Biology subjects

Gibbins, M. P.

Publications and source records attributed to Gibbins, M. P..

4 recordsLinked to original sources

bioRxiv2021

Host cell maturation modulates parasite invasion and sexual differentiation in Plasmodium.

Malaria remains a global health problem with over 400,000 deaths annually1. Plasmodium parasites, the causative agents of malaria, replicate asexually in red blood cells (RBCs) of their vertebrate host, while a subset differentiates into sexual stages (gametocytes) for mosquito transmission. Parasite replication and gametocyte maturation in the erythropoietic niches of the bone marrow and spleen contribute to pathogenesis and drive transmission2, but the mechanisms underlying this organ enrichment remain unknown. We performed a comprehensive single cell analysis of rodent P. berghei in spleen, bone marrow and blood to define parasite phenotypes specific to those niches. Single cell RNA-seq analysis of host and parasite cells reveals an interferon-driven host response to infection as well as transcriptional adaptations of Plasmodium to RBC maturation status. We show that P. berghei exhibits a bimodal invasion pattern into either normocytes or early reticulocytes and, using functional assays, identify CD71 as a host receptor for reticulocyte invasion. Importantly, we observe an increased rate of gametocyte formation in reticulocytes that is nutrient-dependent and triggered post invasion (i.e., same cycle sexual commitment). Our data provides a thorough characterisation of host-parasite interactions in erythropoietic niches and defines host cell maturation state as the key driver of parasite adaptation.

microbiology↗

bioRxiv2020

Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination

Vaccine discovery and development critically depends on predictive assays, which prioritise protective antigens. Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation, including phase I/II trials. Here, we tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells either as an antigen in the circumsporozoite protein (CSP), the surface coat protein of extracellular sporozoites or in the upregulated in sporozoites 4 (UIS4), a major protein associated with the parasitophorous vacuole membrane (PVM) that surrounds the intracellular exo-erythrocytic forms (EEF). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust and superior antigen-specific CD8+ T cell responses, whilst an EEF antigen evokes poor responses. However, despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced, antigen-specific effector CD8+ T cells results in high levels of protection when targeting both antigens. Our study is the first demonstration that poor immunogenicity of EEF antigens does not preclude their susceptibility to antigen-specific CD8+ T cell killing. Our findings that antigen immunogenicity is an inadequate predictor of vaccine susceptibility have wide-ranging implications on antigen prioritisation for the design and testing of next-generation pre-erythrocytic malaria vaccines.

immunology↗

bioRxiv2020

The importance of the immunodominant CD8+ T cell epitope of Plasmodium berghei circumsporozoite protein in parasite- and vaccine-induced protection

The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ T cell responses that are capable of eliminating developing parasites in hepatocytes resulting in protective immunity. In this study, we characterised the importance of the immunodominant CSP-derived epitope, SYIPSAEKI, of Plasmodium berghei in both sporozoite- and vaccine-induced protection in murine infection models. In BALB/c mice, where SYIPSAEKI is efficiently presented in the context of the major histocompatibility complex class I (MHC-I) molecule H-2-Kd, we established that epitope-specific CD8+ T cell responses contribute to parasite killing following sporozoite immunisation. Yet, sterile protection was achieved in the absence of this epitope substantiating the concept that other antigens can be sufficient for parasite-induced protective immunity. Furthermore, we demonstrated that SYIPSAEKI-specific CD8+ T cell responses elicited by viral-vectored CSP-expressing vaccines effectively targeted parasites in hepatocytes. The resulting sterile protection strictly relied on the expression of SYIPSAEKI. In C57BL/6 mice, which are unable to present the immunodominant epitope, CSP-based vaccines did not confer complete protection, despite the induction of high levels of CSP-specific antibodies. These findings underscore the significance of CSP in protection against malaria pre-erythrocytic stages and demonstrate that a significant proportion of the protection against the parasite is mediated by CD8+ T cells specific for the immunodominant CSP-derived epitope.

immunology↗

bioRxiv2019

P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

Transmission of Plasmodium falciparum depends on the presence of mature gametocytes that can be ingested by mosquitoes taking a bloodmeal when feeding on human skin. It has long been hypothesised that skin sequestration contributes to efficient transmission. Although skin sequestration would have major implications for our understanding of transmission biology and the suitability of mosquito feeding methodologies to measure the human infectious reservoir, it has never been formally tested. In two populations of naturally infected gametocyte carriers from Burkina Faso, we assessed transmission potential to mosquitoes and directly quantified male and female gametocytes and asexual parasites in: i) finger prick blood, ii) venous blood, iii) skin biopsies, and in pools of mosquitoes that fed iv) on venous blood or, v) directly on the skin. Whilst more mosquitoes became infected when feeding directly on the skin compared to venous blood, concentrations of gametocytes in the subdermal skin vasculature were identical to that in other blood compartments. Asexual parasite densities, gametocyte densities and sex ratios were identical in the mosquito blood meals taken directly from the skin of parasite carriers and their venous blood.\n\nWe also observed sparse gametocytes in skin biopsies from legs and arms of gametocyte carriers by microscopy. Taken together, we provide conclusive evidence for the absence of significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes. Quantifying this human malaria transmission potential is of pivotal importance for the deployment and monitoring of malaria elimination initiatives.\n\nIMPORTANCEOur observations settle a long-standing question in the malaria field and close a major knowledge gap in the parasite cycle. By deploying mosquito feeding experiments and stage-specific molecular and immunofluorescence parasite detection methodologies in two populations of naturally infected parasite carriers, we conclusively reject the hypothesis of gametocyte skin sequestration. Our findings provide novel insights in parasite stage composition in human blood compartments, mosquito bloodmeals and their implications for transmission potential. We demonstrate that gametocyte levels in venous or finger prick blood can be used to predict onward transmission potential to mosquitoes. Our findings thus pave the way for methodologies to quantify the human infectious reservoir based on conventional blood sampling approaches to support the deployment and monitoring of malaria elimination efforts for maximum public health impact.

microbiology↗