Defining the human immune signature following infection with Crimean-Congo haemorrhagic fever virus
Crimean-Congo haemorrhagic fever virus (CCHFV) causes severe haemorrhagic disease in humans that can be fatal. Symptoms are wide ranging, and patients are classified with mild, moderate or severe disease according to a well-defined severity scoring system. Understanding of disease progression and pathogenesis of CCHF is limited due mainly to the difficulty of studying this hazard group four (HG4) pathogen, access to samples and the confined range of animal models available. Immune responses that lead to protection are poorly defined and these studies explored CCHF pathogenesis, disease progression and the immune responses to infection. Unique samples were collected from Turkish patients residing in CCHFV endemic regions up to six times over the course of two years and were analysed for antibody, serum circulating biomarker and T-cell memory responses. The studies demonstrated that neither IgM nor IgG antibodies were raised to CCHFV antigens in patients with severe disease despite each patient surviving for long enough such that a suitable immune response could have been mounted. A comparison of CCHFV antigens highlighted nucleoprotein (NP), glycoprotein subunit Gc (Gc) and to a lesser extent glycoprotein subunit 38 (GP38) as adventitious vaccine targets while demonstrating that IgG response to glycoprotein subunit Gn (Gn) in natural CCHFV infection in humans is limited. Analysis of acute and convalescent sera highlighted extensive production of many biomarkers with wide ranging functions in the first seven days post-symptom onset with some biomarkers (particularly Tumour necrosis factor – alpha (TNF-α) and C-X-C motif chemokine ligand - 10 (CXCL10)) remaining elevated in patients of all disease severities for 24-months following infection. Memory T-cell responses were highly variable between patients and not determined by the severity of disease. Multi-functionality of cells highlighted the diversity of the peripheral blood mononuclear cell (PBMC) population. A consistent, elevated antibody response that remains high for many years post-infection compared to a highly patient variable memory T-cell response, would suggest long-term protection is related more to B-cell activity and antibodies are the main correlate of protection.
Networked Digital Library of Theses and Dissertations