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Key Points Malaria is the most deadly parasitic infection of humans, killing up to 1 million people per year. No vaccine is currently available, and the development of drug-resistant Plasmodium spp. is of increasing concern. The first phase of infection, the pre-erythrocytic (PE) phase, is clinically asymptomatic. Only after parasite replication in the liver and infection of large numbers of erythrocytes do symptoms arise. The PE phase comprises sporozoites (the infectious stage) and the liver stages. Once injected by a mosquito, the sporozoites can remain in the skin, be transported in lymph vessels to draining lymph nodes or travel through the bloodstream to the liver. In the liver, sporozoites undergo an elaborate replication and developmental programme and transform into the merozoites that are released from the liver to infect erythrocytes. The PE phase of infection is a formidable window of opportunity for therapeutic interventions owing to the small number of parasites present. Thus, targeting this 'bottleneck' of Plasmodium spp. infection with vaccines is an attractive strategy. Live attenuated parasites mimicking the PE phase of infection can be used as vaccines. Attenuation is achieved by radiation, genetic alterations or drug-mediated developmental arrest. The symptoms of malaria are associated with the erythrocytic phase of Plasmodium spp. infection, but the pre-erythrocytic (PE) phase, which is clinically silent, has long been of interest as a potential vaccination target. Robert Ménard and colleagues review how our understanding of the PE phase has changed over the past decade and how this in turn has informed our understanding of the host immune response. Malaria, which is caused by Plasmodium spp., starts with an asymptomatic phase, during which sporozoites, the parasite form that is injected into the skin by a mosquito, develop into merozoites, the form that infects erythrocytes. This pre-erythrocytic phase is still the most enigmatic in the parasite life cycle, but has long been recognized as an attractive vaccination target. In this Review, we present what has been learned in recent years about the natural history of the pre-erythrocytic stages, mainly using intravital imaging in rodents. We also consider how this new knowledge is in turn changing our understanding of the immune response mounted by the host against the pre-erythrocytic forms.

The merozoite stage of the malaria parasite that infects erythrocytes and causes the symptoms of the disease is initially formed inside host hepatocytes. However, the mechanism by which hepatic merozoites reach blood vessels (sinusoids) in the liver and escape the host immune system before invading erythrocytes remains unknown. Here, we show that parasites induce the death and the detachment of their host hepatocytes, followed by the budding of parasite-filled vesicles (merosomes) into the sinusoid lumen. Parasites simultaneously inhibit the exposure of phosphatidylserine on the outer leaflet of host plasma membranes, which act as \"eat me\" signals to phagocytes. Thus, the hepatocyte-derived merosomes appear to ensure both the migration of parasites into the bloodstream and their protection from host immunity.

CD8 ⁺ T cells are specialized cells of the adaptive immune system capable of finding and eliminating pathogen-infected cells. To date it has not been possible to observe the destruction of any pathogen by CD8 ⁺ T cells in vivo. Here we demonstrate a technique for imaging the killing of liver-stage malaria parasites by CD8 ⁺ T cells bearing a transgenic T cell receptor specific for a parasite epitope. We report several features that have not been described by in vitro analysis of the process, chiefly the formation of large clusters of effector CD8 ⁺ T cells around infected hepatocytes. The formation of clusters requires antigen-specific CD8 ⁺ T cells and signaling by G protein-coupled receptors, although CD8 ⁺ T cells of unrelated specificity are also recruited to clusters. By combining mathematical modeling and data analysis, we suggest that formation of clusters is mainly driven by enhanced recruitment of T cells into larger clusters. We further show various death phenotypes of the parasite, which typically follow prolonged interactions between infected hepatocytes and CD8 ⁺ T cells. These findings stress the need for intravital imaging for dissecting the fine mechanisms of pathogen recognition and killing by CD8 ⁺ T cells.

