A recent study offers insights into how the blood-borne parasite that triggers African sleeping sickness in humans and similar illnesses in livestock maintains long-term infections in their hosts. With a mouse model, researchers demonstrated that Trypanosoma brucei effectively engages in a form of hide-and-seek by taking refuge in the tissues of its hosts, which allows it to continually modify its protective outer layer and evade detection by antibodies.
A recent investigation conducted by experts from the Johns Hopkins Bloomberg School of Public Health reveals how the blood-borne parasite responsible for African sleeping sickness in humans and related conditions in cattle and other animals sustains long-term infections. By utilizing a mouse model, the scientists illustrated that Trypanosoma brucei essentially employs a strategy akin to hide-and-seek by establishing residence in the tissues of its hosts, enabling it to frequently alter its protective surface coat and avoid the host’s antibodies.
The findings, published on October 30 in Nature, may pave the way for a better understanding of the immune responses to various pathogens.
African sleeping sickness, also known as human African trypanosomiasis, is a neglected tropical disease that can be fatal if left untreated. Efforts in treatment and tsetse fly control have somewhat mitigated the impact of human African trypanosomiasis, yet T. brucei continues to pose a significant challenge for African agriculture, resulting in the death of approximately three million cattle annually.
The T. brucei parasite is known to frequently alter its outer layer, which consists of countless copies of a single protein known as the variant surface glycoprotein (VSG). When one specific VSG is recognized by the host’s antibody response, the parasite has typically transitioned to a different one that remains unnoticed by the immune system. By switching which variant genes are active, the parasite modifies its appearance sufficiently to dodge the host’s immune reaction for extended periods.
After entering the bloodstream through a tsetse fly bite, the T. brucei parasite also infects areas outside of the blood vessels. The role of this “extravascular” residence for the parasite has been unclear until now. In an effort to enhance understanding of how T. brucei eludes the immune system, researchers employed a specialized RNA sequencing technique to track the various VSG types over time during T. brucei infections in mice.
The researchers found that the vast majority of VSGs emerged in tissues, not in the bloodstream. They also discovered that the immune system clears the parasite more slowly from these tissues. These results indicate that by migrating from the bloodstream to extravascular areas, T. brucei gains significant “breathing room” for generating sufficient VSG variants to endure in hosts over long periods, ensuring ongoing transmission.
“This research lays the groundwork for a novel perspective on immune evasion in T. brucei infections and potentially in other chronic infections,” commented study senior author Monica Mugnier, PhD, an associate professor in the Bloomberg School’s Department of Molecular Microbiology and Immunology.
The lead author of the study, Alexander Beaver, PhD, was a doctoral candidate in Mugnier’s lab during the research.
Spread by the tsetse fly, T. brucei parasites inhabit many regions of sub-Saharan Africa. Numerous wild mammals in Africa carry the parasite without displaying any disease symptoms, thus acting as reservoirs. In humans, as well as in livestock like cattle, sheep, and goats, T. brucei infections can lead to chronic illness, which in advanced stages is characterized by severe fatigue and other neurological issues.
The parasite enters mammalian hosts via the bloodstream when bitten by a tsetse fly, and it typically exits through the same route. The reason T. brucei travels from blood into extravascular areas has remained an open question. In this study, Mugnier and her team utilized their unique VSG-targeted RNA-sequencing method to track the expression of different VSGs over time in T. brucei parasites retrieved from both the blood and tissues of infected mice.
They observed that after an infection persisted for more than a week, the number of detectable VSGs in the tissues of the mice was, on average, several times greater than in the blood. Therefore, the majority of VSG diversity, which is crucial for the pathogen’s ability to avoid the immune system, was found in tissues rather than the blood. This pattern was consistent whether the mice were infected through injection or tsetse fly bites.
When the researchers monitored specific VSGs from the initial infection, they noted that the immune system took significantly longer to clear the parasites bearing these VSGs from the tissues compared to blood. Additionally, when they used genetically modified mice that delayed tissue clearance of the parasite, a corresponding increase in tissue VSG diversity was observed.
Overall, the findings indicate that T. brucei utilizes tissues as relatively sheltered environments where it can persist longer, producing a greater variety of variants and potentially reinfecting the bloodstream with these forms faster than the immune system can counteract.
“Tissues were previously regarded as incidental sites of infection for T. brucei, yet they now seem to play a critical role in sustaining long-term infections for this parasite while the bloodstream may primarily function as a transportation route between tissues and for eventual transmission back into the tsetse fly,” states Mugnier.
This new understanding suggests, she continues, that interrupting T. brucei‘s movement from blood into tissues might be sufficient to allow the immune system to catch up and eliminate the infection, presenting a promising new treatment approach.
Mugnier and her team also theorize that this method of exploiting extravascular spaces might be used by other pathogens, such as the Lyme disease bacterium, to establish chronic infections.
“T. brucei infections could serve as a valuable model for understanding why extravascular spaces are less effective at clearing pathogens and how some pathogens take advantage of that,” Mugnier concludes.
This study was supported by the National Institutes of Health (T32AI007417, T32OD011089, 1K99GM132557-01, DP5OD023065, R01AI58805), the Chan Zuckerberg Initiative, the German Research Foundation, and the European Research Council.
