Liver Granulomas Research Articles

Impact of nanostructured formulations for schistosomiasis treatment: a systematic review of in vivo preclinical evidence.

Schistosomiasis is a neglected tropical disease caused by Schistosoma sp., and praziquantel (PZQ) is the first-line treatment. However, traditional PZQ formulations have low solubility and fast metabolism, limiting its effectiveness. Thus, nanoparticles have been proposed to improve the bioavailability and efficacy of poorly soluble antischistosomal drugs. This systematic review used in vivo preclinical studies to map the available evidence and compare the efficacy of free PZQ and PZQ-based nanostructured formulations (N-PZQ) for schistosomiasis treatment. PubMed, Embase, Scopus, and Web of Science were searched, and 1186 experimental studies published between 1974 and 2024 were screened. Parasitological, histopathological, pharmacokinetic, and toxicological outcomes were evaluated. Twelve relevant studies were identified exploring N-PZQ formulations based on liposomes, nanoliposomes, and nanocrystals. N-PZQ demonstrated better therapeutic efficacy than free PZQ, reducing parasite load, modifying oogram profiles, and down-regulating liver granuloma development (number and size). N-PZQ also exhibited improved pharmacokinetic profile, with enhanced bioavailability and longer half-life, as well as reduced toxicity (cytotoxicity, genotoxicity, and hepatotoxicity) compared to free PZQ. PZQ-based nanostructured formulations represent a promising strategy to enhance schistosomiasis treatment by improving chemotherapy efficacy, optimizing antiparasitic responses, pharmacokinetics, and reducing drug toxicity.

Downregulation of proinflammatory cytokines and dynamic expression of TGF-β1 molecules induced by anti-IL-17 mAb in murine schistosomiasis mansoni

Hepato-intestinal schistosomiasis is characterized by severe pathological changes at advanced chronic stages, including granulomatous lesions and liver fibrosis. The objective of our research was to assess the dynamic expression of profibrotic molecules, the transforming growth factor beta 1 (TGF-β1), and proinflammatory cytokines immunomodulation induced by interleukin 17 (IL-17) neutralization in murine Schistosomiasis mansoni. The study included 56 specific pathogen-free male C57BL/6 mice, divided into 3 main groups: GI uninfected normal controls, GII S. mansoni infected with 70±5 cercariae/non-treated, GIII S. mansoni infected and treated with anti-IL-17 monoclonal antibody (mAb), GIV S. mansoni infected and isotype-matched IgG2a mAb was given as a challenge. Mice were sacrificed at 6, 8, and 10 weeks after infection, then their liver enzymes and cytokines assessed, histopathological and immunohistochemical tested. The present study demonstrated a statistically significant elevation in serum levels of IL-17 (p<0.01), TGF-β1 (p<0.01), IL-1β (p≤0.001), IL-4 (p≤0.003), IL-6 (p≤0.05), and liver enzymes (ALT: p≤0.001; AST: p≤0.002). Additionally, granulomatous lesions and TGF-β1 expression were significantly increased (p<0.001) in infected mice at 6, 8, and 10 weeks after infection. All showed significant reduction by neutralization with anti-IL-17 mAb. Finally, IL-17 exhibited potent profibrogenic activity, and anti-IL-17 mAb can be used to alleviate and counteract this impact in murine S. mansoni.

ICOSL deficiency promotes M1 polarization to alleviate liver fibrosis in Schistosomiasis Mice

