Human Schistosome Infection and Allergic Sensitisation

Several field studies have reported an inverse relationship between the prevalence of helminth infections and that of allergic sensitisation/atopy. Recent studies show that immune responses induced by helminth parasites are, to an extent, comparable to allergic sensitisation. However, helminth products induce regulatory responses capable of inhibiting not only antiparasite immune responses, but also allergic sensitisation. The relative effects of this immunomodulation on the development of protective schistosome-specific responses in humans has yet to be demonstrated at population level, and the clinical significance of immunomodulation of allergic disease is still controversial. Nonetheless, similarities in immune responses against helminths and allergens pose interesting mechanistic and evolutionary questions. This paper examines the epidemiology, biology and immunology of allergic sensitisation/atopy, and schistosome infection in human populations

Down Regulation of the TCR Complex CD3ζ-Chain on CD3+ T Cells: A Potential Mechanism for Helminth-Mediated Immune Modulation.

The CD3ζ forms part of the T cell receptor (TCR) where it plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways leading to T cell effector functions. Down regulation of CD3ζ leads to impairment of immune responses including reduced cell proliferation and cytokine production. In experimental models, helminth parasites have been shown to modulate immune responses directed against them and unrelated antigens, so called bystander antigens, but there is a lack of studies validating these observations in humans. This study investigated the relationship between expression levels of the TCR CD3ζ chain with lymphocyte cell proliferation during human infection with the helminth parasite, Schistosoma haematobium, which causes uro-genital schistosomiasis. Using flow cytometry, peripheral blood mononuclear cells (PBMCs) from individuals naturally exposed to S. haematobium in rural Zimbabwe were phenotyped, and expression levels of CD3ζ on T cells were related to intensity of infection. In this population, parasite infection intensity was inversely related to CD3ζ expression levels (p < 0.05), consistent with downregulation of CD3ζ expression during helminth infection. Furthermore, PBMC proliferation was positively related to expression levels of CD3ζ (p < 0.05) after allowing for confounding variables (host age, sex, and infection level). CD3ζ expression levels had a differing relationship between immune correlates of susceptibility and immunity, measured by antibody responses, indicating a complex relationship between immune activation status and immunity. The relationships between the CD3ζ chain of the TCR and schistosome infection, PBMC proliferation and schistosome-specific antibody responses have not previously been reported, and these results may indicate a mechanism for the impaired T cell proliferative responses observed during human schistosome infection

Circulating cytokine levels and antibody responses to human Schistosoma haematobium: IL-5 and IL-10 levels depend upon age and infection status

Experimental schistosome infections induce strong parasite-specific Th2 responses. This study aims to relate human systemic cytokine and antibody levels to schistosome infection levels and history. Levels of anti-Schistosoma haematobium antibodies (directed against crude cercariae, egg and adult worm antigens) and plasma cytokines (IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-21, and IL-23) were measured by ELISA in 227 Zimbabweans (6–60 years old) in a schistosome-endemic area and related to age and infection status. Egg-positive people had significantly higher levels of specific antibodies, IL-2, IFN-γ and IL-23. In contrast, egg-negative individuals had significantly higher circulating IL-10, IL-4, IL-13 and IL-21 that were detected with high frequency in all participants. Subjects with detectable plasma IL-17 produced few or no eggs. When analyzed by age, IL-4 and IL-10 increased significantly, as did schistosome-specific antibodies. However, when age was combined with infection status, IL-5 declined over time in egg-positive people, while increased with age in the egg-negative group. Older, lifelong residents had significantly higher IL-4 and IL-5 levels than younger egg-negative people. Thus, a mixed Th1/Th2 systemic environment occurs in people with patent schistosome infection, while a stronger Th2-dominated suite of cytokines is evident in egg-negative individuals

What does equitable global health research and delivery look like?:Tackling Infections to Benefit Africa (TIBA) partnership as a case study

There is a current global push to identify and implement best practice for delivering maximum impact from development research in low-income and middle-income countries. Here, we describe a model of research and capacity building that challenges traditional approaches taken by western funders in Africa. Tackling Infections to Benefit Africa (TIBA) is a global health research and delivery partnership with a focus on strengthening health systems to combat neglected tropical diseases, malaria and emerging pathogens in Africa. Partners are academic and research institutions based in Ghana, Sudan, Rwanda, Uganda, Kenya, Tanzania, Zimbabwe, Botswana, South Africa and the UK. Fifteen other African countries have participated in TIBA activities. With a starting budget of under £7 million, and in just 4 years, TIBA has had a verified impact on knowledge, policy practice and capacity building, and on national and international COVID-19 responses in multiple African countries. TIBA’s impact is shown in context-specific metrics including: strengthening the evidence base underpinning international policy on neglected tropical diseases; 77% of research publications having Africa-based first and/or last authors; postgraduate, postdoctoral and professional training; career progression for African researchers and health professionals with no net brain drain from participating countries; and supporting African institutions. Training in real-time SARS-CoV-2 viral genome sequencing provided new national capabilities and capacities that contributed to both national responses and global health security through variant detection and tracking. TIBA’s experience confirms that health research for Africa thrives when the agenda and priorities are set in Africa, by Africans, and the work is done in Africa. Here, we share 10 actionable recommendations for researchers and funders from our lessons learnt

Helminth parasite proteomics: from experimental models to human infections

Schistosomiasis is a major human helminth infection endemic in developing countries. Urogenital schistosomiasis, caused by S. haematobium, is the most prevalent human schistosome disease in sub-Saharan Africa. Currently control of schistosome infection is by treatment of infected people with the anthelmintic drug praziquantel, but there are calls for continued efforts to develop a vaccine against the parasites. In order for successful vaccine development, it is necessary to understand the biology and molecular characteristics of the parasite. Ultimately, there is need to understand the nature and dynamics of the relationship between the parasite and the natural host. Thus, my studies have focused on molecular characterization of different parasite stages and integrating this information with quantitative approaches to investigate the nature and development of protective immunity against schistosomes in humans. Proteomics has proved a powerful tool in these studies allowing the proteins expressed by the parasite to be characterized at a molecular and immunological level. In this review, the application of proteomic approaches to understanding the human-schistosome relationship as well as testing specific hypotheses on the nature and development of schistosome-specific immune responses is discussed. The contribution of these approaches to informing schistosome vaccine development is highlighted

Infection and treatment immunizations for successful parasite vaccines

Since the advent of techniques for the expression of recombinant peptide antigens, the availability of human vaccines for parasitic diseases has been ‘imminent’. Yet vaccines based on recombinant proteins are still largely aspirations, not realities. It is now apparent that vaccine development needs additional knowledge about host protective immune response(s), antigen characteristics, and the delivery required to induce those responses. The most successful immune protection against parasites has been generated by infection and treatment, the induction of protective immunity by truncating the course of an infection with drug treatment. Here, we consider the characteristics of an effective, protective anti-parasite vaccine and propose a conceptual framework to aid parasite vaccine development using malaria and schistosomiasis as examples