Changes in the molecular and functional phenotype of bovine monocytes during Theileria parva infection

Authors: BASTOS, REGINALDO - Washington State University; SEARS, KELLY - Washington State University; DINKEL, KELCEY - Washington State University; KNOWLES, DONALD - Washington State University; Fry, Lindsay

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2019
Publication Date: 11/18/2019
Citation: Bastos, R.G., Sears, K.P., Dinkel, K.D., Knowles, D.P., Fry, L.M. 2019. Changes in the molecular and functional phenotype of bovine monocytes during Theileria parva infection. Infection and Immunity. 87(12). https://doi.org/10.1128/IAI.00703-19.
DOI: https://doi.org/10.1128/IAI.00703-19

Interpretive Summary: Theileria parva is the causative agent of East Coast Fever (ECF), a tick-borne disease that kills over a million cattle each year in sub-Saharan Africa. Currently, there is no way to reliably and objectively assess disease progression and prognosis. Without such correlates of protection and disease, development of vaccines to prevent ECF is severely hindered because subtle differences in protection, or in the immune response following challenge with T. parva, is not possible. Thus, we may be missing indicators of vaccine potential. Furthermore, without objective correlates of protection and disease, direct comparison of different vaccines for ECF is difficult. Our group recently found that the innate immune system plays a key role in the development of ECF. As the innate immune system comprises the earliest response to infection, changes in these cells may provide early indicators of severe disease following T. parva infection. Indeed, in this study, we found that lethal T. parva infection, but not non-lethal infection, results in alterations in innate immune cells known as monocytes, and that these alterations can be used as markers of severe disease development in ECF. This information will be valuable to future vaccine development projects in T. parva and other closely related tick borne diseases of cattle.

Technical Abstract: Theileria parva is the causative agent of East Coast Fever (ECF), a tick-borne disease that kills over a million cattle each year in sub-Saharan Africa. Immune protection against T. parva involves CD8+ cytotoxic T cell response to parasite-infected cells. However, there is currently a paucity of knowledge regarding the role played by innate immune cells in ECF pathogenesis and T. parva control. Here we demonstrate an increase in intermediate monocytes (CD14++CD16+) with a concomitant decrease in the classical (CD14++CD16-) and non-classical (CD14+CD16+) subsets at 12 days post-infection (DPI) during lethal infection, but not during non-lethal T. parva infection. Ex vivo analyses of monocytes demonstrated up-regulation of IL-1ß and TNFa mRNA and increased nitric oxide production during T. parva lethal infection compared to non-lethal infection at 10 DPI. Interestingly, no significant differences in peripheral blood parasite load were observed between lethally and non-lethally infected animals at 12 DPI. In vitro stimulation with T. parva schizont-infected cells or Escherichia coli LPS resulted in significant up-regulation of IL-1ß production by monocytes from lethally infected cattle compared to those from non-lethally infected animals. Strikingly, monocytes from lethally infected animals produced significant amounts of IL-10 mRNA after stimulation with T. parva schizont-infected cells. In conclusion, we demonstrate that T. parva infection leads to alterations in the molecular and functional phenotype of bovine monocytes. Importantly, since these changes primarily occur in lethal infection, they can serve as biomarkers for ECF progression and severity, thereby aiding in the standardization of protection assessment for T. parva candidate vaccines.