Basic Science Programme /Dissecting the immunological interplay between poverty-related diseases and helminth infection (IDEA Project)

Co-infections between worms and HIV, tuberculosis (TB) and malaria occur in tens of millions of people and in both children and adults. Preliminary data from a small number of studies indicate that about 25% of individuals affected by HIV, malaria or TB were co-infected with worms. Although these infections have each been extensively investigated in their own right, attention to the potential impact of co-infections between worms on one hand and HIV, TB and malaria on the other has arisen only recently. Because these infections are so frequent, possible interactions between worms and HIV, TB and malaria may have major public health implications. Secondly, although it is known that the human body reacts to all these infections with specific immune responses, it is not understood which of the responses confer protection against renewed infection or disease progression. Thirdly, there is yet no information on whether worm-induced immunity responses alter HIV-, TB- and malaria-specific immune responses. Fourthly, there is limited knowledge of the influence of underlying worm infections on the clinical course of HIV, TB and malaria. Finally, the impact of worm infections on vaccination requires further investigation although limited data suggest that effectiveness of vaccination may be reduced in subjects with worm infections. The study will investigate these issues in different populations in Uganda, Tanzania, Nigeria, Kenya and Italy.

Major aim: Although worm infections and HIV, TB and malaria have been extensively investigated, only recently there has been increasing attention to the potential impact of co-infections between worms and HIV, TB and malaria. Firstly, the interaction between these diseases may have major public health implications by increasing the diseases burden since effective vaccines are not yet available for worms, HIV, TB and malaria. Secondly, although the worm-, HIV-, TB- and malaria-specific immune responses have been the target of extensive investigation, the immune correlates of protection remain unknown for these diseases. Thirdly, there is no information on whether worms-induced immunity modulates HIV-, TB- and malaria-specific immune responses. Fourthly, there is limited knowledge of the influence of underlying worm infections on the clinical course of HIV, TB and malaria. Finally, the impact of worm infections on various vaccinations requires further investigation as limited data suggest reduced effectiveness of vaccination in subjects with worm infections. The project has the following major objectives: 1) to determine the modulation of polarized worm-specific immune responses on the functional and molecular profile of HIV-, TB- and malaria-specific immune responses; 2) to determine the impact of worm co-infections on the parameters of disease activity for HIV, TB and malaria; 3) to determine the effects of the complex interaction between worms and HIV on HIV-specific immune response and HIV replication; and 4) to determine the modulation of worm co-infections on vaccination and vaccine-induced immune responses. Methods: Flow cytometry will be used to study both adaptive and innate immune responses. Innate immune responses will be characterized by flow cytometry, Luminex technology and RT-MLPA or gene microarray. For adaptive immunity we will look at Th1, Th2 and Tregs, and will study the cytotoxic capacity of HIV speficific CD8 T cells, profiling the homing and migratory properties. At MRC/UVRI Entebbe we will study the effect of worm infection on the incidence of HIV infection in a fishing population cohort, using a case-control design to determine the odds of worm infections among people who become HIV infected compared to controls. These individuals will also be investigated for adaptive and innate immune responses. The effect of worms and worm treatment on HIV disease progression (CD4, viral load and HIV immune responses) will be studied in 400 HIV+/schistosome+ participants and a comparison group of 100 HIV+/schistosome –ve participants, by randomising HIV+/schistosome+ individuals participants to high intensity versus low intensity praziquantel treatment. Work conducted at MRC/UVRI Entebbe is funded by the EU with co-funding from MRC (UK).