Abstract
African trypanosomes are single-celled extracellular protozoan parasites transmitted by tsetse fly vectors across sub-Saharan Africa, causing serious disease in both humans and animals. Mammalian infections begin when the tsetse fly penetrates the skin in order to take a blood meal, depositing trypanosomes into the dermal layer. Similarly, onward transmission occurs when differentiated and insect pre-adapted forms are ingested by the fly during a blood meal. Between these transmission steps, trypanosomes access the systemic circulation of the vertebrate host via the skin-draining lymph nodes, disseminating into multiple tissues and organs, and establishing chronic, and long-lasting infections. However, most studies of the immunobiology of African trypanosomes have been conducted under experimental conditions that bypass the skin as a route for systemic dissemination (typically via intraperitoneal or intravenous routes). Therefore, the importance of these initial interactions between trypanosomes and the skin at the site of initial infection, and the implications for these processes in infection establishment, have largely been overlooked. Recent studies have also demonstrated active and complex interactions between the mammalian host and trypanosomes in the skin during initial infection and revealed the skin as an overlooked anatomical reservoir for transmission. This highlights the importance of this organ when investigating the biology of trypanosome infections and the associated immune responses at the initial site of infection. Here, we review the mechanisms involved in establishing African trypanosome infections and potential of the skin as a reservoir, the role of innate immune cells in the skin during initial infection, and the subsequent immune interactions as the parasites migrate from the skin. We suggest that a thorough identification of the mechanisms involved in establishing African trypanosome infections in the skin and their progression through the host is essential for the development of novel approaches to interrupt disease transmission and control these important diseases.
Highlights
African trypanosomiasis has historically been the cause of large outbreaks of human disease, likely contributing to the deaths of millions of people across sub-Saharan Africa in the early twentieth century [1, 2] and inflicting substantial economic damage on the African agriculture industry to this day [3, 4]
African trypanosomes have evolved sophisticated mechanisms to swiftly adapt to rapid changes in their microenvironment, like those encountered by metacyclic trypomastigotes delivered by the tsetse fly in the vertebrate skin when taking a blood meal
It seems plausible that a combination of extrinsic factors, such as those encountered in the skin, exerts a selection pressure for trypomastigotes that are able to overcome these barriers when migrating to nearby lymphatics, leading to the establishment of systemic infections
Summary
African trypanosomiasis has historically been the cause of large outbreaks of human disease, likely contributing to the deaths of millions of people across sub-Saharan Africa in the early twentieth century [1, 2] and inflicting substantial economic damage on the African agriculture industry to this day [3, 4]. Following intradermal (i.d.) inoculation of metacyclic forms, the parasites differentiate into long-slender trypomastigotes that are proliferative and able to establish patent infections in the vertebrate host. African trypanosomes (and T. brucei in particular) actively colonize multiple tissues in the vertebrate host, including the skin. Skin-dwelling parasites functionally and behaviorally adapt to their microenvironment, allowing them to thrive and persist [18, 19] These recent studies demonstrate that there is a previously underappreciated heterogeneity in the population of parasites residing within the vertebrate host, with important implications for understanding the biology of trypanosomes and the way in which the host responds to infection. The mechanisms deployed by trypanosomes to inhabit and migrate from the cutaneous environment, and the interplay between resident skin cells (including immune cells), and trypanosomes during the onset of the infection, remain largely unexplored. We aim to (i) highlight current knowledge on trypanosome establishment of infection in the skin; (ii) examine the interactions between the host immune system and trypanosomes in the skin; (iii) explore the mechanisms of trypanosome migration from the skin toward systemic infection and further transmission; and (iv) discuss the potential of novel therapeutic and intervention strategies being developed as a consequence of these studies
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