Primary infection by E. multilocularis induces distinct patterns of crosstalk between hepatic regulatory T and natural killer T cells in mice

Abstract

The larval stage of the helminthic cestode Echinococcus multilocularis can inflict tumor-like hepatic lesions that cause the parasitic disease alveolar echinococcosis in humans, with high mortality in untreated patients. Recently, opportunistic properties of the disease have been proposed based on the increased incidence in immunocompromised patients and mouse models, indicating that an appropriate adaptive immune response is required for the control of the disease. However, little is known about how the local hepatic immune responses modulate the infection with E. multilocularis. In a mouse model of oral infection that mimics the normal infection route in human patients, the adaptive immune response in the liver was assessed using single-cell RNA sequencing of isolated hepatic CD3+ T cells at different infection stages. We observed an early significant increase in regulatory T and natural killer T cells in parallel with an active downregulation of CD4+ and CD8+ T cells. Early interactions between regulatory T cells and natural killer T cells indicate a promotion of the formation of hepatic lesions and later contribute to suppression of the resolution of parasite-induced pathology. The obtained data provides a fresh insight on the adaptive immune responses and local regulatory pathways at different infection stages of E. multilocularis in mice. Author summaryAlveolar echinococcosis is an endemic parasitic infection leading to slowly growing but potentially lethal liver lesions if untreated. Transmission by increasing populations of urban foxes and the raise of immunosuppressed patients in mainly industrializsed endemic zones are the main causes responsible for increased incidence of alveolar echinococcosis. Observations in humans and mice indicate that reactions of the adaptive immune system are required to control the disease and to protect from a chronic infection. Therefore, we analysed the responses of T cells in the liver at single-cell resolution in a murine model mimicking the typical route of infection in humans. This so called single-cell RNA sequencing revealed specific temporal changes of T cell subsets such as natural killer T cells and regulatory T cells, indicating that these two cell types are recruited in the early phase to try to protect from parasite proliferation and are subsequently inhibited in the late phase of infection thus indicating immune escape mechanisms of the parasite. This study shows temporal changes of the immune cell profile in the liver over the course of a natural infection with E. multilocularis at the single cell level and reveals putative targets for novel therapeutic approaches for human AE and possibly other (parasitic/helminthic) diseases.