Significant upregulation of signaling and pro-inflammatory markers indicate adaptation for tolerance in bovine trypanosomosis

Abstract

The initial immune response on exposure to trypanosomosis is a significant factor mitigating disease tolerance or susceptibility in cattle. CD14 is a signaling receptor involved in the activation of the TLR signaling pathway, contributing to the production of cytokines, including tumor necrosis factor-α (TNF-α). We had shown that CD14 expression in trypanotolerant cattle is an adaptation footprint, not found in susceptible animals. To further our analysis in delineating the role of TLR-4 and TNF-α genes in disease tolerance or susceptibility, we examined whole transcriptome and interactome of the two genes by elucidating their expression profiles in bovine tissues (liver, lungs, heart and kidney). Our analyses demonstrate a significant (p< 0.05) upregulation of TLR-4 and TNF-α in trypanotolerant cattle but not others. The upregulation of these genes in tolerant animals reflects a complete activation of the innate immune pathway, thereby hampering disease establishment, which is absent in the susceptible animals. This is contrary to reports in human studies, where the expression of these genes lead to disease chronicity, rather than tolerance. This indicates an evolutionary differentiation between cattle and human during speciation. Furthermore, we catalogued microRNA expression between disease groups via network analysis and identified 13 candidate microRNAs targeting CD14, TLR-4 and TNF-α, amongst others, which GO analysis reveal are involved in gene silencing, cellular protein modification process, etc. We conclude that the upregulation of these markers and the significant co-regulatory interactome is indicative of adaptation footprint in tolerant animal, helpful for bovine immune response against trypanosomiasis.