Eosinophils and Macrophages within the Th2-Induced Granuloma: Balancing Killing and Healing in a Tight Space

Ariyaratne, Anupama; Finney, Constance A. M.

doi:10.1128/iai.00127-19

Cited by 43 publications

(64 citation statements)

References 186 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The circumoval granulomas represent an accumulation of host immune cells including macrophages, eosinophils and neutrophils, around schistosome eggs [67]. The host immune cells act to protect the surrounding host tissue from toxins produced by the egg, resulting in a physical barrier and the sequestering of these secreted egg products [68]; yet these cells are ineffective at clearing infection [69]. To date, the underlying mechanisms of granuloma formation remain poorly understood, and our current knowledge is based on in vitro studies using cells that have not been obtained from granulomas, thereby hindering an improved understanding of the dual functions of immune killing and healing of granulomas generated by schistosome eggs [69].…”

Section: Discussionmentioning

confidence: 99%

“…The host immune cells act to protect the surrounding host tissue from toxins produced by the egg, resulting in a physical barrier and the sequestering of these secreted egg products [68]; yet these cells are ineffective at clearing infection [69]. To date, the underlying mechanisms of granuloma formation remain poorly understood, and our current knowledge is based on in vitro studies using cells that have not been obtained from granulomas, thereby hindering an improved understanding of the dual functions of immune killing and healing of granulomas generated by schistosome eggs [69]. Granuloma formation is driven by chemokines released by T lymphocytes and resident liver cells, including HSC, which attract migrating immune cells to the site of egg deposition [70].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CRISPR/Cas9-mediated genome editing ofSchistosoma mansoniacetylcholinesterase

You

Mayer

Johnston

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractCRISPR/Cas9-mediated genome editing shows cogent potential for the genetic modification of helminth parasites. Here we report successful gene knock-in (KI) into the genome of the egg of Schistosoma mansoni by combining CRISPR/Cas9 with single-stranded oligodeoxynucleotides (ssODNs). We edited the acetylcholinesterase (AChE) gene of S. mansoni targeting two guide RNAs (gRNAs), X5 and X7, located on exon 5 and exon 7 of Smp_154600, respectively. A CRISPR/Cas9-vector encoding gRNA X5 or X7 was introduced by electroporation into eggs recovered from livers of experimentally infected mice. Simultaneously, eggs were transfected with a ssODN donor encoding a stop codon in all six frames, flanked by 50 nt-long 5’- and 3’-homology arms matching the predicted Cas9-catalyzed double stranded break at X5 or X7. Next generation sequencing analysis of reads of amplicon libraries spanning targeted regions revealed that the major modifications induced by CRISPR/Cas9 in the eggs were generated by homology directed repair (HDR). Furthermore, soluble egg antigen from AChE-edited eggs exhibited markedly reduced AChE activity, indicative that programmed Cas9 cleavage mutated the AChE gene. Following injection of AChE-edited schistosome eggs into the tail veins of mice, a significant decrease in circumoval granuloma size was observed in the lungs of the mice. Notably, there was an enhanced Th2 response involving IL-4, −5, −10, and-13 induced by lung cells and splenocytes in mice injected with X5-KI eggs in comparison to control mice injected with unmutated eggs. A Th2-predominant response, with increased levels of IL-4, −13 and GATA3, also was induced by X5 KI eggs in small intestine-draining mesenteric lymph node cells when the gene-edited eggs were introduced into the subserosa of the ileum of the mice. These findings confirmed the potential and the utility of CRISPR/Cas9-mediated genome editing for functional genomics in schistosomes.Author SummarySchistosomiasis is the most devastating of the parasitic helminth diseases. Currently, no vaccines are available for human use and praziquantel is the only available treatment raising considerable concern that drug resistance will develop. A major challenge faced by the schistosomiasis research community is the lack of suitable tools to effectively characterise schistosome gene products as potential new drug and/or vaccine targets. We introduced CRISPR/Cas9 mediated editing into S. mansoni eggs targeting the gene encoding acetylcholinesterase (AChE), a recognized anthelminthic drug target. We found that the major modifications induced by CRISPR/Cas9 in the eggs were generated by homology directed repair (HDR). This platform provides a unique opportunity to generate precise loss-of-function insertions into the schistosome genome. We pre-screened the activity of two guide RNAs of the AChE gene and compared/validated the mutation efficacy using next-generation sequencing analysis at the genomic level and phenotypic modifications at the protein level. That resulted in reduced AChE activity observed in AChE-edited eggs, and decreased lung circumoval granuloma size in mice injected with those edited eggs. The CRISPR/Cas9-genome editing system we established in this study provides a pivotal platform for gene functional studies to identify and test new anti-schistosome intervention targets, which can be extended to the other human schistosome species and other important parasitic helminths.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated genome editing ofSchistosoma mansoniacetylcholinesterase

