PhD Student, Heinrich Pette Institute
I focus on the importance of HLA and TCR diversity during EVD and in the outcome to the disease.
The HLA class I and II genes play a very important role in the initiation of the adaptive immune responses. These molecules expressed on the surface of antigen presenting cells are highly polymorphic in order to present a wide array of antigenic peptides and different levels of this diversity as well as the expression of specific alleles have been associated to improved immune responses to viral infections. Facing the HLA-peptide complex during the immunological synapse, the CDR3 sequence in the T cell receptor (TCR) determines antigen specificity of the T cell responses. In order to be able to recognize the infinite possibility of peptides presented, the TCR display a highly diverse repertoire which can also be correlated to an improved capacity of the host to clear viral infections. In this study we genotyped the HLA class I and II alleles from fatal cases and survivors in order to evaluate the potential influence of these alleles polymorphism in disease outcome. Heterozygosity at the HLA-A locus was significantly associated with survival supporting the important role of CD8 T cell responses during EVD disease. We also sequenced the TCR of Ebola virus disease (EVD) patients who succumbed or survived the disease and evaluated the possible influence of the TCR repertoire diversity in the clearance of Ebola virus (EBOV) and in recovery. Our results indicated that survival is significantly associated with an elevated TCR diversity as well as with a lower amount of shared TCR sequences between individuals. Our findings support the importance of HLA and TCR polymorphisms for the activation of a broad and effective adaptive immune response.
Abstract: The HLA class I and II genes encode molecules that lie at the heart of the acquired immune response against infectious diseases. Associations between these polymorphic loci and genetically complex infectious diseases have been historically elusive, in contrast to the more obvious HLA associations with autoimmune diseases. High resolution molecular typing of large, clinically well-defined cohorts has begun to uncover evidence for the influence of HLA diversity on diseases of viral etiology, such as those caused by HIV-1, hepatitis B virus, hepatitis C virus and human papilloma virus. Combinations of HLA and KIR also appear to affect outcome to viral infection, supporting a role for HLA class I diversity in the innate immune response in addition to the acquired immune response.
Pub.: 09 Aug '05, Pinned: 09 Aug '17
Abstract: Host genetic factors are a major contributing factor to the inter-individual variation observed in response to human immunodeficiency virus (HIV) infection and are linked to resistance to HIV infection among exposed individuals, as well as rate of disease progression and the likelihood of viral transmission. Of the genetic variants that have been shown to affect the natural history of HIV infection, the human leukocyte antigen (HLA) class I genes exhibit the strongest and most consistent association, underscoring a central role for CD8(+) T cells in resistance to the virus. HLA proteins play important roles in T-cell-mediated adaptive immunity by presenting immunodominant HIV epitopes to cytotoxic T lymphocytes (CTLs) and CD4(+) T cells. Genetic and functional data also indicate a function for HLA in natural killer cell-mediated innate immunity against HIV by interacting with killer cell immunoglobulin-like receptors (KIR). We review the HLA and KIR associations with HIV disease and discuss the mechanisms underlying these associations.
Pub.: 19 Jun '13, Pinned: 09 Aug '17
Abstract: Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD1. In particular, very little is known about human immune responses to Ebola virus2, 3. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4+ and CD8+ T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.
Pub.: 04 May '16, Pinned: 09 Aug '17
Abstract: A number of previous studies have identified antigen-presenting cells (APCs) as key targets of Ebola virus (EBOV), but the role of APCs in human Ebola virus disease (EVD) is not known. We have evaluated the phenotype and kinetics of monocytes, neutrophils, and dendritic cells (DCs) in peripheral blood of patients for whom EVD was diagnosed by the European Mobile Laboratory in Guinea. Acute EVD was characterized by reduced levels of circulating nonclassical CD16(+) monocytes with a poor activation profile. In survivors, CD16(+) monocytes were activated during recovery, coincident with viral clearance, suggesting an important role of this cell subset in EVD pathophysiology.
Pub.: 16 Aug '16, Pinned: 09 Aug '17
Abstract: Ebola virus (EBOV) causes severe systemic disease in humans and non-human primates characterized by high levels of viremia and virus titers in peripheral organs. The natural portals of virus entry are the mucosal surfaces and the skin where macrophages and dendritic cells (DCs) are primary EBOV targets. Due to the migratory properties of DCs, EBOV infection of these cells has been proposed as a necessary step for virus dissemination via draining lymph nodes and blood. Here we utilize chimeric mice with competent hematopoietic-driven immunity, to show that EBOV primarily infects CD11b(+) DCs in non-lymphoid and lymphoid tissues, but spares the main cross-presenting CD103(+) DC subset. Furthermore, depletion of CD8 and CD4 T cells resulted in loss of early control of virus replication, viremia and fatal Ebola virus disease (EVD). Thus, our findings point out at T cell function as a key determinant of EVD progress and outcome.
Pub.: 04 Mar '17, Pinned: 09 Aug '17