Molecular Characterization of a Dirofilaria immitis Cysteine Protease Inhibitor (Cystatin) and Its Possible Role in Filarial Immune Evasion

Dong, Xiao; Xu, Jing; Song, Hai-Liang; Liu, Yuchen; Wu, Maodi; Zhang, Haojie; Jing, Bo; Lai, Weimin; Gu, Xiaobin; Xie, Yue; Peng, Xuerong; Yang, Guangyou

doi:10.3390/genes10040300

Cited by 8 publications

(4 citation statements)

References 56 publications

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“…bacteria complicate immunopathogenesis through shifting Th2 pathway to the Th1 [174] . The parasite however was speculated to exert immune evasion via cysteine protease inhibitors (also, cystatins) that modulate host immune reaction by triggering IL-10 production whilst IL-12 and TNF-α are reduced [175] .…”

Section: Dirofilariasismentioning

confidence: 99%

Zoonotic parasites with significant importance for tropical dermatology

AO Elsaftawy,

Samanoudy,

M Wassef

et al. 2023

Parasitologists United Journal

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Zoonotic arthropods Myiasis (myia, Greek word for "fly)The chief zoonotic potential occurs in humans through skin invasion by the developing larvae (maggots) of Diptera. Infested larvae feed on dead or living tissues of the skin [9] . The recorded prevalence of the disease relies only on published case reports. Myiasis is considered a differential diagnosis of skin diseases in tropical poor communities due to bad hygiene and poor housing conditions [10,11] . However, human myiasis may also occur in countries with enhanced hygiene, as reported from New York [12] , and in France [13] . Notably, in temperate countries, myiasis occurs in summer when fly breeding is at its maximum [14] . Predisposing factors involve skin cancers, diabetes, and vascular diseases [10,15] . Nosocomial infection with Sarcophaga larvae was recorded revealing the ability of maggots to reach to

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Section: Dirofilariasismentioning

confidence: 99%

Zoonotic parasites with significant importance for tropical dermatology

AO Elsaftawy,

Samanoudy,

M Wassef

et al. 2023

Parasitologists United Journal

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“…The investigators recorded that DiCYS inhibited canine T-cell proliferation, increased IL-10, and reduced IL-12 and TNF-α expression. It was concluded that DiCYS was an immunoevasion molecule that modulated inflammatory responses, and had an essential role in host-parasite interactions [82] . Interestingly, a recent American review concluded that helminth' CYSs are immunomodulatory molecules.…”

Section: Endogenous Protease Inhibitors (A) Cystatinsmentioning

confidence: 99%

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part II: Parasite targets

Abaza

2022

Parasitologists United Journal

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Growth and replication (DNA synthesis and gene expression) 1. Nucleic acids synthesisNucleotides serve as monomeric units of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). They are formed of a nitrogenous base (nucleoside), five-carbon sugars (ribose or deoxyribose), and a phosphate group (1-3 phosphates). Accordingly, they are termed monophosphate (MP), diphosphate (DP), and triphosphate (TP), respectively. Symthesis of DNA and RNA copies requires supply of two nitrogenous bases (purines and pyrimidines) in similar quantities. As long as both bases are available, synthesis is self-activated, and when there are no more bases, the synthesis is self-inhibited. While purines include adenine (A), and guanine (G), pyrimidines include cytosine (C), thymine (T), and uracil (U). Notably, DNA is formed of two purines (A and G), and two pyrimidines (C and T), while (U) replaces (T) in RNA. Nucleotides have several cellular functions including growth and replication via synthesis of DNA and RNA signaling pathways since they are involved in synthesis of intracellular cyclic second messengers (cAMP, and cGMP). They are energy sources due to involvement of nitrogenous bases in the components of nucleoside TPs (ATP, GTP, TTP, CTP, and UTD). Energy is required for protein and cell membrane syntheses, cell division, and motility. Moreover, adenine contributes in formation of several cofactors required for enzymatic reactions such as coenzyme A, nicotinamide adenine dinucleotide (NAD), NAD phosphate (NADP), flavine adenine dinucleotide (FAD) and flavine mononucleotide (FMN). Lastly, uracil diphosphate (UDP) is utilized in glucogenesis; a ubiquitous metabolic pathway required for production of glucose from non-carbohydrate carbon substrates [2] .Synthesis of purine and pyrimidine nucleotides is either de novo or through a salvage pathway. In such a pathway, nucleoside transporters (NTs), known also as permeases, carry salvaged bases and nucleosides across parasite plasma membrane to synthesize nucleotides. Therefore, nucleoside transporters and enzymes involved in purine or pyrimidine synthesis, either de novo or via salvage pathways contributing to nucleic acid processing, are potential drug targets.Transporters: There are four balanced NTs (ENTs). While ENT1 and ENT2 are the major

