TGF-beta activation by gut dendritic cells: identifying a critical pathway in regulation of chronic parasitic infection
Lead Research Organisation:
University of Manchester
Department Name: Life Sciences
Abstract
Our immune system functions to detect and destroy harmful pathogens that enter the body. Upon infection, immune responses are rapidly activated, to ensure the threat is dealt with as quickly as possible. However, pathogens known as helminth parasites can hijack the immune system to suppress responses aimed at eliminating the infection, therefore allowing the pathogen to live and breed inside the body. These so-called chronic helminth infections are major world health problems, with over one quarter of the world population affected, mostly in developing countries. Infections with helminth parasites cause major health and economic problems, but at present treatments for the infections are extremely limited. A vital area of scientific research therefore aims to understand how helminths control immune responses to allow their survival inside our body. Such work will therefore lead to the identification of potential novel therapeutic targets for treating chronic helminth infection.
Our new exciting data has identified important molecules that are critically involved in the development of chronic helminth infection. Hence, when cells of the immune system called dendritic cells have reduced ability to activate an important molecule called TGFbeta, chronic infection cannot develop in a mouse model of an important human gut helminth infection. However, why protection from chronic infection occurs is completely unknown. The work proposed here aims to uncover why lack of a specific pathway in the immune system causes complete protection from chronic infection in the gut, determining the cells and molecules of the immune system involved in such protection. We will also determine whether such resistance from infection is seen for other types of parasites, or whether protection is specific to helminth parasites that infect the gut.
Our work will therefore provide important insights into immune molecules, cells and mechanisms that are involved in allowing parasites to develop chronic infection, thus identifying potential novel therapeutic targets for treatment of these devastating diseases.
Our new exciting data has identified important molecules that are critically involved in the development of chronic helminth infection. Hence, when cells of the immune system called dendritic cells have reduced ability to activate an important molecule called TGFbeta, chronic infection cannot develop in a mouse model of an important human gut helminth infection. However, why protection from chronic infection occurs is completely unknown. The work proposed here aims to uncover why lack of a specific pathway in the immune system causes complete protection from chronic infection in the gut, determining the cells and molecules of the immune system involved in such protection. We will also determine whether such resistance from infection is seen for other types of parasites, or whether protection is specific to helminth parasites that infect the gut.
Our work will therefore provide important insights into immune molecules, cells and mechanisms that are involved in allowing parasites to develop chronic infection, thus identifying potential novel therapeutic targets for treatment of these devastating diseases.
Technical Summary
A massive world health problem is chronic infection with helminth parasites, which affect ~ 2.5 billion people in the developing world. Helminth infections result in severe economic and health burdens in affected countries, but at treatments at present are extremely limited. To develop chronicity, helminths must somehow evade host Th2-type immune responses aimed at expelling the parasite. However, the mechanisms underlying how helminths avoid host immunity during chronic infection are poorly understood. Determining the cellular and molecular pathways utilised by helminths during development of chronicity will be critical in identifying potential novel therapeutic targets to alleviate chronic helminth infection.
A vital immune regulatory cytokine is transforming growth factor-beta (TGFbeta), which is produced by many cells but always as a latent complex that must be activated in order to function. TGFbeta has important immunosuppressive properties, with mice lacking TGFbeta1 (the major isoform expressed in the immune system) dying from multi-organ inflammatory disease. An attractive hypothesis therefore is that helminths can manipulate the TGFbeta activation/signalling axis to dampen host immune responses directed against the parasite, thus facilitating development of chronic infection. Our exciting preliminary data indicate that this is indeed the case. Thus, we show that mice lacking expression of the TGFbeta-activating integrin alphavbeta8 specifically on dendritic cells are completely protected from chronic infection with the intestinal helminth Trichuris muris (an established model for the human parasite Trichuris trichura, which affects over 1 billion people world-wide). However, how reduced TGFbeta activation by dendritic cells results in protection from chronic parasitic infection, and how helminths modulate this important pathway to facilitate chronicity is completely unknown.
Our proposal therefore aims to determine fundamental cellular and molecular mechanisms that are critical for the development of chronic intestinal helminth infection, highlighting a central role for integrin-mediated TGFbeta activation by dendritic cells. Additionally, we will determine how gut helminths modulate this critical pathway, and whether important mechanisms identified can be extended to other helminth and non-helminth infections. Our cutting edge approaches and expertise, coupled with key collaborations in place, will therefore identify a potential novel therapeutic target for preventing and treating chronic helminth infection.
A vital immune regulatory cytokine is transforming growth factor-beta (TGFbeta), which is produced by many cells but always as a latent complex that must be activated in order to function. TGFbeta has important immunosuppressive properties, with mice lacking TGFbeta1 (the major isoform expressed in the immune system) dying from multi-organ inflammatory disease. An attractive hypothesis therefore is that helminths can manipulate the TGFbeta activation/signalling axis to dampen host immune responses directed against the parasite, thus facilitating development of chronic infection. Our exciting preliminary data indicate that this is indeed the case. Thus, we show that mice lacking expression of the TGFbeta-activating integrin alphavbeta8 specifically on dendritic cells are completely protected from chronic infection with the intestinal helminth Trichuris muris (an established model for the human parasite Trichuris trichura, which affects over 1 billion people world-wide). However, how reduced TGFbeta activation by dendritic cells results in protection from chronic parasitic infection, and how helminths modulate this important pathway to facilitate chronicity is completely unknown.
Our proposal therefore aims to determine fundamental cellular and molecular mechanisms that are critical for the development of chronic intestinal helminth infection, highlighting a central role for integrin-mediated TGFbeta activation by dendritic cells. Additionally, we will determine how gut helminths modulate this critical pathway, and whether important mechanisms identified can be extended to other helminth and non-helminth infections. Our cutting edge approaches and expertise, coupled with key collaborations in place, will therefore identify a potential novel therapeutic target for preventing and treating chronic helminth infection.