SUMMARYPathogenic animal trypanosomes affecting livestock have represented a major constraint to agricultural development in Africa for centuries, and their negative economic impact is increasing in South America and Asia. Chemotherapy and chemoprophylaxis represent the main means of control. However, research into new trypanocides has remained inadequate for decades, leading to a situation where the few compounds available are losing efficacy due to the emergence of drug-resistant parasites. In this review, we provide a comprehensive overview of the current options available for the treatment and prophylaxis of the animal trypanosomiases, with a special focus on the problem of resistance. The key issues surrounding the main economically important animal trypanosome species and the diseases they cause are also presented. As new investment becomes available to develop improved tools to control the animal trypanosomiases, we stress that efforts should be directed towards a better understanding of the biology of the relevant parasite species and strains, to identify new drug targets and interrogate resistance mechanisms.

Gastrointestinal disease caused by the apicomplexan parasite Cryptosporidium parvum is one of the most important diseases of young ruminant livestock, particularly neonatal calves. Infected animals may suffer from profuse watery diarrhoea, dehydration and in severe cases death can occur. At present, effective therapeutic and preventative measures are not available and a better understanding of the host–pathogen interactions is required. Cryptosporidium parvum is also an important zoonotic pathogen causing severe disease in people, with young children being particularly vulnerable. Our knowledge of the immune responses induced by Cryptosporidium parasites in clinically relevant hosts is very limited. This review discusses the impact of bovine cryptosporidiosis and describes how a thorough understanding of the host–pathogen interactions may help to identify novel prevention and control strategies.

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Cattle are an economically important domestic animal species. In vitro 2D cultures of intestinal epithelial cells or epithelial cell lines have been widely used to study cell function and host–pathogen interactions in the bovine intestine. However, these cultures lack the cellular diversity encountered in the intestinal epithelium, and the physiological relevance of monocultures of transformed cell lines is uncertain. Little is also known of the factors that influence cell differentiation and homeostasis in the bovine intestinal epithelium, and few cell-specific markers that can distinguish the different intestinal epithelial cell lineages have been reported. Here we describe a simple and reliable procedure to establish in vitro 3D enteroid, or “mini gut”, cultures from bovine small intestinal (ileal) crypts. These enteroids contained a continuous central lumen lined with a single layer of polarized enterocytes, bound by tight junctions with abundant microvilli on their apical surfaces. Histological and transcriptional analyses suggested that the enteroids comprised a mixed population of intestinal epithelial cell lineages including intestinal stem cells, enterocytes, Paneth cells, goblet cells and enteroendocrine cells. We show that bovine enteroids can be successfully maintained long-term through multiple serial passages without observable changes to their growth characteristics, morphology or transcriptome. Furthermore, the bovine enteroids can be cryopreserved and viable cultures recovered from frozen stocks. Our data suggest that these 3D bovine enteroid cultures represent a novel, physiologically-relevant and tractable in vitro system in which epithelial cell differentiation and function, and host–pathogen interactions in the bovine small intestine can be studied.Electronic supplementary materialThe online version of this article (10.1186/s13567-018-0547-5) contains supplementary material, which is available to authorized users.

We describe 2 spatially distinct foci of human African trypansomiasis in eastern Uganda. The Tororo and Soroti foci of Trypanosoma brucei rhodesiense infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and hostimmune response. In particular, infections with the Tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage and higher plasma interferon (IFN)-␥ concentration, compared with those with the Soroti genotype. We propose that the magnitude of the systemic IFN-␥ response determines the time at which infected individuals develop central nervous system infection and that this is consistent with the recently described role of IFN-␥ in facilitating blood-brain barrier transmigration of trypanosomes in an experimental model of infection. The identification of trypanosome isolates with differing disease progression phenotypes provides the first field-based genetic evidence for virulence variants in T. brucei rhodesiense.

