Theileria-transformed bovine leukocytes have cancer hallmarks

doi:10.1016/j.pt.2015.04.001

Trends in Parasitology

Volume 31, Issue 7, July 2015, Pages 306-314

https://doi.org/10.1016/j.pt.2015.04.001 Get rights and content

Highlights

•
Increased international attention to food security has raised the focus on pathogens of livestock, such as Theileria.
•
Some species of Theileria induce host phenotypes shared with cancer cells.
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Understanding Theileria–host interactions can reveal novel chemotherapeutics for treating Theileria infection.

The genus Theileria includes tick-transmitted apicomplexan parasites of ruminants with substantial economic impact in endemic countries. Some species, including Theileria parva and Theileria annulata, infect leukocytes where they induce phenotypes that are shared with some cancers, most notably immortalization, hyperproliferation, and dissemination. Despite considerable research into the affected host signaling pathways, the parasite proteins directly responsible for these host phenotypes remain unknown. In this review we outline current knowledge on the manipulation of host cells by transformation-inducing Theileria, and we propose that comparisons between cancer biology and host–Theileria interactions can reveal chemotherapeutic targets against Theileria-induced pathogenesis based on cancer treatment approaches.

Section snippets

Theileria-induced bovine immune cell transformation

Of the estimated 1.2–10 million species in the phylum Apicomplexa, only ∼6000 have been described [1]. Almost all are intracellular parasites of vertebrate and invertebrate hosts, but the degree of diversity amongst these species is astounding. They have complex life cycles with diverse morphologies and are distributed over much of the globe. A member of the class Hematozoa, the genus Theileria includes tick-transmitted parasites of wild and domestic ruminants that cause a substantial economic

Phenotypes Theileria-infected immune cells share with cancer cells

Despite many well-characterized differences among them, all cancer types share a defined set of phenotypes [13]. Several of these properties are also observed during Theileria infection.

Differences between Theileria-infected bovine cells and cancer cells

In contrast to the phenotypes already reviewed, Theileria-transformed bovine cell proliferation may lack some of the characteristics of cancer cells. Alternatively, the relevant evidence may have yet to be uncovered. Two such phenotypes are the evasion of growth suppression and a breakdown in genomic integrity.

Multigene families

A mesmerizing question persists in the study of Theileria–host interactions: which parasite molecules (proteins, lipids, RNA, other) are required for, or contribute to, these cancer-like phenotypes? Because these parasites induce an acute infection in cattle, one might expect that interactions with host signaling ‘hubs’ play a crucial role in transformation, such as NF-κB [93]. Scale is a primary reason why this matter remains unresolved: while viral genomes tend to be ∼10³ to 10⁵ base pairs in

Concluding remarks

Theileria parasites bind the host mitotic spindle to maintain an approximately 1:1 host-to-parasite ratio, and the proliferation of infected cells is rapid and unchecked. Therefore, it is not surprising that some Theileria species have evolved mechanisms to directly modify host signaling pathways similarly to some cancers 34, 35. We propose that each of the hallmarks that Theileria transformation shares with some cancer cells represents an opportunity for insights into host pathogenesis (Box 1)

Acknowledgments

We thank Drs Wendy Brown, Donald Knowles, and Vish Nene for valuable comments on the manuscript. This work was supported by the US Department of Agriculture (Scientific Cooperative Agreement #58-5348-4-013). This study was also made possible by the support of the American People through the US States Agency for International Development (USAID). The contents of this study are the sole responsibility of authors and do not necessarily reflect the views of USAID or the US Government.

Glossary

Autophagy: a process whereby cells degrade intracellular components to promote their own survival in response to cellular stress.
Classical dendritic cells: leukocytes that sense tissue injury, capture antigens, and present those antigens to T lymphocytes to induce immunity to foreign antigens and enforce tolerance to self-antigens.
Fas ligand: a protein that binds the Fas receptor and induces apoptosis upon binding, a mechanism used by cytotoxic T lymphocytes to induce apoptosis in target cells.

