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

ABSTRACT: 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 were known. Here, we performed controlled B. rossi inoculations in canines and evaluated disease progression through clinical tests and whole blood transcriptomic profiling. Three subjects were administered a low inoculum (104 parasites) while two received a high (109 parasites). Subjects were monitored for 8 consecutive days; anti-parasite treatment 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 pro-inflammatory cytokine storm and metabolic acidosis. Rate of onset and severity were proportional to 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. These findings enhance our understanding of B. rossi pathogenesis, identify novel pathways for interventions to reduce disease severity, and establish a new mammalian model of hemolytic inflammatory disease.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE167201 | GEO | 2021/08/25

REPOSITORIES: GEO

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Project description:Baris Hancioglu, David Swigon & Gilles Clermont. A dynamical model of human immune response to influenza A virus infection. Journal of Theoretical Biology 246, 1 (2007). We present a simplified dynamical model of immune response to uncomplicated influenza A virus (IAV) infection, which focuses on the control of the infection by the innate and adaptive immunity. Innate immunity is represented by interferon-induced resistance to infection of respiratory epithelial cells and by removal of infected cells by effector cells (cytotoxic T-cells and natural killer cells). Adaptive immunity is represented by virus-specific antibodies. Similar in spirit to the recent model of Bocharov and Romanyukha [1994. Mathematical model of antiviral immune response. III. Influenza A virus infection. J. Theor. Biol. 167, 323-360], the model is constructed as a system of 10 ordinary differential equations with 27 parameters characterizing the rates of various processes contributing to the course of disease. The parameters are derived from published experimental data or estimated so as to reproduce available data about the time course of IAV infection in a naïve host. We explore the effect of initial viral load on the severity and duration of the disease, construct a phase diagram that sheds insight into the dynamics of the disease, and perform sensitivity analysis on the model parameters to explore which ones influence the most the onset, duration and severity of infection. To account for the variability and speed of adaptation of the adaptive response to a particular virus strain, we introduce a variable that quantifies the antigenic compatibility between the virus and the antibodies currently produced by the organism. We find that for small initial viral load the disease progresses through an asymptomatic course, for intermediate value it takes a typical course with constant duration and severity of infection but variable onset, and for large initial viral load the disease becomes severe. This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load.

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

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