Interleukin-22 Mediates Early Host Defense against Rhizomucor pusilluscan Pathogens

Bao, Wei; Jin, Lei; Fu, Haijing; Shen, Ya; Lu, Guixia; Mei, Huan; Cao, Xia; Wang, Hongsheng; Liu, Weida

doi:10.1371/journal.pone.0065065

Cited by 13 publications

(13 citation statements)

References 30 publications

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“…irregularis infection, especially the Th-1 and Th-17 pathway, consistent with our previous study that IL-17 and IFN-γ mRNA expression was significantly increased over time in M . irregularis infected skin lesion 43 ; second, the mating type may have a potential correlation with the severity of inflammation; third, although the mating type gene is not a direct virulence factor, but link to virulent progression through unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The influence of the mating type on virulence of Mucor irregularis

Liang

Peng

et al. 2017

Sci Rep

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Mucor irregularis is an emerging fungal pathogen that cause cutaneous infection and could cause death. However, little is known about its mechanism of pathogenesis. There is evidence suggesting virulence vary with mating types in fungi, including the Mucorales. Here, we characterized the mating type locus of M. irregularis and the mating type ratio of 17 clinical isolates in China. Genomic data indicated M. irregularis is heterothallic having two mating types – bearing either SexP or SexM allele. Also, we employed a mice model to study the inflammation and pathological effects of different mating types. The comparison of the inflammatory response, cytokine profiles and Th-1, Th-2 and Th-17 cells numbers in each mating type treated mice showed that the severity and disease progress were enhanced in (+) mating type treated mice. One (+/0) mutant strain, with multiple mutations at the mating locus, had defects in sexual mating ability but appeared to be more virulent than the (−) mating type. Although (+) mating type appeared to be more virulent, most of our clinical isolates presented belonged to (−) mating type. Our findings support the involvement of MAT genes in sexual fertility, and the influence of mating type on the severity of cutaneous infection.

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Section: Discussionmentioning

confidence: 99%

The influence of the mating type on virulence of Mucor irregularis

Liang

Peng

et al. 2017

Sci Rep

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“…30 This leads to activation and homodimerization of signal transducer and activator of transcription 3, which translocates to the nucleus and activates the expression of response genes. [30][31][32] Although the main function of IL-22 is induction of anti-microbial defense proteins, 26,[32][33][34][35][36] it is also involved in wound regeneration and development, and has a role in tumorigenesis 25,26,[37][38][39][40][41][42][43] and antiviral defenses. [44][45][46] Finally, IL-22 is an important factor in the etiology of some autoimmune diseases, such as psoriasis and Crohn's disease.…”

Section: Introductionmentioning

confidence: 99%

The crystal structure of zebrafish IL-22 reveals an evolutionary, conserved structure highly similar to that of human IL-22

Siupka

Frétaud

et al. 2014

Genes Immun

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The class II cytokine family consists of small α-helical signaling proteins including the interleukin-10 (IL-10)/IL-22 family, as well as interferons (IFNs). They regulate the innate immune response and in addition have an important role in protecting epithelial tissues. Teleost fish possess a class II cytokine system surprisingly similar to that of humans, and thus zebrafish offers an attractive model organism for investigating the role of class II cytokines in inflammation. However, the evolution of class II cytokines is critical to understand if we are to take full advantage of zebrafish as a model system. The small size and fast evolution of these cytokines obscure phylogenetic analyses based purely on sequences, but one can overcome this obstacle by using information contained within the structure of those molecules. Here we present the crystal structure of IL-22 from zebrafish (zIL-22) solved at 2.1 Å, which displays a typical class II cytokine architecture. We generated a structure-guided alignment of vertebrate class II cytokines and used it for phylogenetic analysis. Our analysis suggests that IL-22 and IL-26 arose early during the evolution of the IL-10-like cytokines. Thus, we propose an evolutionary scenario of class II cytokines in vertebrates, based on genomic and structural data.

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“…This approach was validated by our identification of two pathways that were already linked to infection by Mucorales: interleukin-22 (IL-22) and IL-17A ( Fig. 1A ) ( 17 ). Our analysis also predicted the activation of signaling pathways that have not been tied to mucormycosis but have been associated with the host response to fungal infection, including colony-stimulating factor 2 (CSF2), extracellular signal-regulated kinases (ERKs), myeloid differentiation primary response 88 (MYD88), and JNK (Jun N-terminal kinase) ( 18 – 24 ) ( Fig.…”

Section: Resultsmentioning

confidence: 92%

Inhibition of EGFR Signaling Protects from Mucormycosis

Watkins

Gebremariam

Swidergall

et al. 2018

mBio

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Mucormycosis is a life-threatening, invasive fungal infection that is caused by various species belonging to the order Mucorales. Rhizopus species are the most common cause of the disease, responsible for approximately 70% of all cases of mucormycosis. During pulmonary mucormycosis, inhaled Rhizopus spores must adhere to and invade airway epithelial cells in order to establish infection. The molecular mechanisms that govern this interaction are poorly understood. We performed an unbiased survey of the host transcriptional response during early stages of Rhizopus arrhizus var. delemar (R. delemar) infection in a murine model of pulmonary mucormycosis using transcriptome sequencing (RNA-seq). Network analysis revealed activation of the host’s epidermal growth factor receptor (EGFR) signaling. Consistent with the RNA-seq results, EGFR became phosphorylated upon in vitro infection of human alveolar epithelial cells with several members of the Mucorales, and this phosphorylated, activated form of EGFR colocalized with R. delemar spores. Inhibition of EGFR signaling with cetuximab or gefitinib, specific FDA-approved inhibitors of EGFR, significantly reduced the ability of R. delemar to invade and damage airway epithelial cells. Furthermore, gefitinib treatment significantly prolonged survival of mice with pulmonary mucormycosis, reduced tissue fungal burden, and attenuated the activation of EGFR in response to pulmonary mucormycosis. These results indicate EGFR represents a novel host target to block invasion of alveolar epithelial cells by R. delemar, and inhibition of EGFR signaling provides a novel approach for treating mucormycosis by repurposing an FDA-approved drug.

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Interleukin-22 Mediates Early Host Defense against Rhizomucor pusilluscan Pathogens

Cited by 13 publications

References 30 publications

The influence of the mating type on virulence of Mucor irregularis

The influence of the mating type on virulence of Mucor irregularis

The crystal structure of zebrafish IL-22 reveals an evolutionary, conserved structure highly similar to that of human IL-22

Inhibition of EGFR Signaling Protects from Mucormycosis

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