To the Skin and Beyond: The Immune Response to African Trypanosomes as They Enter and Exit the Vertebrate Host

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.

Application of single-cell transcriptomics to kinetoplastid research

“…scRNA-seq has been extensively used to analyse the immune response (Chattopadhyay et al ., 2014; Chattopadhyay and Roederer, 2015; Buchholz et al ., 2016; Buchholz and Flossdorf, 2018) and could be applied to study the host response to kinetoplastid infection. Comparison of parasites resident in differing host tissues, such as an invasion of the lymph and blood systems, skin (Capewell et al ., 2016), adipose tissue (Trindade et al ., 2016; Tanowitz et al ., 2017) and brain (Grab and Kennedy, 2008; Kristensson et al ., 2010) by African trypanosomes (Alfituri et al ., 2020), should also be facilitated by scRNA-seq. In the case of T. cruzi , 10–30% of infected individuals will develop chronic Chagas (World Health Organization, 2002), where parasites invade the heart (Bellotti et al ., 1996), and, in infected mice, parasites have been detected in the skeletal muscle, heart, bladder, peripheral nerve, liver, spleen, adrenal gland, brain and adipose tissue (Buckner et al ., 1999).…”

Vector-borne Trypanosoma brucei parasites develop in artificial human skin and persist as skin tissue forms

“…Single-parasite RNAseq revealed an upregulation of two RNA-binding proteins (RBPs), PUF9 and ZC3H20, within 4 hours. These proteins have been shown to be involved in replicative and translational processes (Archer et al, 2009. In addition, we found upregulation of two previously undescribed RBPs, ZC3H35 and ZC3H48, which could well be functional during differentiation of the parasites in the skin.…”

“…The RBPs PUF9 (Tb927.1.2600), ZC3H20 (Tb927.7.2660), ZC3H35 (Tb927.10.12740), and ZC3H48 (Tb927.9.10280) were all upregulated during skin infection (Figure 5 D). PUF9 had been previously identified as important for the progression through the cell cycle (Archer et al, 2009). In a number of publications, ZC3H20 was shown to oscillate throughout the life cycle of T. brucei (Christiano et al, 2017, Vigneron et al, 2020, Cayla et al, 2020, Liu et al, 2020 and to be implicated in the increase of protein translation or in mRNA stability (Erben et al, 2014, Singh et al, 2014.…”

Dermal bacterial LPS-stimulation reduces susceptibility to intradermal Trypanosoma brucei infection

“…4 C). These data imply that ID LPS-treatment may have induced the production of pro-inflammatory mediators such as NO in local CSF1R + MNP, and these may have enhanced their ability to clear the parasites from the infection site 20 . However, it is plausible that the production of trypanosome-derived metabolites such as indolepyruvate may offer some protection against this.…”