Neoehrlichiosis - latent infection of endothelium and immune defense

Abstract

This thesis is a study of the tick-borne pathogen Neoehrlichia (N.) mikurensis that causes the infectious disease neoehrlichiosis in humans. The disease affects both individuals with competent and suppressed immune defense with the majority of the affected being immunosuppressed. The most common symptoms of neoehrlichiosis are recurrent fever, nightly sweats as well as muscle and joint pain. The most prominent clinical features are vascular events with thrombosis and arteritis. The aims of this thesis were to identify the target cells of the infection and get a deeper understanding of the immune responses evoked by N. mikurensis. In the first paper, it is described how some patients diagnosed with neoehrlichiosis also have antibodies targeted against another member of the Anaplasmataceae family, Anaplasma phagocytophilum. This can lead to patients with neoehrlichiosis mistakenly being diagnosed with anaplasmosis. In the second paper we describe for the first time that N. mikurensis can be cultivated and propagated both in tick cells and human endothelial cells. N. mikurensis was also demonstrated inside of circulating endothelial cells isolated from the blood of patients with neoehrlichiosis. These findings indicate that endothelial cells are a target cell of the infection, which could also explain the many vascular events affecting patients. In paper III we show that immunosuppressed patients with N. mikurensis infection had increased serum levels of cytokines involved in B-cell responses (CXCL13 and B-cell activating factor), the pro-inflammatory cytokine CXCL10 as well as cytokines associated with growth of blood vessels (vascular endothelial growth factor and fibroblast growth factor basic). We also show the importance of confirming results obtained with multiplex cytokine assays with single plex tests. In the last paper IV, we lend support to the hypothesis that N. mikurensis infections in humans are latent infections that can reactivate when B-cell responses are suppressed in patients with B-cell lymphomas. Out of 97 patients treated with anti-CD20 antibody therapy, 8 % had a latent N. mikurensis infection, it was only the patients with latent infection that had T cells specific for N. mikurensis. These T cells were of the gamma delta type, T-helper 1 and cytotoxic T lymphocyte types and expressed the cytolytic protein perforin. This work and future N. mikurensis projects will lead to a greater understanding of the infectious disease neoehrlichiosis.