The expression of inducible co-stimulator ligand (ICOSL) on macrophage (Mφ) implies their ability to interact with inducible co-stimulator (ICOS)-expressing T cells, thereby modulating immune responses within the liver microenvironment. This study aimed to elucidate the mechanism underlying ICOS/ICOSL signaling in the regulation of Mφ polarization during Schistosomiasis-induced liver fibrosis. To investigate this, ICOSL-knock out (KO) and wildtype (WT) C57BL/6 mice were infected with Schistosoma japonicum (S. japonicum) to examine the dynamic changes in Mφ phenotype and observe the pathology alterations in the liver. There was significantly decreased expression of ICOSL both in monocytes of cirrhosis patients and the liver tissue of mice infected with S. japonicum. Furthermore, ICOSL-KO mice exhibited reduced liver granuloma formation and fibrosis during S. japonicum infection. Simultaneously, Mφ in ICOSL-KO mice polarized towards M1-type and induced apoptosis of hepatic stellate cells (HSCs). Overall, the blockade of ICOSL signaling could promote M1 polarization, induce HSCs apoptosis, and ameliorate hepatic fibrosis, suggesting that ICOSL may serve as a potential biomarker for prognosis and therapeutic target for schistosomiasis-induced hepatic fibrosis.

Severe murine schistosomiasis results from disrupted CD4+ T-cell modulation by immunodominance of a single egg epitope.

This study examined the correlation between immunodominance of the major egg antigen Sm-p40234-246, a robust Th1/Th17 anti-egg CD4 T-cell response, and severe liver immunopathology in experimental murine schistosomiasis. It serves as a platform to analyze how varying degrees of immunodominance affect CD4+ T cell modulation and disease outcomes. We used a murine model of schistosomiasis to investigate the effects of immunodominance. Infected mice were divided into two groups: one treated with a combination of epitopes targeting immunodominance of the major egg antigen Sm-p40 and the other with a mock mixture of non-immunogenic epitopes. Liver granuloma area, a hallmark of schistosomiasis pathology, was quantified using histological and morphometric analyses. The average granuloma areas between the treated and untreated groups were compared using one-way ANOVA with Tukey's multiple comparison test. Additionally, we isolated CD4+ T cells from mesenteric lymph nodes, stimulated them with specific egg antigens, and collected purified supernatants to assess their signature cytokine secretion profiles for each treatment group. Results showed that strong immunodominance of a single egg epitope undermines effective CD4+ T-cell modulation, promoting a strongly polarized Th1/Th17 pathogenic response. Conversely, neutralizing this immunodominance produces the opposite restorative effect. Immunodominance is an important pathogenic component that influences CD4+ T cell modulation in experimental murine schistosomiasis. Moreover, immunodominance can be used to treat these and other important CD4+ T cell-mediated diseases.

In vivo antischistosomal activity profiling and efficacy of niosomal Spirulina platensis and praziquantel combined remedy against murine Schistosoma mansoni infection

Schistosomiasis is a serious parasite disease with a high rate of mortality and negative financial impacts in subtropical and tropical locations like Egypt. The goal of this study was to investigate the anti-schistosomal effect of Spirulina platensis (SP) and Spirulina loaded niosomes (SPN), either in the presence or absence of praziquantel (PZQ) against S. mansoni in experimentally infected mice. Six groups have been involved in the study, five groups were infected with S. mansoni cercariae and subjected independently to different treatments of SP, SPN, and PZQ or the preceding two combinations, in addition to one untreated group which acts as a control. At the 8th week, mice were euthanized, and besides a histopathological assessment of the liver granuloma, the number of worms, tissue egg load, and oogram pattern were estimated. To evaluate the condition of the liver oxidative stress, the levels of malondialdehyde and reduced glutathione in liver homogenates were investigated. Additionally, to assess the anti-inflammatory properties, serum cytokines (IFN-γ, TNF-α, IL-13, and IL-10) and CD4+ immunohistochemistry expression were determined. The results demonstrated that each of the investigated parameters was significantly changed by both SPN and/or SPN with PZQ treatments alongside PZQ. The highest therapeutic effect was obtained in SPN combined with a half dose of PZQ which achieved 100 % reduction in both the total worm burden and the highest reduction in the intestinal (93.22 %) and hepatic (94.4 %) egg content, as well, moreover 40.5 % reduction of the granuloma size. Furthermore, serum cytokine levels {(TNF-α (11 ± 0.5 (P ˂ 0.001)), (IFN-γ (19.7 ± 1.2 (P ˂ 0.001)) and (IL-13 (53.65 ± 1.4 (P ˂ 0.001))}, as well as CD4+ cells (6.5 ± 0.65 (P ˂ 0.001)) were reduced. While, IL-10 (61.1 ± 2.1 (P ˂ 0.001)) was increased due to the same treatment additional to its antioxidant properties by reduced lipid peroxidation (LPO) (1.1975 ± 0.05(P ˂ 0.001)) but increased reduced glutathione (GSH) (2.31± 0.15 (P˂0.001)). In conclusion, SPN has a schistosomicidal, antioxidant, and hepatoprotective role. SPN has a strong synergistic effect when combined with PZQ which showed anti-inflammatory action. Hence, SPN + PZQ offers promising alternatives for future schistosomiasis therapeutic research.

