Relationship between HLA and T cell responses to Ebola virus

Abstract

Ebola virus disease (EVD) is a severe illness caused by infection with Ebola virus (EBOV) which causes sporadic outbreaks in African countries, the last one taking place in West Africa and affecting over 28000 people. Even though several decades have passed since the description of the first EVD cases, there are still many unanswered questions regarding the involvement of the human immune response in the pathophysiology of EVD. Research in this field is challenging because of the requirement of biosafety level 4 containment and the scarcity of human data. During the last EVD outbreak in West Africa, we had the opportunity to establish an immunology lab at Donka hospital in Conakry, Guinea where we collected and analysed leftover blood samples from patients diagnosed by the European Mobile Laboratory. With the use of benchtop multiparametric flow cytometry and subsequent analysis in the biosafety level 4 laboratory in Hamburg, we evaluated the kinetics and phenotype of antigen-presenting cells as well as T cells with the goal to identify immune biomarkers of disease outcome. Our approach was to utilize flow cytometry to characterize cell profiles in blood as well as immunogenetics, in particular analysis of the T-cell receptor clonotypes and HLA polymorphisms. Immune data was then correlated with clinical and epidemiological findings to try to detect potential predictors of outcome and targets for immunotherapy. Our observations highlight the importance of CD16 monocytes in the innate immune response to EBOV infection and in viral clearance. Additionally, we could identify a dysregulation of the adaptive immune response in fatal cases, characterised by the upregulation of the T cell inhibitory markers CTLA-4 and PD-1 and the inability to control viral replication. These results identify CD16 monocytes and the regulatory pathways of T cell responses as potential targets for post-exposure EVD immunotherapy. Moreover, our immunogenetics study evidenced the relevance of the expression of various HLA alleles and the activation of a T cell response through a broad and diverse T cell receptor repertoire in improved disease outcome.