Distinct hepatic myeloid and lymphoid cell repertoires are associated with susceptibility and resistance to Ascaris infection.

The soil-transmitted helminth Ascaris lumbricoides infects ~800 million people worldwide. Some people are heavily infected, harbouring many worms, whereas others are only lightly infected. The mechanisms behind this difference are unknown. We used a mouse model of hepatic resistance to Ascaris, with C57BL/6J mice as a model for heavy infection and CBA/Ca mice as a model for light infection. The mice were infected with the porcine ascarid, Ascaris suum or the human ascarid, A. lumbricoides and immune cells in their livers and spleens were enumerated using flow cytometry. Compared to uninfected C57BL/6J mice, uninfected CBA/Ca mice had higher splenic CD4+ and γδ T cell counts and lower hepatic eosinophil, Kupffer cell and B cell counts. Infection with A. suum led to expansions of eosinophils, Kupffer cells, monocytes and dendritic cells in the livers of both mouse strains and depletions of hepatic natural killer (NK) cells in CBA/Ca mice only. Infection with A. lumbricoides led to expansions of hepatic eosinophils, monocytes and dendritic cells and depletions of CD8+, αß, NK and NK T cells in CBA/Ca mice, but not in C57BL/6J mice where only monocytes expanded. Thus, susceptibility and resistance to Ascaris infection are governed, in part, by the hepatic immune system.

Global prevalence of Ascaris infection in humans (2010-2021): a systematic review and meta-analysis.

BACKGROUND: Ascariasis is one of the most important neglected tropical diseases of humans worldwide. The epidemiology of Ascaris infection appears to have changed with improvements in sanitation and mass drug administration, but there is no recent information on prevalence worldwide. Here, we performed a systematic review and meta-analysis to assess the global prevalence of human Ascaris infection from 2010 to 2021. METHODS: We searched MEDLINE/PubMed, and Scopus databases for studies measuring prevalence of Ascaris infection, published between 1 January 2010 and 1 January 2022. We included studies of the general human population in endemic regions, which used accepted coprodiagnostic methods, and excluded studies of people with occupations with an increased risk or probability of ascariasis and/or specific diseases other than ascariasis. We applied random-effects models to obtain pooled prevalence estimates for six sustainable development goal regions of the world. We extrapolated the prevalence estimates to the global population in 2020, to estimate the number of individuals with Ascaris infection. We conducted multiple subgroup and meta-regression analyses to explore possible sources of heterogeneity, and to assess relationships between prevalence estimates and demographic, socio-economic, geo-climatic factors. RESULTS: Of 11,245 studies screened, we analysed 758 prevalence estimates for a total number of 4,923,876 participants in 616 studies from 81 countries. The global prevalence estimated was 11.01% (95% confidence interval: 10.27-11.78%), with regional prevalences ranging from 28.77% (7.07-57.66%) in Melanesia (Oceania) to 1.39% (1.07-1.74%) in Eastern Asia. We estimated that ~ 732 (682-782) million people harboured Ascaris worldwide in 2021. The infected people in Latin America and the Caribbean region had a higher prevalence of high intensity infection (8.4%, 3.9-14.1%). Prevalence estimates were higher in children, and people in rural communities or in countries or regions with lower income and human development indices. There was a trend for a higher prevalence in regions with increasing mean annual relative humidity, precipitation and environmental temperature. CONCLUSIONS: Our findings indicate that, despite a renewed commitment by some communities or authorities to control ascariasis, a substantial portion of the world's human population (> 0.7 billion) is infected with Ascaris. Despite the clinical and socioeconomic importance of ascariasis, many past routine surveys did not assess the intensity of Ascaris infection in people. We propose that the present findings might stimulate the development of customised strategies for the improved control and prevention of Ascaris infection worldwide.

The liver proteome in a mouse model for Ascaris suum resistance and susceptibility: evidence for an altered innate immune response.