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Theileria annulata subtelomere-encoded variable secreted protein-TA05560 interacts with bovine RNA binding motif protein 39 (RBM39)
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Theileria annulata is the only eukaryotic pathogen able to transform bovine leukocytes, including B cells, macrophages and dendritic cells. T. annulata-transformed cells exhibit several cancer-like phenotypes, such as hyperproliferation, immortalization and dissemination. Although several parasite factors involved in bovine cell transformation have been explored, the roles of subtelomere-encoded variable secreted proteins (SVSPs) of the parasite in host-cell interactions are largely unknown. In the present study, the target molecule TA05560, a member of the SVSP multigene family of T. annulata, was identified at the mRNA level during different life cycles through a quantitative real-time PCR assay, and the subcellular distribution of TA05560 was examined via confocal microscopy. The results showed that the parasite molecule TA05560 was transcribed mainly in the schizont stage of T. annulata infection, and the protein was distributed in the nucleus and cytoplasm of the parasitized cells. The potential host cell proteins that interact with TA05560 were screened using the yeast two-hybrid system, and the direct interaction between TA05560 and its prey protein, Bos taurus RNA binding motif protein 39 (RBM39) was further identified in HEK293T cells by using confocal microscopy, coimmunoprecipitation and bimolecular fluorescence complementation assays. Moreover, the interaction between TA05560 and its host protein was observed in T. annulata-infected cells via confocal microscopy. Therefore, our study is the first to show that the T. annulata-secreted TA05560 protein directly binds to both the exogenous and endogenous host cell molecule RBM39, laying the foundation for exploring host-parasite interactions and understanding the transformation mechanisms induced by T. annulata and other transforming parasites.
Hijacking of GPCRs and RTKs by pathogens
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Pathogens exploit multiple cellular and molecular pathways in the host organisms for their entry, survival and dissemination. The cell surface receptors such as G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) constitute the targets of many pathogens. This is due to the ubiquitous expression of these two receptor families in the organism and their pivotal role in various cellular and physiological processes. At the molecular level, receptor hijacking implies either direct or indirect interactions between pathogens' effectors or toxins with GPCRs and RTKs at the cell surface thereby interfering with their activation and their downstream signaling pathways inside the host cells. As a result, the pathogens manipulate and redirect GPCR/RTK-mediated signaling pathways and different aspects of cell function for their benefit. The review presents a compilation of the major examples of pathogen infections where GPCRs and RTKs and their related intracellular signaling pathways are targeted. This provides a molecular basis for pathogens hijacking cell signaling and their virulence. Our understanding of such complex host-pathogen interactions at the molecular level will open new opportunities to develop new prophylactic and therapeutic approaches against infections. In this context, the pharmacological targeting of GPCRs and RTKs may be a promising approach.
A single exon-encoded Theileria parva strain Muguga cysteine protease (ThpCP): Molecular modelling and characterisation
2023, Biochimie
Citation Excerpt :
The cysteine protease inhibitors E64d and ALLN inhibited merozoite growth in vitro, showing the importance of these enzymes in parasite survival [21]. Furthermore, it is important to note that T. parva also infects lymphocytes and has a complex lifecycle in its host were it exhibits cancer-like symptoms [78]; hence this cysteine protease may have other functions which are not demonstrated by its orthologs. The relevance of papain-like cysteine proteases in cancer has been established [79] and this raises the question of what role Theileria parva cysteine proteases play in maintaining the cancer-like phenotype [80] induced by parasite infection.
The tick-transmitted apicomplexan Theileria parva causes East Coast fever, a bovine disease of great economic and veterinary importance in Africa. Papain-like cysteine proteases play important roles in protozoan parasite host cell entry and egress, nutrition and host immune evasion. This study reports the identification and characterisation of a T. parva strain Muguga cathepsin L-like (C1A subfamily) cysteine protease (ThpCP). Molecular modelling confirmed the papain-like fold of ThpCP, hydrophobic character of the S2 substrate binding pocket and non-covalent interaction between the pro- and catalytic domains preceding low pH autoactivation. ThpCP was recombinantly expressed in a protease deficient E. coli (Rosetta (DE3)pLysS strain) expression host as a 46 kDa proenzyme. Following Ni-chelate affinity chromatography and acidification, the 27 kDa mature ThpCP was purified by cation-exchange chromatography. Purified ThpCP hydrolysed typical cathepsin L substrates N-α-benzyloxycarbonyl (Z)-Phe-Arg-7-amino-4-methyl-coumarin (AMC) (k_cat/K_m = 4.49 × 10⁵ s⁻¹M⁻¹) and Z-Leu-Arg-AMC (k_cat/K_m = 4.20 × 10⁵ s⁻¹M⁻¹), but showed no activity against the cathepsin B-selective substrate Z-Arg-Arg-AMC. Recombinant ThpCP was active over a broad pH range from pH 4.5 to 7.5, thereby showing potential activity in the acidic parasite food vacuole and close to neutral pH of the host lymphocyte cytoplasm. Recombinant ThpCP was inhibited by the cysteine protease inhibitors E64, iodoacetate, leupeptin, chymostatin, Z-Phe-Ala-diazomethylketone (DMK) and Z-Phe-Phe-DMK and hydrolysed bovine proteins: haemoglobin, immunoglobulin G, serum albumin and fibrinogen as well as goat IgG at pH 6 and 7. Functional expression and characterisation of Theileria cysteine proteases should enable high throughput screening of cysteine protease inhibitor libraries against these proteases.
Longitudinal transcriptome analysis of cattle infected with Theileria parva
2022, International Journal for Parasitology
Citation Excerpt :
This has been associated with production of certain cytokines that mediate this process, in addition to changes in the transcription factors involved in regulation of the cell cycle (Eichhorn et al., 1990; Dobbelaere et al., 2000; Heussler et al., 2001; Tretina et al., 2020). It has been proposed that a better understanding of host-Theileria interactions may identify cancer drugs that can be co-opted to treat Theileria infection as well as, potentially, provide insights into the shared mechanisms underlying cellular immortalization (Tretina et al., 2015). Here, we characterise the transcriptional response in cattle across the course of natural infection with buffalo-derived T. parva.
