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

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Conservation of S20 As an Ineffective and Disposable Ifnγ-Inducing Determinant of Plasmodium Sporozoites Indicates Diversion of Cellular Immunity fmicb-12-703804 August 2, 2021 Time: 13:31 # 1 ORIGINAL RESEARCH published: 06 August 2021 doi: 10.3389/fmicb.2021.703804 Conservation of S20 as an Ineffective and Disposable IFNg-Inducing Determinant of Plasmodium Sporozoites Indicates Diversion of Cellular Immunity Calvin Hon1, Johannes Friesen2,3, Alyssa Ingmundson1,2, Diana Scheppan2†, Julius C. R. Hafalla4, Katja Müller1,2 and Kai Matuschewski1,2* Edited by: 1 Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany, 2 Parasitology Unit, Max Yongliang Zhang, Planck Institute for Infection Biology, Berlin, Germany, 3 Medical Care Unit Labor 28 GmbH, Berlin, Germany, 4 Department National University of Singapore, of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom Singapore Reviewed by: Sanjeev Kumar, Despite many decades of research to develop a malaria vaccine, only one vaccine Assam University, India candidate has been explored in pivotal phase III clinical trials. This candidate subunit Jessica N. McCaffery, vaccine consists of a portion of a single Plasmodium antigen, circumsporozoite protein Centers for Disease Control and Prevention (CDC), United States (CSP). This antigen was initially identified in the murine malaria model and shown to Rajesh Chandramohanadas, contain an immunodominant and protective CD8C T cell epitope specific to the H-2Kd National University of Singapore, C Singapore (BALB/c)-restricted genetic background. A high-content screen for CD8 epitopes in b b *Correspondence: the H2K /D (C57BL/6)-restricted genetic background, identified two distinct dominant Kai Matuschewski epitopes. In this study, we present a characterization of one corresponding antigen, [email protected] the Plasmodium sporozoite-specific protein S20. Plasmodium berghei S20 knockout † Present address: sporozoites and liver stages developed normally in vitro and in vivo. This potent infectivity Diana Scheppan, The Lübeck Institute of Experimental of s20(-) sporozoites permitted comparative analysis of knockout and wild-type Dermatology, University Medical parasites in cell-based vaccination. Protective immunity of irradiation-arrested s20(-) Center Schleswig-Holstein, Lübeck, Germany sporozoites in single, double and triple immunizations was similar to irradiated unaltered sporozoites in homologous challenge experiments. These findings demonstrate the Specialty section: presence of an immunogenic Plasmodium pre-erythrocytic determinant, which is not This article was submitted to Infectious Diseases, essential for eliciting protection. Although S20 is not needed for colonization of the a section of the journal mammalian host and for initiation of a blood infection, it is conserved amongst Frontiers in Microbiology Plasmodium species. Malarial parasites express conserved, immunogenic proteins that Received: 30 April 2021 are not required to establish infection but might play potential roles in diverting cellular Accepted: 07 July 2021 Published: 06 August 2021 immune responses. Citation: Keywords: malaria, Plasmodium, sporozoite, whole organism vaccine, antigen, CD8C T cells, immunization, pre- Hon C, Friesen J, Ingmundson A, erythrocytic stage Scheppan D, Hafalla JCR, Müller K and Matuschewski K (2021) Conservation of S20 as an Ineffective INTRODUCTION and Disposable IFNγ -Inducing Determinant of Plasmodium Sporozoites Indicates Diversion Sustained anti-malaria therapy, exposure prophylaxis, and vector control have resulted in stable of Cellular Immunity. incidence and mortality rates in the tropics (World Health Organisation, 2020). To reduce Front. Microbiol. 12:703804. global malaria burden and transmission of Plasmodium parasites, access to a safe and efficacious doi: 10.3389/fmicb.2021.703804 prophylactic vaccine will be needed. An established method to achieve lasting sterile protection Frontiers in Microbiology| www.frontiersin.org 1 August 2021| Volume 12| Article 703804 fmicb-12-703804 August 2, 2021 Time: 13:31 # 2 Hon et al. Plasmodium S20 as Immune Decoy against natural Plasmodium sporozoite infection is intravenous RTS,S/AS01 vaccine they also highlight the need to investigate administration of multiple doses of live g-irradiation-attenuated non-CSP antigens. sporozoites (gspz) (Nussenzweig et al., 1967; Clyde et al., 1973; For the identification and evaluation of immunogenic pre- Hoffman et al., 2002; Richie et al., 2015). Identification of erythrocytic stage CD8C T cell epitopes two inbred mice strains, immunogenic antigens and immune correlates of protection H2-K/Db- and H2-Kd-restricted C57BL/6 (B6) and BALB/c vs. sporozoite exposure remain research priorities to develop mice, respectively, have been largely