Low potential of fish as a source of infection with Angiostrongylus cantonensis

Abstract Objectives Fish are hypothesized to act as paratenic hosts for the zoonotic nematode Angiostrongylus cantonensis, cause of human eosinophilic meningitis. There is a lack of data confirming the relevance of fish in A. cantonensis life cycle and their contribution to human infection. Materials and methods We conducted a series of experiments to investigate survival and infectivity of A. cantonensis larvae in Clarias gariepinus (catfish; n=30) and Oreochromis niloticus (tilapia; n=24). Each fish was inoculated with 10,000 third-stage larvae (L3). Larval survival was assessed through artificial digestion of fish tissues one, two, and three weeks post-infection. To investigate early stages of infection, four catfish were inoculated with 10,000 L3 each and sacrificed 3 days post-infection. qPCR and histopathological examinations were performed to evaluate larval distribution and tissue reactions. Two infected catfish, sacrificed one week post-infection, were used to feed Wistar rats. Results After 45 days, the rats were not shedding L1, indicating the absence of infection. One week post-infection, dead larvae were present in digested tissues of both fish species, and the same was observed two and three weeks after exposure. qPCR analysis revealed that intestine was the most heavily infected organ. Histopathology identified dead larvae within granulomas in intestines and liver. Early-stage infection experiment showed that fish sacrificed three days post-inoculation contained viable L3 which were infective to Wistar rats. Conclusions While A. cantonensis L3 can survive and remain infective in fish for a short period, they typically die within first few days post-infection. This suggests that fish may not be significant long-term paratenic hosts for A. cantonensis but may play a temporary role in its transmission to mammals (including humans) and birds. These results are consistent with previous studies on freshwater shrimps and highlight the importance of understanding aquatic host interactions in the epidemiology of this zoonotic food-borne pathogen.

NLRP3 inflammasome inhibition decreases Schistosomiasis japonica-induced granulomatous inflammation and fibrosis in BALB/c mice.

To research the role of the NLRP3 inflammasome in Schistosoma japonicum-induced granuloma formation and liver fibrosis. In in vivo tests, BALB/c mice were used. shNLRP3 plasmid based on adeno-associated virus serotype 8 (AAV8-shNLRP3) was injected to block NLRP3 inflammasome via tail vein. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected to assess liver injury. H&E staining was used for routine histopathological assessment; Masson's trichrome staining was used to detect fibrous tissues and collagen fibers. Hepatic expression of NLRP3, procaspase-1, bioactive caspase-1, collagen-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and α-smooth muscle actin (α-SMA) were detected by western blot. Serum levels of IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). The inflammatory cell infiltration and hepatic expression of IL-1β around the granuloma were detected by immunohistochemistry staining. Treatment of S. japonicum infected mice with AAV8-shNLRP3 significantly reduced the hepatic levels of bioactive caspase-1 and IL-1β, as well as circulating IL-1β concentrations, while reducing the amounts of myeloperoxidase (MPO) and F4/80 positive cells around the granuloma. Moreover, collagen deposition, TIMP-1, and α-SMA, which are markers of hepatic stellate cell (HSC) activation, were reduced around the liver granuloma. These findings highlight a therapeutic potential of AAV8-shNLRP3 in schistosomiasis cirrhosis.