The apicomplexan cattle parasite Theileria parva is a major barrier to improving the livelihoods of smallholder farmers in Africa, killing over one million cattle on the continent each year. Although exotic breeds not native to Africa are highly susceptible to the disease, previous studies have illustrated that such breeds often show innate tolerance to infection by the parasite. The mechanisms underlying this tolerance remain largely unclear. To better understand the host response to T. parva infection we characterised the transcriptional response over 15 days in tolerant and susceptible cattle (n = 29) naturally exposed to the parasite. We identify key genes and pathways activated in response to infection as well as, importantly, several genes differentially expressed between the animals that ultimately survived or succumbed to infection. These include genes linked to key cell proliferation and infection pathways. Furthermore, we identify response expression quantitative trait loci containing genetic variants whose impact on the expression level of nearby genes changes in response to the infection. These therefore provide an indication of the genetic basis of differential host responses. Together these results provide a comprehensive analysis of the host transcriptional response to this under-studied pathogen, providing clues as to the mechanisms underlying natural tolerance to the disease.
Deciphering the kinome of Theileria annulata for identification of drug targets and anti-theilerial drug
2022, Ticks and Tick-borne Diseases
Citation Excerpt :
However, reports suggest the development of resistance to this drug in the parasite, which has added more complications to the treatment of this disease (Mhadhbi et al., 2010). Theileria-infected bovine cells share several hallmarks of cancer, such as deregulation of energetic metabolism, resistance to apoptosis, uncontrolled proliferation, and acquisition of an invasive phenotype (Tretina et al., 2015). Various protein kinases are upregulated in many cancer cells, and studies have shown that protein kinases are promising targets in cancer therapy (Cicenas and Raciene, 2021; Cicenas et al., 2018).
Tropical theileriosis is one of the major parasitic diseases of ruminants. It is a tick-borne disease caused by an apicomplexan parasite, Theileria annulata. In the infected cells, these parasites induce phenotypes similar to cancerous cells. Among the most critical changes induced by the parasite are immortalization, hyperproliferation, and dissemination. The proliferative signal in the T. annulata transformed cells are provided by different kinases such as mitogen-activated protein kinases, SRC family kinases, casein kinase-2, and phosphatidylinositide 3-kinase. Deregulation of protein kinases in cancer is also well known. Targeting protein kinases in a cancerous cell is one of the most common methods in cancer therapy. Here, we revisited the kinome of T. annulata and studied its evolutionary relationship with other piroplasms. This analysis revealed that T. annulata kinome encodes 54 protein kinases. Based on our analysis, 12 of these 54 kinases were identified for the first time in the T. annulata proteome. Three protein kinases, TA16570, TA09820, and TA07000, had <40% identity with Bos taurus and >40% identity with the previously identified potential drug targets present in the Therapeutic Target Database (TTD). These 3 proteins were predicted to be essential for the survival of T. annulata and were selected as drug targets. Screening these drug targets in the Protein Kinase Inhibitor Database (PKID) led to shortlisting of 5 drugs. Only Dabrafenib, out of these 5 drugs, could bind to the ATP binding site (in silico) of the Calcium Dependent Protein Kinase 3 of both T. annulata and Theileria parva. Further, dabrafenib could inhibit the proliferation of T. annulata infected bovine leucocytes in 6 days proliferation assay with the IC₅₀ value of 0.66 µM. Also, this drug did not have a cytotoxic effect on bovine peripheral blood mononuclear cells. In summary, the analysis of T. annulata kinome led to the identification of dabrafenib as a potential drug for treating theileriosis.
MMV560185 from pathogen box induces extrinsic pathway of apoptosis in Theileria annulata infected bovine leucocytes
2022, International Journal for Parasitology: Drugs and Drug Resistance
Citation Excerpt :
Tropical theileriosis, transmitted by the tick of Hyalomma anatolicum and other Hyalomma species, is one of the most important tick-borne diseases in Asia, North Africa, and Southern Europe that causes huge economic losses (Noval et al., 1992). Bovine cells infected with Theileria parasite share several hallmarks of cancer such as deregulation of energetic metabolism, resistance to apoptosis, uncontrolled proliferation, and acquiring an invasive phenotype (Tretina et al., 2015). The untreated animal would die within 3–4 weeks post-infection in the acute disease conditions.
Tropical theileriosis is a lymphoproliferative disease caused by the intracellular schizonts of Theileria annulata, an apicomplexan parasite. It causes severe infection in cattle and the untreated cattle would possibly die within 3–4 weeks of infection. The chemotherapy for this disease is largely dependent on the use of hydroxynaphthoquinone, namely buparvaquone. There have been reports recently of the development of resistance against this drug in T. annulata. Hence, identification of new drug molecule(s) or repurposing of existing drug molecule(s) against T. annulata is quite important. Here, we present the screening of 400 compounds included in the open-access Pathogen box from Medicine for Malaria Venture (MMV) to discover the novel compounds with potential inhibitory activity against T. annulata infected bovine leucocytes. We identified two compounds, MMV000062 and MMV560185, with IC₅₀ values of 2.97 μM and 3.07 μM, respectively. MMV000062 and MMV560185 were found non-toxic to BoMac cells with CC₅₀ values 34 μM and > 100 μM, respectively. The therapeutic indices of these compounds, MMV000062 and MMV560185, were calculated as more than 33 and 11, respectively. Further, it was observed that the parasite-infected cells under long-term culture were unable to recover with these compounds. We further deciphered that MMV560185 kills the infected cell by activation of TNFR-1 mediated extrinsic pathway of the apoptosis. The phenotypic characteristics of apoptosis were confirmed by Transmission Electron Microscopy. Our results suggest that it may be possible to develop MMV560185 further for chemotherapeutics of tropical theilerosis.

