Periodic Reporting for period 4 - FatTryp (Exploring the hidden life of African trypanosomes: parasite fat tropism and implications for disease)
Période du rapport: 2023-02-01 au 2024-07-31
This project focuses on a disease called African trypanosomiasis, or sleeping sickness, caused by a parasite called Trypanosoma brucei. This disease is a major health problem in sub-Saharan Africa, with nearly all untreated cases being fatal. Although we know a lot about the parasite when it colonizes the blood, previous findings show that it also lives in body fat, where it may hide and cause problems like treatment relapses, weight loss, and changes in metabolism. Our goal was to learn more about how and why the parasite adapts to fat tissue and what that means for people affected by the disease.
African sleeping sickness affects both people and animals, making it a serious health threat in parts of Africa. Even when treated, some patients experience relapses where the disease comes back, possibly because parasites are hiding in the body fat and returning to the bloodstream later. By studying how parasites survive in fat, our studies could lead to improvements of treatment options and reduce the chance of relapse. This knowledge could improve outcomes for patients and reduce the burden of this deadly disease on communities.
Our first aim was to understand how the parasite adapts to fat tissue. We characterized what changes occur when the parasite colonizes the fat, which involve the generation of a persistent-like parasite form. We initiated genetic screens to identify parasite genes required for adaptation in these two environments. By studying these genes, we hope to identify Achilles heel of this parasite and stop tissue colonization.
Our second aim was to determine the impact of parasites in fat on disease and the host. We discarded the possibility that the adipose tissue is an immune safe haven. In contrast, parasite infection induces lipid breakdown in the host via ATGL-dependent lipolysis in adipocytes, leading to loss of fat mass. Surprisingly, lipolysis appears to be a host protective mechanism.
This project represented a novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we gained more granular information on clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings may help elucidate disease mechanisms relevant to other infectious diseases.
African sleeping sickness affects both people and animals, making it a serious health threat in parts of Africa. Even when treated, some patients experience relapses where the disease comes back, possibly because parasites are hiding in the body fat and returning to the bloodstream later. By studying how parasites survive in fat, our studies could lead to improvements of treatment options and reduce the chance of relapse. This knowledge could improve outcomes for patients and reduce the burden of this deadly disease on communities.
Our first aim was to understand how the parasite adapts to fat tissue. We characterized what changes occur when the parasite colonizes the fat, which involve the generation of a persistent-like parasite form. We initiated genetic screens to identify parasite genes required for adaptation in these two environments. By studying these genes, we hope to identify Achilles heel of this parasite and stop tissue colonization.
Our second aim was to determine the impact of parasites in fat on disease and the host. We discarded the possibility that the adipose tissue is an immune safe haven. In contrast, parasite infection induces lipid breakdown in the host via ATGL-dependent lipolysis in adipocytes, leading to loss of fat mass. Surprisingly, lipolysis appears to be a host protective mechanism.
This project represented a novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we gained more granular information on clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings may help elucidate disease mechanisms relevant to other infectious diseases.
In Aim1, using a combination of mathematical modelling and cellular tools, we discovered that in the adipose tissue trypanosomes acquire persister-like behavior: they replicate more slowly, synthesize proteins at a lower rate and switch their metabolism. We initiated genetic screens to identify parasite genes required for adaptation in these two environments. By studying these genes, we hope to identify Achilles heel of this parasite and stop tissue colonization.
In Aim 2, we have investigated how parasites cross the vasculature to colonize the fat tissue. We found that parasite extravasation is an active process and interactions of parasites with endothelial cell receptors appear to be necessary for tissue tropism. In this aim we also investigated the association between Trypanosomiasis and emaciation. We found that a trypanosoma infection activates lipolysis of triglycerides in adipose tissue. Genetic ablation of this pathway prevents loss of fat mass, but increased disease severity. The triggers of lipolysis appear to multiple and include both soluble factors dependent of an immune response and a direct effect via molecules secreted by the parasite.
These results have a significant potential for exploitation. The identification of parasite-derived lipolytic factors as mediators of fat metabolism opens the door to the development of novel therapeutics, not only for trypanosomiasis but also for metabolic diseases. Additionally, the insights into endothelial interactions can guide the development of drugs that target tissue-specific parasite reservoirs, which could improve treatment efficacy.
The project’s results were disseminated via high-impact scientific publications in journals such as Nature Microbiology and Cell Reports and presentations at major conferences, including the Kinetoplastid Molecular Cell Biology (KMCB) meeting and Gordon Conference on Host-Parasite Interactions, where we also engaged with key stakeholders in the field.