Artemisitene shows superiority over artemisinin in preventing Schistosoma japonica-induced liver disease

BackgroundArtemisinin (ART) analogs, such as dihydroartemisinin, arteether, artemether, and artesunate, all featuring an endoperoxide bridge, have demonstrated efficacy against schistosomiasis. Artemisitene (ATT), which contains an additional α, β-unsaturated carbonyl structure, has shown enhanced biological activities. This study aims to evaluate the anti-schistosomaiasis japonica activity of ATT and compare it with ART.MethodsWe assessed liver inflammation and fibrosis in mice using hematoxylin and eosin staining and Sirius red staining, respectively. RNA sequencing analyzed transcriptomics in female and male Schistosoma japonicum (S. japonicum) adult worms and mice livers, with cytokine profiling and flow cytometry to study immune responses under ART or ATT treatment.ResultsATT exhibits a marked reduction in female S. japonicum adult worms and egg numbers, damaging the adult worms’ surface. It also influences the transcription of genes related to cellular anatomical structures. Notably, ATT treatment resulted in significant reductions in liver granuloma size and collagen area, alongside lowering serum levels of glutamic pyruvic and glutamic oxaloacetic transaminase more effectively than ART. Both ART and ATT markedly decreased neutrophil frequency in the liver and elevated eosinophil counts. However, only ATT treatment significantly reduced the M1/M2 and Th1/Th2 indices, indicating a pronounced shift in immune response profiles. ATT-affected host immunity correlated with the extent of liver fibrosis and the count of single males more strongly than ART.ConclusionATT, as a novel preventive strategy for schistosomiasis japonica in mice, significantly outperforms ART.Graphical

Emerging immunological challenges in post-COVID individuals: insights from a case series and review

The Coronavirus Disease 2019 (COVID-19) pandemic has unveiled diverse immunological complications extending beyond the acute phase of infection. We present a case series of four patients who developed autoimmune vasculitis and sarcoidosis post-recovery from COVID-19. Case presentations include recurrent fever and respiratory symptoms in a 36-year-old female, granulomatous liver lesions in a 63-year-old male, progressive dyspnea in a 44-year-old female, and diffuse alveolar hemorrhage in a 74-year-old female following severe pneumonia. These cases underscore the importance of vigilance for immunological sequelae in post-COVID-19 patients, particularly those with predisposing comorbidities. We tried to elucidate pathophysiological mechanisms and optimize management strategies for these rare but clinically significant manifestations.

Autophagy in hepatic progenitor cells modulates exosomal miRNAs to inhibit liver fibrosis in schistosomiasis.

Schistosoma infection is one of the major causes of liver fibrosis. Emerging roles of hepatic progenitor cells (HPCs) in the pathogenesis of liver fibrosis have been identified. Nevertheless, the precise mechanism underlying the role of HPCs in liver fibrosis in schistosomiasis remains unclear. This study examined how autophagy in HPCs affects schistosomiasis-induced liver fibrosis by modulating exosomal miRNAs. The activation of HPCs was verified by immunohistochemistry (IHC) and immunofluorescence (IF) staining in fibrotic liver from patients and mice with Schistosoma japonicum infection. By coculturing HPCs with hepatic stellate cells (HSCs) and assessing the autophagy level in HPCs by proteomic analysis and in vitro phenotypic assays, we found that impaired autophagy degradation in these activated HPCs was mediated by lysosomal dysfunction. Blocking autophagy by the autophagy inhibitor chloroquine (CQ) significantly diminished liver fibrosis and granuloma formation in S. japonicum-infected mice. HPC-secreted extracellular vehicles (EVs) were further isolated and studied by miRNA sequencing. miR-1306-3p, miR-493-3p, and miR-34a-5p were identified, and their distribution into EVs was inhibited due to impaired autophagy in HPCs, which contributed to suppressing HSC activation. In conclusion, we showed that the altered autophagy process upon HPC activation may prevent liver fibrosis by modulating exosomal miRNA release and inhibiting HSC activation in schistosomiasis. Targeting the autophagy degradation process may be a therapeutic strategy for liver fibrosis during Schistosoma infection.

