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

Abstract

Background Babesia 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. Results Two 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. Conclusions This 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.

Pathogenesis of Anemia in Canine Babesiosis: Possible Contribution of Pro-Inflammatory Cytokines and Chemokines—A Review

“…The same studies showed similar transient increases in CXCL1-like concentration four days after infection, followed by decrease to a low level [ 27 , 93 ]. According to Smith et al [ 93 ], increased production of IL-10 may be a possible explanation for a decrease in IL-8. This speculation is supported by the results of Galán et al [ 30 ], who observed a negative correlation between IL-8 and hematocrit and increased levels of this chemokine even on the seventh day of the disease.…”

“…Surprisingly, IL-8 levels have previously been reported as lower in dogs naturally infected with B. rossi in comparison to healthy dogs [ 28 ]. A possible explanation for this observation was missing the peak chemokine concentration, and later studies on experimental B. rossi infections have confirmed this supposition [ 27 , 93 ]. In dogs infected with B. gibsoni , both an increase and a decrease in IL-8 levels have been observed [ 94 ], while a transient increase of CXCL1-like has been reported, similar to IL-8, in B. canis infection.…”

“…As mentioned earlier, experimental studies on B. rossi infections showed a transient increase of IL-8 four days after infection, when the level of parasitemia was high. The level of IL-8 subsequently decreases, but not to low values [ 27 , 93 ]. The same studies showed similar transient increases in CXCL1-like concentration four days after infection, followed by decrease to a low level [ 27 , 93 ].…”

“…The level of IL-8 subsequently decreases, but not to low values [ 27 , 93 ]. The same studies showed similar transient increases in CXCL1-like concentration four days after infection, followed by decrease to a low level [ 27 , 93 ]. According to Smith et al [ 93 ], increased production of IL-10 may be a possible explanation for a decrease in IL-8.…”

“…Increased concentrations of this cytokine have been demonstrated both during bovine and murine babesiosis and human malaria [ 160 , 213 , 214 ]. Moreover, upregulation of the expression of genes related to erythropoesis, heme, haptoglobin, peroxiredoxin 2 (antioxidant enzyme), arachidonate 15-lipoxygenase, and cytosolic phospholipase 2 syntheses, and related to positive regulation of IL-1β production and IFN-γ signaling, have been observed in B. rossi -infected dogs during disease progression [ 93 ].…”