Schistosomiasis is a neglected tropical disease of a significant public health impact. The water rat Nectomys squamipes is one of the most important non-human hosts in the schistosomiasis mansoni transmission in Brazil, being considered a wild reservoir. Cellular mechanisms that contribute to the physiological adaptation of this rodent to the Schistosoma mansoni parasite are poorly understood. Here we identified, for the first time, that a hepatic steatosis, a condition characterized by excessive lipid accumulation with formation of lipid droplets (LDs) within hepatocytes, occurs in response to the natural S. mansoni infection of N. squamipes, captured in an endemic region. Significant increases of LD area in the hepatic tissue and LD numbers/hepatocyte, detected by quantitative histopathological and ultrastructural analyses, were paralleled by increased serum profile (total cholesterol and triglycerides) in infected compared to uninfected animals. Raman spectroscopy showed high content of polyunsaturated fatty acids (PUFAs) in the liver of both groups. MALDI-TOFF mass spectroscopy revealed an amplified pool of omega-6 PUFA arachidonic acid in the liver of infected animals. Assessment of liver functional activity by the levels of hepatic transaminases (ALT and AST) did not detect any alteration during the natural infection. In summary, this work demonstrates that the natural infection of the wild reservoir N. squamipes with S. mansoni elicits hepatic steatosis in the absence of liver functional harm and that accumulation of lipids, markedly PUFAs, coexists with low occurrence of inflammatory granulomatous processes, suggesting that lipid stores may be acting as a protective mechanism for dealing with the infection.

Schistosoma japonicum eggs in the host liver form granuloma and liver fibrosis and then lead to portal hypertension and cirrhosis, seriously threatening human health. Natural killer (NK) cells can kill activated hepatic stellate cells (HSCs) against hepatic fibrosis. We used single-cell sequencing to screen hepatic NK cell subsets against schistosomiasis liver fibrosis. Hepatic NK cells were isolated from uninfected mice and mice infected for four and six weeks. The NK cells underwent single-cell sequencing. The markers’ expression in the NK subsets was detected through Reverse Transcription–Quantitative PCR (RT-qPCR). The proportion and granzyme B (Gzmb) expression of the total NK and Thy1+NK were detected. NK cells overexpressing Thy1 (Thy1-OE) were constructed, and functions were detected. The results revealed that the hepatic NK cells could be divided into mature, immature, regulatory-like, and memory-like NK cells and re-clustered into ten subsets. C3 (Cx3cr1+NK) and C4 (Thy1+NK) increased at week four post-infection, and other subsets decreased continuously. The successfully constructed Thy1-OE NK cells had significantly higher effector molecules and induced greater HSC apoptosis than the control NK cells. It revealed a pattern of hepatic NK cells in a mouse model of schistosomiasis. The Thy1+NK cells could be used as target cells against hepatic fibrosis.

Cystic Echinococcosis (CE) is a zoonotic disease causing fibrosis and necrosis of diseased livers caused by infection with Echinococcus granulosus (E.g). There is evidence that E.g is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of CE. Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in regulating the progression of E.g-infected liver lesions is not clear. Serum and hepatic Ghrelin levels were observed in E.g-infected mice (4, 12 and 36 weeks) and compared with healthy control groups. Co-localization analysis is performed between protein expression of Ghrelin in and around the hepatic lesions of E.g-infected 12-week mice and protein expression of different hepatic histiocytes by mIHC. HepG2 cells and protoscoleces (PSCs) protein were co-cultured in vitro, as well as PSCs were alone in vitro, followed by exogenously administered of Ghrelin and its receptor blocker, [D-Lys3]-GHRP-6, to assess their regulatory effects on immunoinflammation, fibrosis and survival rate of PSCs. Serum Ghrelin levels were increased in E.g-infected 4- and 12-week mice, and reduced in 36-week mice. E.g-infected mice consistently recruited Ghrelin in and around the hepatic lesions, which was extremely strongly co-localized with the protein expression of hepatic stellate cells (HSCs), T cells and the TGF-β1/Smad3 pathway. The secretion of Ghrelin was increased with increasing concentrations of PSCs protein in HepG2 cells culture medium. Moreover, Ghrelin could significantly inhibit the secretion of IL-2, INF-γ and TNF-α, as well as the expression of Myd88/NF-κB and TGF-β1/Smad3 pathway protein, and promoted the secretion of IL-4 and IL-10. Blocking Ghrelin receptor could significantly inhibit PSCs growth in in vitro experiment. Ghrelin is highly expressed in the early stages of hepatic E.g infection and may be involved in regulating the progression of liver lesions by suppression immunoinflammation and fibrosis.