Therapeutic efficacy of candidate antischistosomal drugs in a murine model of schistosomiasis mansoni.

Schistosomiasis is a neglected tropical disease associated with considerable morbidity. Praziquantel (PZQ) is effective against adult schistosomes, yet, it has little effect on juvenile stages, and PZQ resistance is emerging. Adopting the drug repurposing strategy as well as assuming enhancing the efficacy and lessening the doses and side effects, the present study aimed to investigate the in vivo therapeutic efficacy of the widely used antiarrhythmic, amiodarone, and diuretic, spironolactone, and combinations of them compared to PZQ. Mice were infected by Schistosoma mansoni "S. mansoni" cercariae (Egyptian strain), then they were divided into two major groups: Early- [3weeks post-infection (wpi)] and late- [6 wpi] treated. Each group was subdivided into seven subgroups: positive control, PZQ, amiodarone, spironolactone, PZQ combined with amiodarone, PZQ combined with spironolactone, and amiodarone combined with spironolactone-treated groups. Among the early-treated groups, spironolactone had the best therapeutic impact indicated by a 69.4% reduction of total worm burden (TWB), 38.6% and 48.4% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 49%. Whereas, among the late-treated groups, amiodarone combined with PZQ was superior to PZQ alone evidenced by 96.1% reduction of TWB with the total disappearance of female and copula in the liver and intestine, 53.1% and 84.9% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 67.6%. Comparatively, spironolactone was superior to PZQ and amiodarone in the early treatment phase targeting immature stages, while amiodarone had a more potent effect when combined with PZQ in the late treatment phase targeting mature schistosomes.

Sanguinarine: an alkaloid with promising in vitro and in vivo antiparasitic activity against different developmental stages of Schistosoma mansoni and in silico pharmacokinetic properties (ADMET).

The objective of the study was to evaluate the in vitro and in vivo schistosomicidal activity of sanguinarine (SA) on Schistosoma mansoni and its in silico pharmacokinetic parameters. ADMET parameters and oral bioavailability were evaluated using the PkCSM and SwissADME platforms, respectively. The activity of SA in vitro, at the concentrations of 1.0-25µM, was analyzed through the parameters of motility, mortality, and cell viability of the worms at intervals of 3-24h. Mice were infected with cercariae and treated by gavage with SA (5mg/kg/day, in a single dose or two doses of 2.5mg/kg every 12h for 5 consecutive days) on the 1st (skin schistosomula), 14th (pulmonary schistosomula), 28th (young worms), and 45th (adult worms) days after infection. In vitro and in vivo praziquantel was the control. In vitro, SA showed schistosomicidal activity against schistosomula, young worms, and couples; with total mortality and reduced cell viability at low concentrations and incubation time. In a single dose of 5mg/kg/day, SA reduces the total worm load by 47.6%, 54%, 55.2%, and 27.1%, and female worms at 52.0%, 39.1%, 52.7%, and 20.2%, respectively, results which are similar to the 2.5mg/kg/day dose. SA reduced the load of eggs in the liver, and in histopathological and histomorphometric analyses, there was a reduction in the number and volume of hepatic granulomas, which exhibited less inflammatory infiltrate. SA has promising in vitro and in vivo schistosomicidal activity against different developmental stages of S. mansoni, in addition to reducing granulomatous liver lesions. Furthermore, in silico, SA showed good predictive pharmacokinetic ADMET profiles.

Auranofin attenuates Schistosoma mansoni egg-induced liver granuloma and fibrosis in mice.

