Active migration and passive transport of malaria parasites
2015; Elsevier BV; Volume: 31; Issue: 8 Linguagem: Inglês
10.1016/j.pt.2015.04.010
ISSN1471-5007
AutoresRoss G. Douglas, Rogério Amino, Photini Sinnis, Friedrich Frischknecht,
Tópico(s)Mosquito-borne diseases and control
Resumo•Plasmodium undergoes active migration and passive transport during its lifecycle.•Recent literature displays misunderstanding as to when different movement types are used by Plasmodium.•Different dissemination strategies can be targeted by different types of prophylatics and therapeutics. Malaria parasites undergo a complex life cycle between their hosts and vectors. During this cycle the parasites invade different types of cells, migrate across barriers, and transfer from one host to another. Recent literature hints at a misunderstanding of the difference between active, parasite-driven migration and passive, circulation-driven movement of the parasite or parasite-infected cells in the various bodily fluids of mosquito and mammalian hosts. Because both active migration and passive transport could be targeted in different ways to interfere with the parasite, a distinction between the two ways the parasite uses to get from one location to another is essential. We discuss the two types of motion needed for parasite dissemination and elaborate on how they could be targeted by future vaccines or drugs. Malaria parasites undergo a complex life cycle between their hosts and vectors. During this cycle the parasites invade different types of cells, migrate across barriers, and transfer from one host to another. Recent literature hints at a misunderstanding of the difference between active, parasite-driven migration and passive, circulation-driven movement of the parasite or parasite-infected cells in the various bodily fluids of mosquito and mammalian hosts. Because both active migration and passive transport could be targeted in different ways to interfere with the parasite, a distinction between the two ways the parasite uses to get from one location to another is essential. We discuss the two types of motion needed for parasite dissemination and elaborate on how they could be targeted by future vaccines or drugs. A recent review on drug discovery in malaria rightly highlighted the need to block all stages of the parasite to achieve disease elimination [1Flannery E.L. et al.Antimalarial drug discovery – approaches and progress towards new medicines.Nat. Rev. Microbiol. 2013; 11: 849-862Crossref PubMed Scopus (229) Google Scholar]. Indeed, the complexity of the parasite life cycle, as this review points out, provides many challenges and opportunities for drug and vaccine design. Nonetheless, the authors miss what is likely an Achilles' heel of the parasite lifecycle in the mammalian host, namely the 'skin phase' [2Sinnis P. Zavala F. The skin: where malaria infection and the host immune response begin.Semin. Immunopathol. 2012; 34: 787-792Crossref PubMed Scopus (56) Google Scholar, 3Menard R. et al.Looking under the skin: the first steps in malarial infection and immunity.Nat. Rev. Microbiol. 2013; 11: 701-712Crossref PubMed Scopus (131) Google Scholar]. This omission of the parasite's obligatory step in the skin can be found surprisingly often in the malaria research and clinical literature [1Flannery E.L. et al.Antimalarial drug discovery – approaches and progress towards new medicines.Nat. Rev. Microbiol. 2013; 11: 849-862Crossref PubMed Scopus (229) Google Scholar, 4Tilley L. et al.The Plasmodium falciparum-infected red blood cell.Int. J. Biochem. Cell Biol. 2011; 43: 839-842Crossref PubMed Scopus (72) Google Scholar, 5Collins W.E. Jeffery G.M. Plasmodium malariae: parasite and disease.Clin. Microbiol. Rev. 2007; 20: 579-592Crossref PubMed Scopus (185) Google Scholar, 6Haldar K. et al.Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease.Annu. Rev. Pathol. 