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“…Together with other immune cells (15)(16)(17)(18)(19)(20)(21), dendritic cells (DCs) are critical cell targets of parasite cystatins, and several studies have confirmed that they inhibit cathepsins L and S, DC differentiation, cytokine secretion, and alter inflammatory DC signaling (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Cystatin from the helminth Ascaris lumbricoides upregulates mevalonate and cholesterol biosynthesis pathways and immunomodulatory genes in human monocyte-derived dendritic cells

Acevedo,

Lozano,

Zakzuk

et al. 2024

Front. Immunol.

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BackgroundAscaris lumbricoides cystatin (Al-CPI) prevents the development of allergic airway inflammation and dextran-induced colitis in mice models. It has been suggested that helminth-derived cystatins inhibit cathepsins in dendritic cells (DC), but their immunomodulatory mechanisms are unclear. We aimed to analyze the transcriptional profile of human monocyte-derived DC (moDC) upon stimulation with Al-CPI to elucidate target genes and pathways of parasite immunomodulation.MethodsmoDC were generated from peripheral blood monocytes from six healthy human donors of Denmark, stimulated with 1 µM of Al-CPI, and cultured for 5 hours at 37°C. RNA was sequenced using TrueSeq RNA libraries and the NextSeq 550 v2.5 (75 cycles) sequencing kit (Illumina, Inc). After QC, reads were aligned to the human GRCh38 genome using Spliced Transcripts Alignment to a Reference (STAR) software. Differential expression was calculated by DESEq2 and expressed in fold changes (FC). Cell surface markers and cytokine production by moDC were evaluated by flow cytometry.ResultsCompared to unstimulated cells, Al-CPI stimulated moDC showed differential expression of 444 transcripts (|FC| ≥1.3). The top significant differences were in Kruppel-like factor 10 (KLF10, FC 3.3, PBH = 3 x 10-136), palladin (FC 2, PBH = 3 x 10-41), and the low-density lipoprotein receptor (LDLR, FC 2.6, PBH = 5 x 10-41). Upregulated genes were enriched in regulation of cholesterol biosynthesis by sterol regulatory element-binding proteins (SREBP) signaling pathways and immune pathways. Several genes in the cholesterol biosynthetic pathway showed significantly increased expression upon Al-CPI stimulation, even in the presence of lipopolysaccharide (LPS). Regarding the pathway of negative regulation of immune response, we found a significant decrease in the cell surface expression of CD86, HLA-DR, and PD-L1 upon stimulation with 1 µM Al-CPI.ConclusionAl-CPI modifies the transcriptome of moDC, increasing several transcripts encoding enzymes involved in cholesterol biosynthesis and SREBP signaling. Moreover, Al-CPI target several transcripts in the TNF-alpha signaling pathway influencing cytokine release by moDC. In addition, mRNA levels of genes encoding KLF10 and other members of the TGF beta and the IL-10 families were also modified by Al-CPI stimulation. The regulation of the mevalonate pathway and cholesterol biosynthesis suggests new mechanisms involved in DC responses to helminth immunomodulatory molecules.

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Molecular Characterization of a Dirofilaria immitis Cysteine Protease Inhibitor (Cystatin) and Its Possible Role in Filarial Immune Evasion

Cited by 8 publications

References 56 publications

Zoonotic parasites with significant importance for tropical dermatology

Zoonotic parasites with significant importance for tropical dermatology

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part II: Parasite targets

Cystatin from the helminth Ascaris lumbricoides upregulates mevalonate and cholesterol biosynthesis pathways and immunomodulatory genes in human monocyte-derived dendritic cells

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