Schistosomiasis is a serious tropical disease. Despite extensive research into the etiology of liver fibrosis, effective therapeutic options remain limited. This study aims to assess the effectiveness of auranofin in treating hepatic granuloma and fibrogenesis produced by Schistosoma (S.) mansoni eggs. Auranofin is a gold complex that contains thioglucose tetraacetate and triethylphosphine. Eighty BALB/c male mice were divided into four groups (n=20/group): negative control (GI), positive control (GII), and early (GIII) and late (GIV) treatment groups with oral auranofin according to beginning of treatment 4th week and 6th week post-infection. Mice were infected subcutaneously in a dose of 60±10 cercariae/mouse. Worm counts, egg loads, and oogram patterns were determined. Biochemical, histological, and immunostaining of interleukin-1β (IL-1β), Sirtuin 3 (SIRT3), and smooth muscle actin (SMA) were assessed. GIII showed a significant decrease in the total S. mansoni worm burden and ova/gram in liver tissue (with reduction percent of 63.07% and 78.26%, respectively). Schistosomal oogram patterns, immature and mature ova, also showed a significant decrease. The reduction in granuloma number and size was 40.63% and 48.66%, respectively, in GIII, whereas in GIV, the reduction percent was 76.63% and 67.08%. In addition, the degree of fibrosis was significantly diminished in both treated groups. GIV showed significant reduction in IL-1β and SMA expression and increase in SIRT3 expression. These findings reveal how auranofin suppresses the development of liver fibrosis. Therefore, it is crucial to take another look at auranofin as a prospective medication for the treatment of S. mansoni egg-induced hepatic granuloma and consequent fibrosis.

Phylogenetic reconstruction, histopathological characterization, and virulence determination of a novel fish pathogen, Nocardia brasiliensis

Nocardiosis is a prevalent disease caused by various cosmopolitan aerobic actinomycetes species within the genus Nocardia, which has been documented across diverse aquatic species. Recently, a distinctive disease manifestation resembling classical nocardiosis emerged among cultured meagre (Argyrosomus regius) along the European coastline adjacent to the North Atlantic Ocean. To identify the causative agent and reproduce the disease, we conducted experiments on specific pathogen-free (SPF) meagre specimens. Employing classical methods, we isolated bacteria from liver granulomas present in multiple diseased specimens. The causative agent was subsequently identified through a combination of differential staining, MALDI-TOF mass spectrometry (MS), genus-specific nested PCR, and sequencing of the 16S ribosomal RNA gene, which facilitated the positive identification of Nocardia brasiliensis. The isolated strain was designated as NORBRACAN1 and considered the causative agent. Remarkably, this marks the first report of this species in fish. The pathogenicity of NORBRACAN1 was further elucidated through in vivo experimentation on a cohort of 360 juvenile meagre. The intraperitoneal administration of NORBRACAN1 led to the development of internal microgranulomas without overt external signs or mortalities. Intriguingly, fish exposed to concentrations below 1 × 106 CFU ml−1 remained unaffected by mortality throughout the two-month trial period. Immunofluorescence assay unveiled the presence of viable bacteria within specific granulomas. Furthermore, our study unveiled the existence of five distinct types of microscopic granulomas characterized by necrotic centers and arranged macrophages. The formation of these granulomas was found to be contingent upon the bacterial dosage. In conclusion, our investigation demonstrates the ability of N. brasiliensis to colonize internal organs in marine fish and induce chronic granulomatosis. This research illuminates the potential pathogenesis of nocardiosis in aquatic species, underscoring the importance of N. brasiliensis as a novel causative agent in fish.

A child with polyarthritis and chronic lung disease: a case report of ataxia-telangiectasia

BackgroundAtaxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare.Case presentationWe herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES).ConclusionsAlthough rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.

TREM2 expression promotes liver and peritoneal M2 macrophage polarization in mice infected with Schistosoma japonicum.

Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of liver granulomas and fibrosis by undergoing polarization from M1 to M2 type during schistosomiasis. Therefore, regulating macrophage polarization is important for controlling pathological changes that occur during this disease. Triggering receptor expressed on myeloid cells 2 (TREM2) expressed on the surface of macrophages, dendritic cells and other immune cells has been shown to play a role in inhibiting inflammatory responses and regulating M2 macrophage polarization, however its role in macrophage polarization in schistosomiasis has not been investigated. In this study, we confirmed that TREM2 expression was upregulated in the livers and peritoneal macrophages of mice infected with Schistosoma japonicum. Moreover, the TREM2 expression trend correlated with the expression of M2 macrophage polarization-related molecules in the liver tissues of S. japonicum-infected mice. Using Trem2-/- mice, we also showed that Trem2 deletion inhibited Arg1 and Ym1 expression in liver tissues. Trem2 deletion also increased the number of F4/80 + CD86+ cells in peritoneal macrophages of infected mice. In summary, our study suggests that TREM2 may be involved in M2 macrophage polarization during schistosomiasis.

Knocking Down Gm16685 Decreases Liver Granuloma in Murine Schistosomiasis Japonica.

Long noncoding RNAs (lncRNAs) can regulate key genes and pathways in liver disease development. Moreover, macrophages are speculated to play an important role in regulating granulomatous inflammation during schistosomiasis. However, the role of lncRNAs in the formation of liver granulomas by influencing the polarization of macrophages in Schistosoma japonicum infection is unclear. Our study aimed to determine whether lncRNAs can play a role in S. japonicum-induced hepatic egg granulomas and elucidate their effect on macrophages. We established S. japonicum infection models and screened the target lncRNA Gm16685 highly expressed in schistosomiasis mice using high-throughput sequencing. Hematoxylin and eosin staining revealed that the knockdown of Gm16685 reduced the area of egg granulomas. Moreover, M1 macrophage factor genes were significantly downregulated in Gm16685 knockdown livers. Meanwhile, M2 macrophage factor genes were significantly upregulated, which was consistent with the protein detection results. Hepatocytes, hepatic stellate cells, and macrophages were isolated from mouse models infected with S. japonicum, with Gm16685 being significantly upregulated in macrophages. Moreover, the knockdown of Gm16685 in RAW264.7 cells revealed similar results to in liver tissue. RNA fluorescence in situ hybridization (FISH) and nucleocytoplasmic separation experiments revealed that Gm16685 was predominantly localized in the cytoplasm of cells. We found that miR-205-5p was upregulated after Gm16685 was knocked down. After overexpression of miR-205-5p, the expression of Gm16685 and inflammatory factors was significantly downregulated. These results indicate that Gm16685 can participate in the pathogenesis of hepatic disease in schistosomiasis and promote M1 macrophage polarization by regulating miR-205-5p. Thus, our study may provide a new target for schistosomiasis japonica treatment.

Advances and Challenges of the Decade: The Ever-Changing Clinical and Genetic Landscape of Immunodeficiency

In the past 10 years, we have witnessed major advances in clinical immunology. Newborn screening for severe combined immunodeficiency has become universal in the United States and screening programs are being extended to severe combined immunodeficiency and other inborn errors of immunity globally. Early genetic testing is becoming the norm for many of our patients and allows for informed selection of targeted therapies including biologics repurposed from other specialties. During the COVID-19 pandemic, our understanding of essential immune responses expanded and the discovery of immune gene defects continued. Immunoglobulin products, the backbone of protection for antibody deficiency syndromes, came into use to minimize side effects. New polyclonal and monoclonal antibody products emerged with increasing options to manage respiratory viral agents such as SARS-CoV-2 and respiratory syncytial virus. Against these advances, we still face major challenges. Atypical is becoming typical as phenotypes of distinct genetic disease overlap whereas the clinical spectrum of the same genetic defect widens. Therefore, clinical judgment needs to be paired with repeated deep immune phenotyping and upfront genetic testing, as technologies rapidly evolve, and clinical disease often progresses with age. Managing patients with organ damage resulting from immune dysregulation poses a special major clinical challenge and management often lacks standardization, from autoimmune cytopenias, granulomatous interstitial lung disease, enteropathy, and liver disease to endocrine, rheumatologic, and neurologic complications. Clinical, translational, and basic science networks will continue to advance the field; however, cross-talk and education with practicing allergists/immunologists are essential to keep up with the ever-changing clinical and genetic landscape of inborn errors of immunity.