SummaryAntigenic variation is an immune evasion strategy that has evolved in viral, bacterial and protistan pathogens. In the African trypanosome this involves stochastic switches in the composition of a variant surface glycoprotein (VSG) coat, using a massive archive of silent VSG genes to change the identity of the single VSG expressed at a time. VSG switching is driven primarily by recombination reactions that move silent VSGs into specialized expression sites, though transcription-based switching can also occur. Here we discuss what is being revealed about the machinery that underlies these switching mechanisms, including what parallels can be drawn with other pathogens. In addition, we discuss how such switching reactions act in a hierarchy and contribute to pathogen survival in the face of immune attack, including the establishment and maintenance of chronic infections, leading to host-host transmission.

16 Animal African trypanosomiasis (AAT), caused by Trypanosoma congolense and 17Trypanosoma vivax, remains one of the most important livestock diseases in sub-18 Saharan Africa, particularly affecting cattle. Despite this, our detailed knowledge 19 largely stems from the human pathogen T. brucei and mouse experimental 20 models. In the post-genomic era the genotypic and phenotypic differences 21 between the AAT-relevant species of parasite or host and their 'model organism' 22 counterparts are increasingly apparent. We aim to outline the timeliness and 23 advantages of increasing the research focus on both the clinically relevant 24 parasite and host species -improved tools and resources for both have been 25 developed in recent years. We propose that this shift of emphasis will improve 26 our ability to efficiently develop tools to combat AAT. 27 congolense and Trypanosoma vivax, our specific knowledge of the biology of 36 these pathogens is dramatically outweighed by that for Trypanosoma brucei, 37 variants of which cause HAT. Additionally, information on the host response, 38 particularly immunological processes, to these two AAT pathogens in the 39 economically and clinically relevant host -cattle -is scanty compared to the data 40 generated using mouse models (there is a lack of data overall relating to T. vivax 41 as most T. vivax strains do not grow in mice). 42In this article we outline the timeliness and benefits of increasing the research 43 emphasis on both the clinically relevant parasites and host species -recent 44 research developments have resulted in significantly improved tools and 45 resources. We contend that an increased emphasis on furthering our 46 understanding through the use of experimental models that incorporate both T. 47 congolense, T. vivax and the bovine host will result in more efficient development 48 of useful tools to combat AAT. 49 50 AAT -one disease, multiple causative agents 51 AAT is often treated as a single 'disease' but one of several factors in the 52 variation in clinical presentation is that AAT is caused by multiple species and 53 strains of trypanosomes, and often mixed infections. While the most 54 economically important are T. congolense and T. vivax, T. b. evansi is a significant 55 pathogen in cattle, and T. brucei s.l. is found in cattle, although it probably has a 56 minor role in pathogenesis. Additionally, within the parasite species, genetic 57 variation results in different clinical outcomes and relevance to disease in cattle, 58exemplified by greater pathogenicity of T. b. evansi compared with T. b. brucei, 59 and of T. congolense Savannah compared with T. congolense Forest or Kilifi 60 (reviewed in [3, 4] where comparative analyses between these species and T. brucei [8, 9] has 79 indicated some stark, and perhaps unexpected, differences. 80 81 Antigenic variation 82African trypanosomes are a paradigmal organism for antigenic variation [10, 11]. 83Trypanosomes express this phenotype through the variant surface glycoprotein 84 (VSG), which...

Pathogens often persist during infection because of antigenic variation in which they evade immunity by switching between distinct surface antigen variants. A central question is how ordered appearance of variants, an important determinant of chronicity, is achieved. Theories suggest that it results directly from a complex pattern of transition connectivity between variants or indirectly from effects such as immune cross-reactivity or differential variant growth rates. Using a mathematical model based only on known infection variables, we show that order in trypanosome infections can be explained more parsimoniously by a simpler combination of two key parasite-intrinsic factors: differential activation rates of parasite variant surface glycoprotein (VSG) genes and densitydependent parasite differentiation. The model outcomes concur with empirical evidence that several variants are expressed simultaneously and that parasitaemia peaks correlate with VSG genes within distinct activation probability groups. Our findings provide a possible explanation for the enormity of the recently sequenced VSG silent archive and have important implications for field transmission.mathematical model ͉ Typanosoma brucei ͉ variant surface glycoprotein ͉ switching ͉ hierarchy