Periodic Reporting for period 1 - TRYPTISSUE (Characterising Trypanosoma tissue tropism: new perspectives for variant surface glycoproteins)
Reporting period: 2019-12-01 to 2021-11-30
Animal African trypanosomiasis (AAT) is a livestock disease in Africa and South America caused by Trypanosoma brucei, T. congolense, and T. vivax that results in frequent epidemics, high animal mortality and economic loss. There is no vaccine, and drug-resistance is swiftly rising, requiring continuous vector control and disease surveillance. T. congolense is one of the most prevalent and pathogenic African trypanosome species in Africa, but little is known about its biology. Whilst T. congolense infections in African cattle mostly cause a chronic, wasting disease, in exotic breeds and in other mammals, including dogs, goats, and horses, the parasite can cause a rapidly fatal, acute disease, characterized by inflammatory syndrome, disseminated intravascular coagulation syndrome, and neurological impairment (also called cerebral trypanosomiasis).
One of the key aspects that distinguishes T. congolense from human-infective T. brucei is the mechanism of tissue tropism. T. congolense cytoadheres to the vascular endothelium, whilst T. brucei egresses the bloodstream and invades tissues (reviewed in Silva Pereira et al., 2019). T. congolense cytoadhesion causes parasite sequestration (Losos et al., 1973; Losos and Gwamaka, 1973; Ojok et al., 2002), which, for other pathogens, such as Babesia spp. and Plasmodium spp., is a key determinant of virulence (Gallego-Lopez et al., 2019; Ghazanfari et al., 2018; Rogerson et al., 2007; Van den Steen et al., 2013; Vargas et al., 2014). Currently, very little is known about the impact of T. congolense sequestration in disease. Yet, parasite presence in the vasculature, and sequestration in particular, usually results in an inflammatory response (Storm and Craig, 2014). We know that T. congolense adhesion to host cell membranes triggers antibody-complement cascades and increases vascular permeability, suggestive of endothelium damage (Banks, 1980). The parasite itself has also been reported to release soluble molecules, like trans-sialidades, that activate the endothelium in vitro, and enhance inflammation in vivo (Ammar et al., 2013). In turn, excessive inflammation is a common driver of pathology in many infectious diseases. It is therefore plausible that the physical damage caused by parasite sequestration in the brain and the resulting host’s immune response affect disease progression.
Until now, the mechanism behind T. congolense sequestration and the reasons behind the differences in disease outcome remained elusive. In this project, we set out to develop mouse models of trypanosomiasis and to use them to understand the sequestration mechanism and its impact in disease progression.
One of the key aspects that distinguishes T. congolense from human-infective T. brucei is the mechanism of tissue tropism. T. congolense cytoadheres to the vascular endothelium, whilst T. brucei egresses the bloodstream and invades tissues (reviewed in Silva Pereira et al., 2019). T. congolense cytoadhesion causes parasite sequestration (Losos et al., 1973; Losos and Gwamaka, 1973; Ojok et al., 2002), which, for other pathogens, such as Babesia spp. and Plasmodium spp., is a key determinant of virulence (Gallego-Lopez et al., 2019; Ghazanfari et al., 2018; Rogerson et al., 2007; Van den Steen et al., 2013; Vargas et al., 2014). Currently, very little is known about the impact of T. congolense sequestration in disease. Yet, parasite presence in the vasculature, and sequestration in particular, usually results in an inflammatory response (Storm and Craig, 2014). We know that T. congolense adhesion to host cell membranes triggers antibody-complement cascades and increases vascular permeability, suggestive of endothelium damage (Banks, 1980). The parasite itself has also been reported to release soluble molecules, like trans-sialidades, that activate the endothelium in vitro, and enhance inflammation in vivo (Ammar et al., 2013). In turn, excessive inflammation is a common driver of pathology in many infectious diseases. It is therefore plausible that the physical damage caused by parasite sequestration in the brain and the resulting host’s immune response affect disease progression.
Until now, the mechanism behind T. congolense sequestration and the reasons behind the differences in disease outcome remained elusive. In this project, we set out to develop mouse models of trypanosomiasis and to use them to understand the sequestration mechanism and its impact in disease progression.
We developed a mouse model of acute cerebral trypanosomiasis and characterized the cellular, behavioral and physiological consequences of this infection. Using in vivo imaging, we showed large parasite sequestration in the brain vasculature for long periods of time (up to 8 hours), that results in extensive brain damage partly caused by ICAM1-mediated recruitment and accumulation of T cells. Antibody-mediated ICAM1 blocking and lymphocyte absence reduce parasite sequestration in the brain and prevent the onset of cerebral trypanosomiasis. Here, we establish a new mouse model of acute cerebral trypanosomiasis and we propose a mechanism whereby parasite sequestration, host ICAM1, and CD4+ T cells play a pivotal role.
Furthermore, using targeted transcriptomics, we have identified parasite genes that may play a role in sequestration and we are conducting a functional screen to assess their role in sequestration in vivo.
We have disseminated these results to the scientific community by presenting the work at international conferences (e.g. Molecular Parasitology Meeting 2019, Molecular Parasitology Meeting 2021, EMBL New Generation in Infection Biology) and in peer-review publications (Silva Pereira et al 2021 Trends in Parasitology; Silva Pereira et al 2022, eLife (under revision)). We also disseminated this work to the general public, at Little iMMers 2019, Soapbox Science Lisbon 2020, FIC.A International Science Festival 2021, and Pint of Science 2022.
During this project, we established collaborations within and outside the institute, two of which have culminated in peer-review publications (Viegas et al 2022 Nature and Silva Pereira et al 2022 Parasites and Vectors).
Furthermore, using targeted transcriptomics, we have identified parasite genes that may play a role in sequestration and we are conducting a functional screen to assess their role in sequestration in vivo.
We have disseminated these results to the scientific community by presenting the work at international conferences (e.g. Molecular Parasitology Meeting 2019, Molecular Parasitology Meeting 2021, EMBL New Generation in Infection Biology) and in peer-review publications (Silva Pereira et al 2021 Trends in Parasitology; Silva Pereira et al 2022, eLife (under revision)). We also disseminated this work to the general public, at Little iMMers 2019, Soapbox Science Lisbon 2020, FIC.A International Science Festival 2021, and Pint of Science 2022.
During this project, we established collaborations within and outside the institute, two of which have culminated in peer-review publications (Viegas et al 2022 Nature and Silva Pereira et al 2022 Parasites and Vectors).
In conclusion, through our murine model of acute cerebral trypanosomiasis, we show that cerebral trypanosomiasis is caused by the combination of parasite sequestration in the brain and immune cell recruitment, and consequently can be prevented. As we reveal that T. congolense sequestration is a virulence factor, we hypothesise that trypanosome sequestration patterns can determine strain virulence, and thus the risk of disease severity. For now, the translation potential of our findings is large as they expose possible drug treatment strategies targeting mediators of sequestration and/or immunomodulators (such as the FDA-approved LFA-1/ICAM-1 antagonist lifitegrast (Paton, 2016)), as well as to the design of targeted strategies for vector control and surveillance frequency, when coupled with epidemiological mapping.