You

Mayer

Johnston

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Traditionally eosinophils are cited as an important anti-helminth effector mechanism [60][61][62] but more recent studies suggest the situation is not so simple; while infection with T. canis is associated with an eosinophilic response, these cells may have a limited capacity to kill the helminth and the larvae can efficiently escape eosinophils in vitro [63][64][65]. In a recent and interesting review, it has been proposed a combined role for macrophages and eosinophils as key players in the mechanisms of granuloma formation during helminth infections and in the balance between parasite killing and healing [66]. Collectively, a scenario is forming in which inflammatory and anti-inflammatory immune responses are important in mediating tissue and helminth destruction.…”

Section: Discussionmentioning

confidence: 99%

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

et al. 2019

View full text Add to dashboard Cite

Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1−/− and STAT6−/−) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1−/− mice; in contrast, STAT6−/− mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing.

show abstract

“…The combination of granulomatous changes, stellate necrosis with neutrophils and few giant cells is characteristic of cat scratch disease, although similar changes may occur in atypical mycobacteriosis, and tularemia [7]. Granulomas due to schistosome infection involve T H 2 lymphocytes, and therefore the presence of eosinophils is very striking [13]. The typical microscopic lesion of sarcoidosis is a small granuloma mainly composed of epithelioid cells, with scattered lymphocytes and Langhans' giant cells.…”

Section: Characteristic (N=207)mentioning

confidence: 99%

The importance of non-necrotising granulomatosis

Alende-Castro¹,

Sopeña²,

Cameselle-Teijeiro³

et al. 2019

J Histol Histopathol

View full text Add to dashboard Cite

Objective: The diagnosis of non-necrotising granulomatosis (NNG) is very frequent in clinical practice. There are few studies, however, within the spectrum of pathologies that cause NNG; consequently, except for sarcoidosis, little information is available. The objective is to determine the prevalence of sarcoidosis, autoimmune diseases and other entities in NNG. Methods: We collected all pathological reports with a diagnosis of non-necrotising granulomatosis from 1 January 2010 to 31 December 2014 in the Clinical University Hospital of Santiago de Compostela, Spain. Results: A total of 290 tissue samples from 207 patients were reviewed. Of these patients, 50.7% were women, with a mean age of 51.2 years. The origins of the samples were: skin 32.9%, lymph nodes 26.6%, transbronchial biopsy 14.5%, lung 5.8% and others 20.2%. Final diagnoses were: sarcoidosis 59.9%; infectious diseases 7.7%, including tuberculosis 4.0% and non-tuberculous mycobacterial infection 1.4%; foreign body granulomatosis 6.3%; neoplasms 5.9%; autoimmune disease 3.1% and others 4.0%. A diagnosis was not determined in 5.9% patients. Conclusion: The prevalence of sarcoidosis in NNG is over 50%, while autoimmune disease prevalence is considerably lower (3.1%), with Wegener granulomatosis being the most commonly reported. The most frequent alternative diagnosis was infectious disease, mainly tuberculosis.

show abstract

Eosinophils and Macrophages within the Th2-Induced Granuloma: Balancing Killing and Healing in a Tight Space

Cited by 43 publications

References 186 publications

CRISPR/Cas9-mediated genome editing ofSchistosoma mansoniacetylcholinesterase

CRISPR/Cas9-mediated genome editing ofSchistosoma mansoniacetylcholinesterase

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

The importance of non-necrotising granulomatosis

Contact Info

Product

Resources

About