by RNA interference (RNAi) mechanisms that transiently silence specific genes to overcome stressful stimuli. The early-diverging fungus Mucor circinelloides exercises a fine control over two interacting RNAi pathways to produce epimutants: the canonical RNAi pathway and a new RNAi degradative pathway. The latter is considered a non-canonical RNAi pathway (NCRIP) because it relies on RNA-dependent RNA polymerases (RdRPs) and a novel ribonuclease III-like named R3B2 to degrade target transcripts. Here in this work, we uncovered the role of NCRIP in regulating virulence processes and transposon movements through key components of the pathway, RdRP1, and R3B2. Mutants in these genes are unable to launch a proper virulence response to macrophage phagocytosis, resulting in a decreased virulence potential. The transcriptomic profile of rdrp1Δ and r3b2Δ mutants revealed a pre-exposure adaptation to the stressful phagosomal environment even when the strains are not confronted by macrophages. These results suggest that NCRIP represses key targets during regular growth and release its control when the fungus is challenged by a stressful environment. NCRIP interacts with the RNAi canonical core to protect genome stability by controlling the expression of centromeric retrotransposable elements. In the absence of NCRIP, these retrotransposons are robustly repressed by the canonical RNAi machinery; thus, supporting the antagonistic role of NCRIP in containing the epimutational pathway. Both interacting RNAi pathways might be essential to govern host-pathogen interactions through transient adaptations, contributing to the unique traits of the emerging infection mucormycosis.Author summaryMucormycosis is an emergent and lethal infectious disease caused by Mucorales, a fungal group resistant to most antifungal drugs. Mucor circinelloides, a genetic model to characterize this infection, can develop drug resistance via RNAi epimutations. This epimutational RNAi mechanism interacts with a novel non-canonical RNAi pathway (NCRIP), where the ribonuclease III-like R3B2 and the RNA-dependent RNA polymerase RdRP1 are essential. The analysis of the transcriptomic response to phagocytosis by macrophage in rdrp1Δ and r3b2Δ mutants revealed that NCRIP might control virulence in M. circinelloides. These mutants showed constitutive activation of the response to phagocytosis and a reduction in virulence in a mouse model, probably caused by a disorganized execution of the genetic program to overcome host defense mechanisms. The antagonistic role of the NCRIP and the RNAi canonical core is evident during post-transcriptional regulation of centromeric retrotransposons. These retrotransposons are silenced by the canonical RNAi pathway, but this regulation is restrained by NCRIP, proven by an overproduction of small RNAs targeting these loci in NCRIP mutants. These new insights into the initial phase of mucormycosis and transposable element regulation point to NCRIP as a crucial genetic regulator of pathogenesis-related molecular processes that could serve as pharmacological targets.

scholarly journals Surgical management of chronic hyperplastic candidiasis refractory to systemic antifungal treatment

2017 ◽  
Vol 9 (02) ◽  
pp. 136-139 ◽  
Author(s):  
Neha Shah ◽  
Jay Gopal Ray ◽  
Sanchita Kundu ◽  
Divesh Sardana
Keyword(s):  
Candida Albicans ◽  
Case Report ◽  
High Risk ◽  
Oral Candidiasis ◽  
Smoking Habit ◽  
Definitive Diagnosis ◽  
Antifungal Drugs ◽  
Antifungal Treatment ◽  
White Patch

AbstractChronic hyperplastic candidiasis (CHC), earlier known as candidal leukoplakia, is a variant of oral candidiasis that classically presents as a white patch on the commissures of the oral mucosa and it is mostly caused by Candida albicans. Clinically, the lesions are usually asymptomatic and regress after appropriate antifungal therapy and correction of the underlying cause. If the lesions are untreated, a small portion may develop dysplasia and later progress into carcinoma. The purpose of this article is to report a case of CHC in a 57-year-old male patient with a significant smoking habit, who presented with a thick, nonscrapable, brownish-white coating on the dorsum of the tongue for 9 years. This case is of particular importance and concern because of the high risk for malignant transformation in CHC. The role of biopsy and histopathology is also stressed through this case report in arriving at a definitive diagnosis and treatment planning. Further, this case is interesting because it was refractory to local and systemic antifungal treatment and so, surgery was chosen as an alternative treatment modality considering the side effects of the prolonged use of antifungal drugs.

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