Understanding and manipulating how Trypanosoma cruzi infects its triatomine insect hosts

Chagas disease, also known as American trypanosomiasis, results in approximately 10,000 deaths annually. It is caused by the protozoan parasite Trypanosoma cruzi. An estimated 6 to 7 million people worldwide are infected with T. cruzi but, despite these large numbers, Chagas disease is a neglected tropical disease for which there are no successful vaccines. The disease is endemic to 21 continental Latin American countries and is mostly transmitted when humans come into contact with faeces and/or urine of infected blood-sucking triatomine bugs, primarily Rhodnius prolixus and Triatoma infestans (vector-borne transmission). We know that the parasite utilises various mechanisms to evade the mammalian host immune system including producing signalling molecules termed lipid mediators that serve to dampen the host immune response. However, just how the parasite establishes itself in the insect host has not been elucidated. Our preliminary data indicates that the production of lipid mediators by insect-infective forms of the parasite likely plays a vital role and exploring this is a focus of the current proposal. We will identify these lipid mediators and investigate how they regulate insect immunity. A critical step is the initial stage of infection, when the parasite establishes itself in the insect gut. Competing gut bacteria create a hostile environment for the parasite. To counter this, the parasite hacks the insect immune system so that the insect produces antimicrobial proteins to reduce the bacterial population in the gut. With BBSRC support, we previously developed and patented a novel technology to repurpose gut bacteria from these insects so that they continuously produce genetic information that can silence specific genes of the insect host. We now intend to apply this technology to target how the insect immune system is regulated. Our goal is to exploit this to counter how the parasite hacks the insect immune response. If successful, this approach will reduce parasite numbers in the insect which will, in turn, lower disease transmission by the vector. The project will demonstrate whether this approach has potential to be used as part of our response to combat climate-change associated increases in vector-borne disease transmission in general.

Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Various mechanisms for how the parasite evades the mammalian immune system have been described, including synthesis of secreted lipid mediators (LMs) by the parasite that modulate mammalian immune responses. One objective of this proposal is to build on preliminary data that strongly suggest that parasite-produced LMs also impact the immune responses of triatomine insect vectors of the parasite. We will identify these LMs using state-of-the-art lipidomic analyses. Using qRT-PCR and RNA interference (RNAi), we will then interrogate the immune regulatory network of the triatomine Rhodnius prolixus, to identify how parasite LMs influence this regulation. With previous BBSRC support, we developed a technology, symbiont-mediated RNAi (SMR) for delivering long-term RNAi to this insect using symbiotic gut bacteria. We will now exploit SMR to silence identified critical immune-regulatory genes and thereby counter how the parasite hacks insect immunity for its benefit, with the objective of reducing parasite numbers and consequently disease transmission. These bacteria will be delivered to the two principal insect vectors of Chagas disease which will subsequently be challenged with the parasite; the outcomes will be determined by comparing parasite numbers in control and test cohorts of the insects.