Schistosomiasis is a parasitic disease characterized by liver fibrosis, a process driven by the activation of hepatic stellate cells (HSCs) and subsequent collagen production. Previous studies from our laboratory have demonstrated the ability of Schistosoma japonicum protein P40 (SjP40) to inhibit HSCs activation and exert an antifibrotic effect. In this study, we aimed to elucidate the molecular mechanism underlying the inhibitory effect of recombinant SjP40 (rSjP40) on HSCs activation. Using a cell model in which rSjP40 inhibited LX‐2 cell activation, we performed RNA‐seq analyses and identified ATF3 as the most significantly altered gene. Further investigation revealed that rSjP40 inhibited HSCs activation partly by suppressing ATF3 activation. Knockdown of ATF3 in mouse liver significantly alleviated S. japonicum‐induced liver fibrosis. Moreover, our results indicate that ATF3 is a direct target of microRNA‐494‐3p, a microRNA associated with anti‐liver fibrosis effects. rSjP40 was found to downregulate ATF3 expression by upregulating microRNA‐494‐3p in LX‐2 cells. This downregulation led to the inhibition of the expression of liver fibrosis proteins α‐SMA and COL1A1, ultimately alleviating liver fibrosis caused by S. japonicum.

Schistosomiasis drastically affects human health, where S. mansoni -induced hepatic fibrosis remains a serious problem with no available drug yet. The current study aimed to evaluate the hepatoprotective effects of Vildagliptin (Vilda), Diaminodiphenyl Sulfone (DDS), and their combination (Vilda/DDS) against S. mansoni -induced hepatic fibrosis and elucidate their underlying molecular mechanisms. S.mansoni -infected mice were administered praziquantel (PZQ) for two consecutive days, or Vilda, DDS, and Vilda/DDS for 14 consecutive days. Schistosomiasis-induced hepatic fibrosis was assessed parasitologically, biochemically, and pathologically. Results revealed that Vilda, DDS, and Vida/DDS treatments significantly reduced worm count, oogram stages, ova count, and ameliorated the granulomatous inflammatory reactions and hepatotoxicity indices. Moreover, they enhanced hepatic Nrf2/HO-1 pathway with significant increasing SOD and reducing MDA levels. Furthermore, they significantly downregulated the hepatic TLR4/NF-κB and NLRP3 inflammasome pathways leading to a significant reduction in TNF-α and caspase-1 levels which is important in the activation of IL-1β and caspase-3. Notably, significant downregulation in hepatic TGF-β1, α-SMA, and MMP-9 expressions were also recorded. In conclusion, Vilda/DDS showed antioxidant, anti-inflammatory and antifibrotic activities in comparison to either Vilda or DDS alone against S. mansoni -induced hepatic fibrosis. Therefore, Vilda/DDS is a promising approach for managing S. mansoni infection, liver fibrosis, and associated disease morbidity.

