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Using mouse models to decipher endotoxic shock during Trypanosoma c ongolense infection in cattle

Using mouse models to decipher endotoxic shock during Trypanosoma c ongolense infection in cattle. Background Animal Trypanosomiasis due to Trypanosoma congolense infection is a major constraint on food security and economic livelihoods in sub-Saharan Africa.

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Using mouse models to decipher endotoxic shock during Trypanosoma c ongolense infection in cattle

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  1. Using mouse models to decipher endotoxic shock during Trypanosoma congolense infection in cattle • Background • Animal Trypanosomiasis due to Trypanosoma congolense infection is a major constraint on food security and economic livelihoods in sub-Saharan Africa. • Microarray studies have shown that T.congolense infection induces a host immune response which is analogous to that elicited by bacterial lipopolysaccharide (LPS). This response is referred to as endotoxic shock (ES). • Endotoxic shock is an extreme host inflammatory response characteristic of infection with gram-negative bacteria. • It involves molecular interplay of toll-like receptors, nuclear transcription factors and inflammatory cytokines. • It is useful for parasite clearance but can also lead to multiple organ failure and rapid death • We have ruled out presence of bacteria and bacterial LPS during in T.congolense infected mice. The current objective is to validate and characterize endotoxic shock elicited by T.congolense. Experimental flow Objectives • To utilize mouse models to validate the ES signal observed from microarray data analysis of T.congolense-infected mice • To ascertain the role of T.congolense total lysate, VSG and DNA in generation of this response • To ascertain the signalling pathways involved in ES induced by T.congolense and role of TLRs • To establish the role of ES in T.congolense pathogenesis • To determine possible linkage of ES to trypanotolerance Tools for the study Key experimental readouts • Gene and Protein expression levels for the following ES indicators:- • Acute-phase proteins - Serum Amyloid A, C-reactive protein and Mannose-binding Protein • Inflammatory cytokines - IL1- α, IL-1β, IL6, IL8, IL12p40, IL12p65, TNF-α and TGF-β • Anti-inflammatory cytokines - IL-4 and IL-10 • TLR2, TLR4, TLR9, CD14 • Phosphorylation of NF-κB, AP-1 and CREB Expected Outcomes • Validation and characterization of endotoxic shock response during T.congolense infection i.e.:- • Trypanosoma congolense factors involved in the ES response • Host signalling pathways involved in the response • Relevance of the ES response to the pathology associated with T.congolense infection • Differences in ES response between susceptible and resistant mice with reference to trypanotolerance. L. Wambua1,2,3 M. Agaba2,3 A. Valentini1 S. Kemp2,3 and members of the 2 Wellcome Trust consortium 1 Universita Degli Studi Della Tuscia, Viterbo Italy www.unitus.it 2 The Wellcome Trust Host/Pathogen Consortium www.genomics.liv.ac.uk/tryps/ 3 International Livestock Research Institute, Nairobi Kenya www.ilri.org ILRI INTERNATIONAL LIVESTOCK RESEARCH INSTITUTE

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