Distinct temporal patterns of liver immune responses to pathogenic and non-pathogenic Entamoeba histolytica clones

Entamoeba histolytica is a protozoan parasite that can cause severe liver disease known as amoebic liver abscess. However, only a subset of infected individuals develops invasive disease, indicating that host-parasite interactions are critical determinants of disease outcome. In this study, we investigated the clone-specific modulation of hepatic immune responses using non-pathogenic A1np and pathogenic B2p E. histolytica clones. Time-resolved transcriptome analyses (6, 12, 24 hours post-infection) in a murine model revealed distinct immune trajectories. Both clones activated innate immune pathways early after infection, but their responses differed markedly in magnitude and composition. A1np infection induced a rapid and controlled inflammatory response associated with antimicrobial activity and resolution-promoting signalling. In contrast, B2p infection triggered a stronger and more complex immune response characterised by pronounced cytokine and chemokine expression, activation of stress and redox pathways, and tissue remodelling processes. The B2p induced response exhibited features of excessive immune activation, accompanied by the upregulation of counter-regulation genes such as Ackr2. These findings indicate that liver pathology is not solely determined by parasite presence, but rather may also be influenced by the nature and regulation of the host immune response. Overall, the observed differences between A1np and B2p infections suggest that parasite-specific properties shape hepatic immune activation and may influence disease progression. Author summaryAlthough infection with the parasite Entamoeba histolytica can lead to severe liver disease, most infected individuals remain asymptomatic. This suggests that the outcome of the disease is not determined solely by the parasite, but also by how the host responds to the infection. In this study, we used a mouse model to compare how the liver reacts to infection with two E. histolytica clones that differ in their ability to cause amoebic liver abscesses. Using this model and time-resolved transcriptome analysis, we found that both clones trigger an early immune response; however, the nature of this response differs markedly. The non-pathogenic clone induced a rapid and controlled reaction associated with antimicrobial defence and tissue protection. In contrast, the pathogenic clone provoked a stronger and more prolonged inflammatory response accompanied by cellular stress and tissue remodelling processes. Notably, this heightened response also activated regulatory mechanisms that attempted to limit excessive inflammation. Our findings demonstrate that differences in disease severity are linked to the activation and regulation of the host immune system, rather than simply to the presence of the parasite.