Importance of the Immunodominant CD8⁺T Cell Epitope of Plasmodium berghei Circumsporozoite Protein in Parasite- and Vaccine-Induced Protection

Abstract

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.

Plasmodium circumsporozoite protein enhances the efficacy of gefitinib in lung adenocarcinoma cells by inhibiting autophagy via proteasomal degradation of LC3B

“…CSP has become a prime vaccine candidate for malaria based on its importance in the physiological processes of the sporozoite. Previous studies have confirmed that the abundant epitopes of CSP trigger the immune response [49] and induce robust CD8 + T-cell responses that are capable of eliminating developing parasites in hepatocytes, resulting in protective immunity [50]. The findings of this study have led to the interesting hypothesis that overexpression of CSP in lung cancer cells could induced a CSP peptide-specific CD8 + T-cell response that combats tumor growth.…”

Plasmodium Circumsporozoite Protein Enhances the Efficacy of Gefitinib in Lung Adenocarcinoma Cells by Inhibiting Autophagy via Proteasomal Degradation of LC3B

“…CSP has become a prime vaccine candidate for malaria based on its importance in the physiological processes of the sporozoite. Previous studies have confirmed that the abundant epitopes of CSP trigger the immune response (Agnandji et al, 2011) and induce robust CD8 + T-cell responses that are capable of eliminating developing parasites in hepatocytes, resulting in protective immunity (Gibbins et al, 2020). In addition, cancer gene therapy also provide an approach, including immune gene therapy, and to suppress tumor growth with other conventional therapy (Cemazar et al, 2017).…”

Conservation of S20 as an Ineffective and Disposable IFNγ-Inducing Determinant of Plasmodium Sporozoites Indicates Diversion of Cellular Immunity

“…Previous work has focused on identifying and investigating individual CD8 + T cell epitopes using subunit vaccine strategies (Bruña-Romero et al, 2001;Hafalla et al, 2013;Doll et al, 2016), but the reverse approach, to test whether individual epitopes are required for sterile immunity offered by γspz, remains largely unexplored. Previous studies have demonstrated the ability to elicit sterile immunity in H-2K d -restricted BALB/c mice in the absence of CSP-specific responses (Grüner et al, 2007;Gibbins et al, 2020). The findings suggested that sterile protection does not necessarily depend on CSP-reactive CD8 + T cells, and indicated that inclusion of additional, non-CSP epitopes to subunit vaccine strategies is warranted.…”

“…Employing murine malaria models it was shown that CSP contains immunogenic targets of protective H2-K d -restricted CD8 + T cell responses that are vital for protection against sporozoite infections (Rodrigues et al, 1991;Sedegah et al, 1992). But more recent studies have shown that sterile protection can also be achieved in the absence of CSP-specific T cells (Kumar et al, 2006;Grüner et al, 2007;Gibbins et al, 2020). While these findings might partly explain the inadequate protective efficacy of the RTS,S/AS01 vaccine they also highlight the need to investigate non-CSP antigens.…”