Cellular immunity and resistance to schistosomiasis in the Philippines

Schistosomiasis, also known as bilharzia or snailfever, is a parasitic worm infection currently infecting more than 200 million people worldwide. Infection remains a major health risk in the Philippines, with an estimated 2 million Filipinos infected and 12 million of the population at risk of infection. Humans are infected though contact with fresh water, such as rice paddies and streams, where the snails carrying the parasite live. Once inside the human host the adult worms produce eggs, which get stuck in the liver and other organs where they evoke inflammation and blockages. No vaccine is currently available and despite attempts to control the infection with mass drug treatment programs, low-grade chronic infections leading to anaemia, growth retardation and cognitive impairment are still prevalent. Re-infection occurs quickly even after treatment since the parasite is still widespread in water sources which people need to access.
The overall aim of this proposal is to assess the role of various types of immune cells in the development of resistance or susceptibility to schistosome reinfection, with a long term goal to support vaccine development. Previous studies have shown that individuals that have high levels of a particular type of antibody (IgE) in their blood are more resistant to becoming reinfected with schistosomiasis after drug treatment, whilst individuals with a different type of antibody (IgG4) are more susceptible to becoming reinfected. However, what is not known is what type of immune cells and mediators are involved in controlling what kind of antibodies are generated in different people. In order to develop effective vaccines against schistosomiasis, we need to have a better understanding of how protective, as well as non-protective immune responses are generated in naturally infected humans. This proposal aim to address this gap in knowledge by analysing immune function correlates of protection and susceptibility in individuals living in a schistosome endemic area of the Philippines. Antibodies are produced by B cells but various types of T cells are important in instructing the B cells in what kind of antibodies they should produce. We are particularly interested two specific types of T cells, known as follicular T helper cells (Tfh) and follicular T regulatory cells (Tfr), as well as the mediators they produce, in order to determine whether these particular cells are responsible for influencing the antibody classes produced during infection. We hypothesise that an individual's Tfh and Tfr numbers and phenotypes are crucial in determining if they become resistant or susceptible to reinfection. No previous studies have investigated the interaction between Tfh, Tfr and B cells in schistosomiasis and the new information gathered from this study will be of great importance for the ability to develop the vaccine needed to combat this debilitating disease in the Philippines and other parts of the world. Schistosomiasis is a major public health problem and a barrier to social and economic development in the resource poor areas of the Philippines. Our application will promote advancement in biotechnology and health sciences that will impact public health in the Philippines and globally. Our proposal also has the added benefit of potentiating both the international mobility of Filipino researchers and the establishment of sustainable global scientific partnerships. Collectively, these advances in scientific understanding and in capacity building will provide a framework for tackling barriers to development and for nurturing progress, with Filipino investigators being key drivers in change.

Schistosomiasis remains a major health risk in the Philippines, with 12 million people at risk of infection. The aim of this proposal is to assess the role of immune cells in resistance or susceptibility to reinfection. Previous studies have shown that anti-schistosome IgE responses are associated with resistance to reinfection, while IgG4 responses are associated with susceptibility, but the mechanisms controlling IgE and IgG4 antibody generation in schistosomiasis remain poorly understood. The current proposal aim to address this gap by analysing correlates of protection in a prospective, longitudinal cohort study of individuals living in a schistosome-endemic area of the Philippines. Cellular and antibody responses will be analysed at baseline and at follow up intervals after treatment to correlate immune phenotype with reinfection status. We hypothesise that the frequency and phenotype of follicular T helper cells (Tfh) and follicular T regulatory cells (Tfr) determine the antibody classes produced and hence, a resistant or susceptible phenotype in infected individuals. No previous studies have investigated the role of Tfh and Tfr cells in schistosomiasis and the new information gained from this study will be of importance to combat this debilitating disease in the Philippines, as it remain a major barrier to social and economic development. Our study will provide a better understanding of the immune response and will inform the future development of vaccines. Thus, our project will promote advancement in biotechnology and health sciences that will impact public health in the Philippines and globally. Our proposal will benefit the international mobility of Filipino researchers and the establishment of sustainable global scientific partnerships. These advances in scientific understanding and in capacity building will provide a framework for tackling barriers to development and for nurturing progress, allowing Filipino investigators to be key drivers in change.

The primary objective of this project is the acquisition of new knowledge and scientific advancement in the field of human immunobiology and vaccinology, leading to the development of intervention strategies for combating schistosomiasis.
Academic and industrial organisations (medium-term)
This proposal describes fundamental research into human cellular immunology and hence, the immediate beneficiary is likely to be academia, including the wider academic community, schools and colleges. Enhanced understanding of resistance and susceptibility to parasitic infections such as schistosomiasis will benefit a wide scientific and medical community, as many types of debilitating parasitic infections are still common in many parts of the world. Our studies may therefore have a significant impact on basic science as well as the understanding of a range of infectious diseases, stimulating the development of new treatments and vaccines.
Our work aimed at exploring the fundamental basis of antibody generation in naturally infected humans will benefit the commercial sector, including pharmaceutical stakeholders with an interest in vaccinology and adjuvant technology, as well as those working to develop treatments for inflammatory, allergic and autoimmune disorders.
Our work will stimulate further research into mechanisms and triggers of immunity to pathogens which may stimulate the recruitment of new scientists into this field of work, and will contribute to teaching and learning in the fields of immunology, parasitology and inflammation at national and international level.
The economy (long-term)
In the longer term, understanding the mechanisms of how helminths establish themselves in the host, which host defence components are critical, and how they can be modulated will provide important information for the design of novel treatments and vaccines, Vaccines are proven for the control of infectious diseases in both humans and in animals, and suitably designed vaccines will reduce the public health burden of schistosomiasis in the Philippines and elsewhere. This will improve human wealth, quality of life, creative output, and enhance national and global economic performance in the long term.
The general public (short to long-term)
The work outlined in this proposal will generate significant new knowledge regarding the function and pathways involved in the generation of human antibody response. Our studies may therefore have a significant impact on basic science as well as the understanding of a range of diseases, involving not only infectious disease immunology but various types of immune related disorders. Therefore, the proposal has the potential to considerably enhance the quality of life for many people across the globe, and not only in schistosomiasis endemic areas.
Training opportunities (short- to medium term)
Our work will stimulate further research into mechanisms and triggers of immunity to pathogens, which may stimulate the recruitment of new scientists into this field of work, and will contribute to teaching and learning in the fields of human immunology, parasitology, and inflammation at national and international level. At a local level the project will give the LSHTM and RITM staff employed training and learning opportunities in current methodologies, data management, research management and scientific writing and presenting, all generic lifelong skills useful in careers in both science and beyond.