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Trends in Parasitology

ReviewTheileria-transformed bovine leukocytes have cancer hallmarks

Highlights

Section snippets

Theileria-induced bovine immune cell transformation

Phenotypes Theileria-infected immune cells share with cancer cells

Differences between Theileria-infected bovine cells and cancer cells

Multigene families

Concluding remarks

Acknowledgments

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Enhancing the Effectiveness of Sustainability Partnerships Summary of a Workshop

The transforming parasite Theileria co-opts host cell mitotic and central spindles to persist in continuously dividing cells

PLoS Biol.

Theileria annulata and T. parva infect and transform different bovine mononuclear cells

Immunology

Genome sequence of Theileria parva, a bovine pathogen that transforms lymphocytes

Science

Comparative genome analysis of three eukaryotic parasites with differing abilities to transform leukocytes reveals key mediators of Theileria-induced leukocyte transformation

MBio

Clinicopathological findings of a natural outbreak of Theileria annulata in cattle: an emerging disease in southern Iran

Parasitol. Res.

Common markers of proliferation

Nat. Rev. Cancer

The role of senescence and immortalization in carcinogenesis

Carcinogenesis

OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes

PLoS Pathog.

Activation and inhibition of lymphocytes by costimulation

J. Clin. Invest.

Theileria parva infection induces autocrine growth of bovine lymphocytes

Proc. Natl. Acad. Sci. U.S.A.

Is interleukin 2 necessary for the autocrine proliferation of Theileria-infected bovine cells?

Parasitol. Res.

Effects of gamma interferon, tumor necrosis factor alpha, and interleukin-2 on infection and proliferation of Theileria parva-infected vovine lymphoblasts and production of interferon by parasitized Cells

Infect. Immun.

Biological and biochemical characterization of bovine interleukin 2. Studies with cloned bovine T cells

J. Immunol.

The role of interleukin 2 (IL 2) in the proliferation of Theileria annulata-infected bovine lymphocytes

Parasitol. Res.

Interferon production by Theileria annulata-transformed cell lines is restricted to the beta family

Parasite Immunol.

Intracellular Theileria annulata promote invasive cell motility through kinase regulation of the host actin cytoskeleton

PLoS Pathog.

A tumour necrosis factor alpha autocrine loop contributes to proliferation and nuclear factor-κB activation of Theileria parva-transformed B cells

Cell. Microbiol.

Theileria parasites secrete a prolyl isomerase to transform host leukocytes

Nature

Techniques for the generation, cloning, and characterization of bovine cytotoxic T cells specific for the protozoan Theileria parva

J. Tissue Cult. Methods

Telomerase directly regulates NF-kappaB-dependent transcription

Nat. Cell Biol.

Telomerase and cancer therapeutics

Nat. Rev. Cancer

A bovine lymphosarcoma cell line infected with Theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

PLoS ONE

Modulation of activation-associated host cell gene expression by the apicomplexan parasite Theileria annulata

Review
Theileria-transformed bovine leukocytes have cancer hallmarks