A metabotropic glutamate receptor affects the growth and development of Schistosoma japonicum.

Schistosomiasis is a zoonotic parasitic disease caused by schistosome infection that severely threatens human health. Therapy relies mainly on single drug treatment with praziquantel. Therefore, there is an urgent need to develop alternative medicines. The glutamate neurotransmitter in helminths is involved in many physiological functions by interacting with various cell-surface receptors. However, the roles and detailed regulatory mechanisms of the metabotropic glutamate receptor (mGluR) in the growth and development of Schistosoma japonicum remain poorly understood. In this study, we identified two putative mGluRs in S. japonicum and named them SjGRM7 (Sjc_001309, similar to GRM7) and SjGRM (Sjc_001163, similar to mGluR). Further validation using a calcium mobilization assay showed that SjGRM7 and SjGRM are glutamate-specific. The results of in situ hybridization showed that SjGRM is mainly located in the nerves of both males and gonads of females, and SjGRM7 is principally found in the nerves and gonads of males and females. In a RNA interference experiment, the results showed that SjGRM7 knockdown by double-stranded RNA (dsRNA) in S. japonicum caused edema, chassis detachment, and separation of paired worms in vitro. Furthermore, dsRNA interference of SjGRM7 could significantly affect the development and egg production of male and female worms in vivo and alleviate the host liver granulomas and fibrosis. Finally, we examined the molecular mechanisms underlying the regulatory function of mGluR using RNA sequencing. The data suggest that SjGRM7 propagates its signals through the G protein-coupled receptor signaling pathway to promote nervous system development in S. japonicum. In conclusion, SjGRM7 is a potential target for anti-schistosomiasis. This study enables future research on the mechanisms of action of Schistosomiasis japonica drugs.

Role of IL-17A in enhancing liver fibrosis induced by TGF-β1 and IL-13 in Schistosoma mansoni infected mice

Schistosoma mansoni liver fibrosis is a complicated multicellular process involving numerous cytokines, chemokines, and growth factors. Transforming growth factor beta 1 (TGF-1) and interleukin (IL)-13 have been identified as critical pro-fibrotic mediators in many studies. IL-17A was linked to enhanced TGF- and IL-13-induced pathologies. This case-control study aimed to explore the effect of IL-17A on TGF- and IL-13-induced liver fibrosis during experimentally schistosomiasis mansoni infection. A total of 40 laboratory-bred female C57BL/6 mice were divided into four equal groups (G), G1 non-infected, G2 infected wild type (WT), G3 infected/anti-IL-17 monoclonal antibodies (mAb) and G4 treated mice. Mice were infected percutaneously with 40±5 cercariae per mouse. Neutralizing IL-17 mAb was administered to G3 intraperitoneally 3 weeks after infection and then every third day until 2 days before sacrification; mice of G4 were treated with a single dose of praziquantel. Serum levels of TGF-, IL-13, IL-17A, and proinflammatory cytokines were measured by ELISA. Liver granulomas were identified by hematoxylin-eosin stain and measured by an ocular micrometer. There was a significantly increased serum concentration of TGF-, IL-13, and IL-17A in infected WT mice (P<0.01), but praziquantel treatment reduced cytokine levels (P<0.03). Neutralization of IL-17A activity remarkably reduced serum concentrations of TGF- and IL-13 (P <0.03) resulting in improved liver functions and reduced granuloma size. Secretion of IL-IL-6 and TNF-were markedly enhanced by infection, however, mice that received anti-mouse IL-17 mAb displayed fewer inflammatory mediators (P<0.03). In conclusion, IL-17A might contribute to the progress of liver fibrosis by enhancing the profibrotic effect of TGF- and IL-13 in mice infected with S. mansoni.