used. Immunizing either second-generation sporozoite vaccines. mouse strains with Plasmodium berghei (Pb) or Plasmodium Protective sporozoite-induced immunity is achieved by yoelii (Py) gspz is able to induce highly protective responses complementary humoral and cellular memory responses (Romero et al., 1989; Rodrigues et al., 1991; Sano et al., 2001). (Rodrigues et al., 1993; Hafalla et al., 2011). Previous studies Candidate CD8C T cell epitopes are typically selected based using gspz vaccination in mice have revealed the pivotal role on the amount of IFNg from activated CD8C T cells upon of circulating and liver-resident CD8C T cells in mediating stimulation with soluble peptides as a proxy for recognition protective immunity to the pre-erythrocytic stages of the parasite of immunogenic MHC I-restricted epitopes. Between the two by cytolytic killing (Ferreira et al., 1986; Schofield et al., 1987; mouse strains, B6 mice appear to represent a more accurate Weiss et al., 1988; Guebre-Xabier et al., 1999; Krzych et al., 2000; model for immunological studies as the elicited H2-Kb-restricted Schmidt et al., 2008). Antigen-specific, cytolytic CD8C T cells CD8C T cell responses during sporozoite infection are more target infected hepatocytes, which present MHC I-restricted diverse. Reliance on multiple doses for protective immunity parasite peptides on the cell surface (Romero et al., 1989; suggest a closer resemblance to that of humans, in contrast to Rodrigues et al., 1991). Upon peptide recognition by CD8C T the ease of eliciting protective immunity in BALB/c mice due cells, cytokines such as interferon-g (IFNg)(Schofield et al., to the immunodominance of the CSP epitope (Hafalla et al., 1987) and tumor necrosis factor (TNF) (Butler et al., 2010; 2013). Furthermore, the inability of B6 mice to recognize the H2- Depinay et al., 2011) are released along with pro-apoptotic Kd-restricted CSP epitope as a consequence of MHC haplotype pore-forming lytic proteins, perforin and granzymes. The central restriction allows identification of non-CSP-mediated immunity. role of CD8C T cells in pre-erythrocytic stage immunity has A genome-wide screening for candidate pre-erythrocytic stage been further highlighted by several studies, where abrogation of H2-K/Db-restricted CD8C T cell epitopes in B6 mice returned immunity in gspz-immunized mice and non-human primates only two epitopes that correlate with protracted CD8C T cell was observed after in vivo depletion of CD8C T cells (Schofield responses (Hafalla et al., 2013). One H2-Db-restricted epitope et al., 1987; Weiss et al., 1988; Doolan and Hoffman, 2000; originated from the thrombospondin-related adhesion protein C C Weiss and Jiang, 2012). CD8 T cells, however, are less likely (TRAP130−138) and displayed cytotoxic CD8 T cell responses to confer protection during the asexual parasite growth inside after a single immunization with gspz. Importantly, partial erythrocytes, simply because MHC I molecules are not found protection could be achieved by eliciting high levels of TRAP- on the surface of mammalian erythrocytes. Accordingly, the specific CD8C T cells via a heterologous prime-boost regimen. key role of cytolytic CD8C T cells in sustained protection Strikingly, the other identified H2-Kb-restricted target of C is largely restricted to the first obligate parasite expansion CD8 T cells (S20318−326) found in that screening, which maps phase in the liver. to the sporozoite-specific gene 20 (Kaiser et al., 2004), did Despite decades of considerable investments in malaria not induce cytotoxic immune responses. In good agreement, research, only one malaria vaccine has been licensed to-date, tolerization with S20318−326 peptide failed to completely known as the RTS,S/AS01 (RTS,S Clinical Trials Partnership, reverse protection, in contrast to TRAP130−138 (Hafalla et al., 2015; Neafsey et al., 2015). This subunit vaccine is based on 2013). In this study, we aimed to investigate this unusual the major Plasmodium falciparum sporozoite surface antigen, CD8C T cell response by generating S20 knock-out parasites termed circumsporozoite protein (CSP) (Cohen et al., 2010). CSP to confirm the origin of the epitope and to study potential is highly conserved amongst Plasmodium species, and essential contributions of S20318−326 toward protection in whole for sporozoite formation, motility and hepatocyte adhesion. sporozoite immunizations. It contains a central repeat structure, which likely further contributes to immune-dominance over minor sporozoite surface antigens (Zavala et al., 1983; Zavala et al., 1985). Modest RESULTS protection offered by this vaccine is strongly associated with humoral immunity and, to a lesser extent, T-cell mediated S20 Is Highly Conserved Among responses (Stoute et al., 1998; Cohen et al., 2010). Employing murine malaria models it was shown
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