BACKGROUND: Ascariasis is a neglected tropical disease that affects 800 million people worldwide. Whereas most people only experience light worm burden, some people experience heavy worm burdens even after several rounds of chemotherapy, a phenomenon known as predisposition. Such heavy infections are associated with more severe symptoms and increased chronic morbidity. METHODS: In order to investigate potential mechanisms that may explain the observed predisposition, we infected mice with the porcine ascarid Ascaris suum using an established mouse model with two different mouse strains, where the C57BL/6J strain is more susceptible to infection and therefore a model for heavy infection and the CBA/Ca strain is more resistant and thus a model for light infection. At day 7 post-infection we investigated the liver proteome, using shotgun mass spectrometry, of both infected and control mice of each strain. RESULTS: We identified intrinsic differences, between the two mouse strains, in both oxidative phosphorylation proteins and proteins involved in retinol metabolism. Additionally, we found differences between the two mouse strains in activation of the complement system, where the CBA/Ca strain has higher protein abundances for lectin pathway proteins and the C57BL/6J strain has higher protein abundances for complement inhibiting proteins. The CBA/Ca strain had a higher abundance of proteins involved in the activation of the complement cascade via the lectin pathway. In contrast, the C57BL/6J strain demonstrated a higher abundance of proteins involved in arresting the complement pathway. CONCLUSIONS: We observed clear differences between the two mouse strains both intrinsically and under infection.

The role of the liver in the migration of parasites of global significance.

Many parasites migrate through different tissues during their life-cycle, possibly with the aim to enhance their fitness. This is true for species of three parasite genera of global importance, Ascaris, Schistosoma and Plasmodium, which cause significant global morbidity and mortality. Interestingly, these parasites all incorporate the liver in their life-cycle. The liver has a special immune status being able to preferentially induce tolerance over immunity. This function may be exploited by parasites to evade host immunity, with Plasmodium spp. in particular using this organ for its multiplication. However, hepatic larval attrition occurs in both ascariasis and schistosomiasis. A better understanding of the molecular mechanisms involved in hepatic infection could be useful in developing novel vaccines and therapies for these parasites.

A Proteomic Investigation of Hepatic Resistance to Ascaris in a Murine Model.

The helminth Ascaris causes ascariasis in both humans and pigs. Humans, especially children, experience significant morbidity including respiratory complications, growth deficits and intestinal obstruction. Given that 800 million people worldwide are infected by Ascaris, this represents a significant global public health concern. The severity of the symptoms and associated morbidity are related to the parasite burden and not all hosts are infected equally. While the pathology of the disease has been extensively examined, our understanding of the molecular mechanisms underlying resistance and susceptibility to this nematode infection is poor. In order to investigate host differences associated with heavy and light parasite burden, an experimental murine model was developed utilising Ascaris-susceptible and -resistant mice strains, C57BL/6J and CBA/Ca, respectively, which experience differential burdens of migratory Ascaris larvae in the host lungs. Previous studies identified the liver as the site where this difference in susceptibility occurs. Using a label free quantitative proteomic approach, we analysed the hepatic proteomes of day four post infection C57BL/6J and CBA/Ca mice with and without Ascaris infection to identify proteins changes potentially linked to both resistance and susceptibility amongst the two strains, respectively. Over 3000 proteins were identified in total and clear intrinsic differences were elucidated between the two strains. These included a higher abundance of mitochondrial proteins, particularly those associated with the oxidative phosphorylation pathway and reactive oxygen species (ROS) production in the relatively resistant CBA/Ca mice. We hypothesise that the increased ROS levels associated with higher levels of mitochondrial activity results in a highly oxidative cellular environment that has a dramatic effect on the nematode's ability to successfully sustain a parasitic association with its resistant host. Under infection, both strains had increased abundances in proteins associated with the oxidative phosphorylation pathway, as well as the tricarboxylic acid cycle, with respect to their controls, indicating a general stress response to Ascaris infection. Despite the early stage of infection, some immune-associated proteins were identified to be differentially abundant, providing a novel insight into the host response to Ascaris. In general, the susceptible C57BL/6J mice displayed higher abundances in immune-associated proteins, most likely signifying a more active nematode cohort with respect to their CBA/Ca counterparts. The complement component C8a and S100 proteins, S100a8 and S100a9, were highly differentially abundant in both infected strains, signifying a potential innate immune response and the importance of the complement pathway in defence against macroparasite infection. In addition, the signatures of an early adaptive immune response were observed through the presence of proteins, such as plastin-2 and dipeptidyl peptidase 1. A marked decrease in proteins associated with translation was also observed in both C57BL/6J and CBA/Ca mice under infection, indicative of either a general response to Ascaris or a modulatory effect by the nematode itself. Our research provides novel insights into the in vivo host-Ascaris relationship on the molecular level and provides new research perspectives in the development of Ascaris control and treatment strategies.