In Aim 2, we have investigated how parasites cross the vasculature to colonize the fat tissue. We found that parasite extravasation is an active process and interactions of parasites with endothelial cell receptors appear to be necessary for tissue tropism. In this aim we also investigated the association between Trypanosomiasis and emaciation. We found that a trypanosoma infection activates lipolysis of triglycerides in adipose tissue. Genetic ablation of this pathway prevents loss of fat mass, but increased disease severity. The triggers of lipolysis appear to multiple and include both soluble factors dependent of an immune response and a direct effect via molecules secreted by the parasite.
These results have a significant potential for exploitation. The identification of parasite-derived lipolytic factors as mediators of fat metabolism opens the door to the development of novel therapeutics, not only for trypanosomiasis but also for metabolic diseases. Additionally, the insights into endothelial interactions can guide the development of drugs that target tissue-specific parasite reservoirs, which could improve treatment efficacy.
The project’s results were disseminated via high-impact scientific publications in journals such as Nature Microbiology and Cell Reports and presentations at major conferences, including the Kinetoplastid Molecular Cell Biology (KMCB) meeting and Gordon Conference on Host-Parasite Interactions, where we also engaged with key stakeholders in the field.
This project has lead to three important discoveries that shed new light on how Trypanosoma brucei colonizes the fat tissue. These discoveries go beyond the state fo the art and could lead to new ways to treat and understand this fatal disease.
1. Discovery of fat breakdown as a protective mechanism during infection.
One of our most surprising findings is that the body’s breakdown of fat (called lipolysis) protects against T. brucei infection. Originally, we expected that the fat loss often seen during infection would be harmful to the host, contributing to the severe weight loss associated with the disease. However, we discovered the opposite: this fat breakdown may be a way for the body to protect itself. Our research identified a specific metabolic pathway—called ATGL-dependent lipolysis—that seems to be activated to help the body resist the infection. This new understanding not only changes the way we think about fat loss during infection but also opens up possibilities for studying whether fat breakdown might defend against other diseases, offering a potential pathway for new treatments.
2. Role of blood vessel surface molecules in parasite spread and disease severity.
Our second major finding shows that T. brucei uses specific molecules on the surface of blood vessel cells to help it settle in different body tissues. Using advanced imaging techniques, we observed that T. brucei interacts with certain surface proteins on cells lining blood vessels, such as a protein called CD36, to enter and colonize tissues. This suggests that T. brucei uses these “adhesion molecules” as docking points to help it colonize the fat tissue. Understanding this interaction could open new strategies to prevent the parasite from invading tissues, which in turn could reduce the severity of the disease.
3. Slow-growing parasites in fat as a possible source of drug resistance and relapse:
Our third discovery focuses on the behavior of T. brucei within fat tissue. We found that when T. brucei enters fat, it shifts to a slow-growing state, resulting in a more diverse population of parasites than we see in the bloodstream. This was an unexpected finding, confirmed through advanced techniques like single-cell RNA sequencing. This slow-growing population may play a role in the parasite’s ability to hide from treatment and potentially re-emerge, leading to disease relapses. Understanding how and why T. brucei adopts this slow-growing state in fat tissue could lead to better treatments that target these harder-to-reach parasites, reducing the chance of relapse after treatment.
1. Discovery of fat breakdown as a protective mechanism during infection.
One of our most surprising findings is that the body’s breakdown of fat (called lipolysis) protects against T. brucei infection. Originally, we expected that the fat loss often seen during infection would be harmful to the host, contributing to the severe weight loss associated with the disease. However, we discovered the opposite: this fat breakdown may be a way for the body to protect itself. Our research identified a specific metabolic pathway—called ATGL-dependent lipolysis—that seems to be activated to help the body resist the infection. This new understanding not only changes the way we think about fat loss during infection but also opens up possibilities for studying whether fat breakdown might defend against other diseases, offering a potential pathway for new treatments.
2. Role of blood vessel surface molecules in parasite spread and disease severity.
Our second major finding shows that T. brucei uses specific molecules on the surface of blood vessel cells to help it settle in different body tissues. Using advanced imaging techniques, we observed that T. brucei interacts with certain surface proteins on cells lining blood vessels, such as a protein called CD36, to enter and colonize tissues. This suggests that T. brucei uses these “adhesion molecules” as docking points to help it colonize the fat tissue. Understanding this interaction could open new strategies to prevent the parasite from invading tissues, which in turn could reduce the severity of the disease.
3. Slow-growing parasites in fat as a possible source of drug resistance and relapse:
Our third discovery focuses on the behavior of T. brucei within fat tissue. We found that when T. brucei enters fat, it shifts to a slow-growing state, resulting in a more diverse population of parasites than we see in the bloodstream. This was an unexpected finding, confirmed through advanced techniques like single-cell RNA sequencing. This slow-growing population may play a role in the parasite’s ability to hide from treatment and potentially re-emerge, leading to disease relapses. Understanding how and why T. brucei adopts this slow-growing state in fat tissue could lead to better treatments that target these harder-to-reach parasites, reducing the chance of relapse after treatment.