Clonorchis sinensis ( C. sinensis ) is a food-borne zoonotic parasite link to liver fibrosis and cholangiocarcinoma. Limited understanding of its mechanisms in causing liver fibrosis has impeded therapeutic advances for C. sinensis -induced liver lesions. Ferroptosis, a novel form of cell death involving iron overload and lipid peroxidation, exacerbates liver fibrosis; however, its role in C. sinensis infection remains unexplored. In this study, ferroptosis were detected in C. sinensis -infected C57BL/6 mice as well as in AML12 cells stimulated by C. sinensis excretory/secretory products (ESPs). 12 ferroptosis related genes were screened and we found glutathione peroxidase 4 (GPX4, 7 d), solute carrier family 7 member 11 (SLC7A11, 7 d) and nuclear factor erythroid 2 related factor 2 (Nrf2, 35 d) was significantly decreased in mice. Western blot results confirmed C. sinensis and ESPs down-regulated the expression of GPX4, SLC7A11 and Nrf2. GSH depletion, malondialdehyde (MDA) accumulation, mitochondrial structure damage, and iron overload were found in C. sinensis- infected mice and ESPs-stimulated AML12 cells, suggesting that ferroptosis occurred in vivo and in vitro . Treatment with ferroptosis inhibitor Fer-1 in C. sinensis- infected mice alleviated ferroptosis, reduced the productions of IFN-γ, TNF-α, IL-12 and IL-6, and downregulated transforming growth factor (TGF)-β/Smad pathway activation. In AML12 cells, Fer - 1 pretreatment reduced ESPs - induced ferroptosis and IL-6, TNF-α production. Fer - 1 also alleviated liver lesions, reduced parasite load (65%), α-SMA expression and collagen fiber deposition in infected mice. In conclusion, C. sinensis could cause ferroptosis, which promoted the secretions of IL-6 and TNF-α as well as the activation of TGF-β/Smad pathway, leading to exacerbated liver fibrosis.

Background The primary pathogenic mechanism of schistosomiasis-associated liver fibrosis involves the deposition of schistosome eggs, leading to the formation of liver egg granulomas and subsequent liver fibrosis. Hepatic stellate cells are abnormally activated, resulting in excessive collagen deposition and fibrosis development. While specific long non-coding RNAs (lncRNAs) have been associated with fibrotic processes, their roles in schistosomiasis-associated liver fibrosis remain unclear. Methods Our previous research indicated that downregulating the ICOSL/ICOS could partially alleviate liver fibrosis. In this study, we established a schistosomiasis infection model in C57BL/6 and ICOSL knockout (KO) mice, and the liver pathology changes were observed at various weeks postinfection (wpi) using hematoxylin and eosin and Masson’s trichrome staining. Within the first 4 wpi, no significant liver abnormalities were observed. However, mice exhibited evident egg granulomas and fibrosis in their livers at 7 wpi. Notably, ICOSL-KO mice had significantly smaller pathological variations compared with simultaneously infected C57BL/6 mice. To investigate the impact of lncRNAs on schistosomiasis-associated liver fibrosis, quantitative real-time polymerase chain reaction (RT-qPCR) was used to monitor the dynamic changes of lncRNAs in hepatic stellate cells of infected mice. Results The results demonstrated that lncRNA-H19, -MALAT1, -PVT1, -P21 and -GAS5 all participated in liver fibrosis formation after schistosome infection. In addition, ICOSL-KO mice exhibited significantly inhibited expression of lncRNA-H19, -MALAT1 and -PVT1 after 7 wpi. In contrast, they showed enhanced expression of lncRNA-P21 and -GAS5 compared with C57BL/6 mice, influencing liver fibrosis development. Furthermore, small interfering RNA transfection (siRNA) in JS-1 cells in vitro confirmed that lncRNA-H19, -MALAT1, and -PVT1 promoted liver fibrosis, whereas lncRNA-P21 and -GAS5 had the opposite effect on key fibrotic molecules, including α- smooth muscle actin and collagen I expression. Conclusions This study uncovers that ICOSL/ICOS may play a role in activating hepatic stellate cells and promoting liver fibrosis in mice infected with Schistosoma japonicum by dynamically regulating the expression of specific lncRNAs. These findings offer potential therapeutic targets for schistosomiasis-associated liver fibrosis. Graphical Abstract