Mutations in the TaPIN1 peptidyl prolyl isomerase gene in Theileria annulata parasites isolated in Sudan

Bashir Salim,Elisha Chatanga,Guillaume Jannot,Ehab Mossaad,Ryo Nakao,Jonathan B Weitzman

doi:10.1016/j.ijpddr.2019.11.001

Bashir Salim, Elisha Chatanga + Show 4 more

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The tick-borne parasite Theileria annulata is the causative agent of tropical theileriosis or Mediterranean theileriosis. Infection of bovine leukocytes by the obligate intracellular parasites induces proliferative and invasive phenotypes associated with activated signaling pathways. The transformed phenotypes of infected cells are reversible by treatment with the theilericidal drug buparvaquone. Recent reports of resistance to buparvaquone in Africa and Asia highlight the need to investigate the mechanisms and prevalence of drug resistance. We screened 67 T. annulata isolates from Sudan to investigate mutations in the T. annulata prolyl isomerase I gene (TaPIN1). The secreted TaPin1 interacts with host proteins to induce pathways driving oncogenic transformation and metabolic reprogramming. We found an Alanine-to-Proline mutation at position 53 (A53P) in the catalytic loop that was previously found in Tunisian drug-resistant samples. This is the first study reporting independent confirmation of the A53P mutation in geographically isolated samples. We found several additional mutations in the predicted N-terminal signal peptide that might affect TaPin1 processing or targeting. We found that many parasites also share mutations in both the TaPIN1 and the cytochrome b genes, suggesting that these two genes represent important biomarkers to follow the spread of resistance in Africa, the Middle East and Asia.

Highlights

Bovine Tropical Theileriosis (BTT) is a lymphoproliferative, tickborne disease of cattle caused by the protozoan parasite Theileria annulata
We aligned the amino acid sequences corresponding to the TaPin1 protein from the 67 Sudanese isolates and compared with the annotated, reference sequence for T. annulata PIN1 PPlase (TA18945)
Sixteen of the isolate sequences had a M1L mutation and two of the sequences had a STOP143Y mutation. These mutations would likely result in the loss of TaPin1 protein, so we cannot speculate on their functional relevance

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Introduction

Bovine Tropical Theileriosis (BTT) is a lymphoproliferative, tickborne disease of cattle caused by the protozoan parasite Theileria annulata. The intracellular Theileria parasites transform mammalian host cells by inducing cancer-like phenotypes, such as immortalization, dissemination and hyper-proliferation of the infected leukocytes (Morrison, 2009). The molecular mechanisms underlying host cell transformation by Theileria parasites likely involve changes in signaling pathways that affect the host epigenome and cause changes in host cell gene/protein expression and activation (Cheeseman and Weitzman, 2015; Lüder et al, 2009; Morrison, 2009). Theileria infection of bovine leukocytes modulates oncogenic signaling pathways such as JNK and IKK (Heussler et al, 2002; Lizundia et al, 2007) and activation of host transcription factors such as c-Myc, AP-1 and HIF-1α (Chaussepied et al, 1998; Dessauge et al, 2005; Marsolier et al, 2013; Medjkane et al, 2014; Metheni et al, 2015). Theileria parasites interact with host microtubules and recruit end-binding protein 1 to the parasite surface (von Schubert et al, 2010; Woods et al, 2013)

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