Plasmodium
Topics: CSP, sporozoite 6Cys proteins, PvTRAgs
Circumsporozoite protein (CSP)
Malaria is a vector-borne disease that is caused by parasites of the Plasmodium genus. The Plasmodium life cycle involves different stages and requires passage through two hosts: vertebrates and female Anopheles mosquitoes (aka the ‘’malaria mosquito’’). The form of the parasite injected into the skin of the vertebrate host upon blood feeding by an infected mosquito is the sporozoite (SPZ)[1,2], which will rapidly travel to the liver employing the host circulatory system. Once arrived at its destination, the SPZ will invade a hepatocyte. This phase of the infection is known as the pre-erythrocytic phase. Inside the liver, the SPZ will develop into thousands of merozoites, i.e. the next stage of the parasite, which will be released from the infected hepatocyte into the host blood stream. This initiates the blood stage of the infection, which causes the notorious malaria pathology[3,4]. Only a small portion of the merozoites will initiate the parasite’s sexual reproduction cycle by developing into male and female gametocytes, which will in turn infect mosquitoes feeding off the infected vertebrate host.
The circumsporozoite protein (CSP) is the major SPZ antigen, uniformly coating the parasite surface. CSP plays a pivotal role in the parasite’s immunobiology, both in the insect and vertebrate hosts[5]. Within the latter, CSP has been described to i) be essential for the recognition and invasion of host hepatocytes[6,7], ii) constitute the immunodominant target for anti-SPZ antibodies[8] (and forms the basis for the RTS,S vaccine produced by GSK)[9], iii) possess both extra- and intracellular effector functions to dampen host inflammatory responses[10,11], and iv) forms a shield around the SPZ to protect its plasma membrane against pore-forming proteins during parasite migration through the skin[12].
The CSPs from different Plasmodium species are 30 to 45 kDa proteins that all have the same modular build-up: i) an N-terminal signal peptide to direct the protein to the SPZ surface, ii) an N-terminal domain with unknown structure, iii) a long linker region consisting of a repeating motif flanked by N- and C-terminal junctions, iv) a C-terminal domain that adopts an α-thrombospondine type-I repeat (αTSR) fold[13], and v) a C-terminal GPI anchor to attach CSP to the parasite surface.
As one of the most important surface antigens of the malaria parasite, CSP has been extensively studied over the past decades. However, despite recent advances and the clear relevance of CSP for SPZ immunobiology, most aspects of its structure-function relationship remain enigmatic. As investigating SPZ antigens has produced significant scientific breakthroughs in the battle against malaria, it is anticipated that filling the existing knowledge gaps will not only yield insights into the parasite’s immunobiology and the events required for the establishment of liver infection, but also generate a molecular basis to contribute to the design of novel anti-malarial therapies.
References
[1] Prudencio et al. (2006). Nat Rev Microbiol, 4 (11), 849-856.
[2] Menard et al. (2013). Nat Rev Microbiol, 11 (10), 701-712.
[3] Miller et al. (2013). Nat Med, 19 (2), 156-167.
[4] Riley et al. (2013). Nat Med, 19 (2), 168-178.
[5] Aly et al. (2009). Annu Rev Microbiol, 63 (1), 195-221.
[6] Pinzon-Ortiz et al. (2001). J Biol Chem, 276 (29), 26784-26791.
[7] Coppi et al. (2007). Cell Host Microbe, 2 (5), 316-327.
[8] Kumar et al. (2006). Nature, 444, 937-940.
[9] Cohen et al. (2010). Hum Vaccin, 6 (1), 90-96.
[10] Usynin et al. (2007). Cell Microbiol, 9 (11), 2610-2628.
[11] Singh et al. (2007). Cell, 131 (3), 492- 504.
[12] Aliprandini et al. (2018). Nat Microbiol, 3 (11), 1224-1233.
[13] Doud et al. (2012). PNAS, 109 (20), 7817-7822.
Trypanosoma
Topics: trypanosomal glycolytic enzymes and their moonlighting function
Leishmania
Topics: leishmanial dynamin-1 like protein as a drug target
Single-domain antibodies (sdAbs)
Topics: generation and application of immune and synthetic sdAb libraries