Experimental Babesia rossi infection induces hemolytic, metabolic, and viral response pathways in the canine host

Rachel L Smith,Johan P Schoeman,Amelia Goddard,Justin Lack,Andrew Leisewitz,Steven Brooks,Hans Ackerman,Arun Boddapati

doi:10.1186/s12864-021-07889-4

Abstract

BackgroundBabesia rossi is a leading cause of morbidity and mortality among the canine population of sub-Saharan Africa, but pathogenesis remains poorly understood. Previous studies of B. rossi infection were derived from clinical cases, in which neither the onset of infection nor the infectious inoculum was known. Here, we performed controlled B. rossi inoculations in canines and evaluated disease progression through clinical tests and whole blood transcriptomic profiling.ResultsTwo subjects were administered a low inoculum (104 parasites) while three received a high (108 parasites). Subjects were monitored for 8 consecutive days; anti-parasite treatment with diminazene aceturate was administered on day 4. Blood was drawn prior to inoculation as well as every experimental day for assessment of clinical parameters and transcriptomic profiles. The model recapitulated natural disease manifestations including anemia, acidosis, inflammation and behavioral changes. Rate of disease onset and clinical severity were proportional to the inoculum. To analyze the temporal dynamics of the transcriptomic host response, we sequenced mRNA extracted from whole blood drawn on days 0, 1, 3, 4, 6, and 8. Differential gene expression, hierarchical clustering, and pathway enrichment analyses identified genes and pathways involved in response to hemolysis, metabolic changes, and several arms of the immune response including innate immunity, adaptive immunity, and response to viral infection.ConclusionsThis work comprehensively characterizes the clinical and transcriptomic progression of B. rossi infection in canines, thus establishing a large mammalian model of severe hemoprotozoal disease to facilitate the study of host-parasite biology and in which to test novel anti-disease therapeutics. The knowledge gained from the study of B. rossi in canines will not only improve our understanding of this emerging infectious disease threat in domestic dogs, but also provide insight into the pathobiology of human diseases caused by Babesia and Plasmodium species.

Highlights

Babesia rossi is a leading cause of morbidity and mortality among the canine population of subSaharan Africa, but pathogenesis remains poorly understood
Cytokine concentrations increased during infection and recovery GM-CSF, IL6, macrophage chemotactic protein, and Tumor necrosis factor (TNF)
The sequence data are available in the National Center for Biotechnology Information (NCBI) database system

Summary

Introduction

Babesia rossi is a leading cause of morbidity and mortality among the canine population of subSaharan Africa, but pathogenesis remains poorly understood. Previous studies of B. rossi infection were derived from clinical cases, in which neither the onset of infection nor the infectious inoculum was known. We performed controlled B. rossi inoculations in canines and evaluated disease progression through clinical tests and whole blood transcriptomic profiling. A common parasite in wild jackals, is known to cause the most severe disease of all the Babesia species infecting canines [10], and is a leading cause of infectious morbidity and mortality among the susceptible domestic dog population in South Africa [11]. Over the course of several decades, observational studies of naturally-occurring B. rossi infections in canines have led to clinical and pathological descriptions of the disease [12, 13]. The clincal and transcriptomic time course of the disease was unable to be characterized

Methods

Results

Discussion

Conclusion