2007; 2: 217-249Crossref PubMed Scopus (161) Google Scholar, 7Hall J. Ross E. Malaria: The Battle Against a Microscopic Killer. EVIMalaR, 2012Crossref Google Scholar, 8Bousema T. et al.Asymptomatic malaria infections: detectability, transmissibility and public health relevance.Nat. Rev. Microbiol. 2014; 12: 833-840Crossref PubMed Scopus (420) Google Scholar]. These reports mention that human infection begins with the transmission of sporozoites into the bloodstream during the bite of an infected female Anopheles mosquito. This implies direct injection of parasites into the bloodstream but overlooks the fact that sporozoites are predominantly, if not completely, injected extravascularly into the skin, where they need to be motile to cross the dermis and enter into either blood or lymph vessels [9Kappe S.H. et al.Plasmodium sporozoite molecular cell biology.Annu. Rev. Cell Dev. Biol. 2004; 20: 29-59Crossref PubMed Scopus (123) Google Scholar, 10Amino R. et al.Quantitative imaging of Plasmodium transmission from mosquito to mammal.Nat. Med. 2006; 12: 220-224Crossref PubMed Scopus (422) Google Scholar, 11Sidjanski S. Vanderberg J.P. Delayed migration of Plasmodium sporozoites from the mosquito bite site to the blood.Am. J. Trop. Med. Hyg. 1997; 57: 426-429Crossref PubMed Scopus (125) Google Scholar, 12Matsuoka H. et al.A rodent malaria, Plasmodium berghei, is experimentally transmitted to mice by merely probing of infective mosquito, Anopheles stephensi.Parasitol. Int. 2002; 51: 17-23Crossref PubMed Scopus (64) Google Scholar, 13Medica D.L. Sinnis P. Quantitative dynamics of Plasmodium yoelii sporozoite transmission by infected anopheline mosquitoes.Infect. Immun. 2005; 73: 4363-4369Crossref PubMed Scopus (157) Google Scholar, 14Amino R. et al.In vivo imaging of malaria parasites – recent advances and future directions.Curr. Opin. Microbiol. 2005; 8: 407-414Crossref PubMed Scopus (48) Google Scholar, 15Yamauchi L.M. et al.Plasmodium sporozoites trickle out of the injection site.Cell. Microbiol. 2007; 9: 1215-1222Crossref PubMed Scopus (159) Google Scholar]. The omission of the skin phase is unfortunate because the necessity of active parasite migration in the skin has opened up new opportunities for stopping the parasites before they enter the bloodstream, and skin migration may be an excellent drug and vaccine target. Indeed, sporozoite mutants with motility defects are significantly more attenuated after inoculation into the skin compared to after intravenous inoculation [16Ejigiri I. et al.Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity.PLoS Pathog. 2012; 8: e1002725Crossref PubMed Scopus (82) Google Scholar, 17Volkmann K. et al.The alveolin IMC1 h is required for normal ookinete and sporozoite motility behaviour and host colonisation in Plasmodium berghei.PLoS ONE. 2012; 7: e41409Crossref PubMed Scopus (46) Google Scholar, 18Hellmann J.K. et al.Environmental constraints guide migration of malaria parasites during transmission.PLoS Pathog. 2011; 7: e1002080Crossref PubMed Scopus (52) Google Scholar, 19Montagna G.N. et al.Critical role for heat shock protein 20 (HSP20) in migration of malarial sporozoites.J. Biol. Chem. 2012; 287: 2410-2422Crossref PubMed Scopus (53) Google Scholar]. Similarly, parasite mutants defective in cell traversal activity, the sporozoite capacity to wound and transmigrate a host cell, also show impaired progression in the skin [20Amino R. et al.Host cell traversal is important for progression of the malaria parasite through the dermis to the liver.Cell Host Microbe. 2008; 3: 88-96Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 21Moreira C.K. et al.The Plasmodium TRAP/MIC2 family member, TRAP-like protein (TLP), is involved in tissue traversal by sporozoites.Cell Microbiol. 2008; 10: 1505-1516Crossref PubMed Scopus (92) Google Scholar, 22Bhanot P. et al.A surface phospholipase is involved in the migration of Plasmodium sporozoites through cells.J. Biol. Chem. 2005; 280: 6752-6760Crossref PubMed Scopus (72) Google Scholar]. Furthermore, antibodies that immobilize sporozoites have a clear effect on sporozoite motility in the dermis [23Sack B.K. et al.Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum.Infect. Immun. 2014; 82: 808-817Crossref PubMed Scopus (67) Google Scholar, 24Vanderberg J.P. Frevert U. Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes.Int. J. Parasitol. 2004; 34: 991-996Crossref PubMed Scopus (257) Google Scholar, 25Kebaier C. et al.Kinetics of mosquito-injected Plasmodium sporozoites in mice: fewer sporozoites are injected into sporozoite-immunized mice.PLoS Pathog. 2009; 5: e1000399Crossref PubMed Scopus (85) Google Scholar]. The majority of the time that sporozoites are in an extracellular environment is spent in the dermis, where they are likely to be much more vulnerable to antibodies and possibly drugs, compared to the blood circulation where they only spend minutes, and the liver where they rapidly find and invade hepatocytes (Table 1) [15Yamauchi L.M. et al.Plasmodium sporozoites trickle out of the injection site.Cell. Microbiol. 2007; 9: 1215-1222Crossref PubMed Scopus (159) Google Scholar, 26Sinnis P. et al.Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.J. Exp. Med. 1996; 184: 945-954Crossref PubMed Scopus (84) Google Scholar, 27Cerami C. et al.Rapid clearance of malaria circumsporozoite protein (CS) by hepatocytes.J. Exp. Med. 1994; 179: 695-701Crossref PubMed Scopus (61) Google Scholar, 28Shin S.C. et al.Direct infection of hepatocytes by sporozoites of Plasmodium berghei.J. Protozool. 1982; 29: 448-454Crossref PubMed Scopus (94) Google Scholar, 29Vanderberg J. et al.Assessment of antibody protection against malaria sporozoites must be done by mosquito injection of sporozoites.Am. J. Pathol. 2007; 171: 1405-1406Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar].Table 1Summary of active movement and passive transport of Plasmodium at different life cycle stagesParasite stageOrgan/tissue/cell/dissemination routeEvent (active/passive)Estimated time for eventSporozoiteHemocoelRelease from oocyst, passive transport in hemolymphUnknown; possibly 1 minute to 1 daySalivary glandInvasion of glandsUnknown; possibly 1–10 minutesProboscisTransport from mosquito to skin with flow of saliva∼1 secondSkinMotility through tissue and invasion of vasculature∼10–100 minutesLymphatic systemTransport in lymph vessels, active movement in node∼10–100 minutesBloodstreamTransport to liver1–10 minutesLiverCell traversal and hepatocyte invasion∼1 minuteMerozoiteMerosomesBud off from infected hepatocytes, passive transport in blood∼1–10 minutesErythrocytes in bloodstreamPassive transport in blood after merosome rupture, invasion of RBC; following RBC rupture, momentary passive transport in blood before actively invading another RBC∼1 minuteGameteMosquito midgutActive swimming by male gamete to fertilize female∼1–10 minutesOokineteMosquito midgut peritrophic matrix and epitheliaPresumably passive transport until contact with peritrophic matrix; active motility to traverse midgut epithelia∼1–10 minutesActive (red)/passive (blue). Open table in a new tab Active (red)/passive (blue). Statements such as 'motile sporozoites migrate to the liver and invade hepatocytes' [1Flannery E.L. et al.Antimalarial drug discovery – approaches and progress towards new medicines.Nat. Rev. Microbiol. 2013; 11: 849-862Crossref PubMed Scopus (229) Google Scholar] could lead to the impression that sporozoites use their capacity for motility to actively migrate in the blood to the liver. However, once sporozoites are in the blood they are carried by the blood flow until they arrest on the endothelium of the liver. In the liver, sporozoites actively migrate again to cross the endothelial barrier and enter hepatocytes [30Frevert U. et al.Intravital observation of Plasmodium berghei sporozoite infection of the liver.PLoS Biol. 2005; 3: e192Crossref PubMed Scopus (270) Google Scholar, 31Tavares J. et al.Role of host cell traversal by the malaria sporozoite during liver infection.J. Exp. Med. 2013; 210: 905-915Crossref PubMed Scopus (134) Google Scholar]. The capacity to actively migrate is clearly important for sporozoite entry into hepatocytes [19Montagna G.N. et al.Critical role for heat shock protein 20 (HSP20) in migration of malarial sporozoites.J. Biol. Chem. 2012; 287: 2410-2422Crossref PubMed Scopus (53) Google Scholar, 32Sultan A.A. et al.TRAP is necessary for gliding motility and infectivity of Plasmodium sporozoites.Cell. 1997; 90: 511-522Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar]. However, fast and robust motility is only needed in the skin because diminished motility still allows sporozoites to effectively enter the liver if they are injected by syringe directly into the bloodstream [16Ejigiri I. et al.Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity.PLoS Pathog. 2012; 8: e1002725Crossref PubMed Scopus (82) Google Scholar, 17Volkmann K. et al.The alveolin IMC1 h is required for normal ookinete and sporozoite motility behaviour and host colonisation in Plasmodium berghei.PLoS ONE. 2012; 7: e41409Crossref PubMed Scopus (46) Google Scholar, 18Hellmann J.K. et al.Environmental constraints guide migration of malaria parasites during transmission.PLoS Pathog. 2011; 7: e1002080Crossref PubMed Scopus (52) Google Scholar, 19Montagna G.N. et al.Critical role for heat shock protein 20 (HSP20) in migration of malarial sporozoites.J. Biol. Chem. 2012; 287: 2410-2422Crossref PubMed Scopus (53) Google Scholar, 21Moreira C.K. et al.The Plasmodium TRAP/MIC2 family member, TRAP-like protein (TLP), is involved in tissue traversal by sporozoites.Cell Microbiol. 2008; 10: 1505-1516Crossref PubMed Scopus (92) Google Scholar, 33Sato Y. et al.Plasmodium berghei sporozoites acquire virulence and immunogenicity during mosquito hemocoel transit.Infect. Immun. 2014; 82: 1164-1172Crossref PubMed Scopus (30) Google Scholar]. This suggests that the malaria parasite has evolved a high speed specifically to cross the dermis, a finding that might well be important in intervention considerations that target their motility. Indeed, a recent study suggests that antibodies that block motility have a greater effect in the dermis (on sporozoites inoculated by mosquito bites) than in the circulation (on sporozoites inoculated directly into the bloodstream) [23Sack B.K. et al.Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum.Infect. Immun. 2014; 82: 808-817Crossref PubMed Scopus (67) Google Scholar]. Nonetheless, the passively-moving sporozoites in the blood might be targeted to prevent them from reaching the liver, once it is known what proteins on the sporozoite surface mediate this process. Several interactions are already known, including those of the thrombospondin-related anonymous protein (TRAP) and circumsporozoite protein (CSP) with hepatic heparan sulfate proteoglycans [34Coppi A. et al.Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells.Cell Host Microbe. 2007; 2: 316-327Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 35Pradel G. et al.Proteoglycans mediate malaria sporozoite targeting to the liver.Mol. Microbiol. 2002; 45: 637-651Crossref PubMed Scopus (100) Google Scholar]. Clearly, the sporozoite's journey from the point of inoculation to final entry into a hepatocyte is complex and requires many different proteins: while some interventions might target an actively-migrating sporozoite, others may only target sporozoite interactions with host factors once the sporozoite enters the bloodstream or becomes arrested in the liver. In addition, while some inhibitors may be specific for a particular phase of the journey, others may target sporozoites at all phases. Thus, the distinction between passive, circulation-driven movement and active, parasite-driven migration is not only of terminological value (Figure 1 and Table 1). Sporozoites inoculated into the dermis also enter the lymphatic system. They can be seen migrating actively within the dermis, and upon entering lymph vessels are passively transported along with the lymph [3Menard R. et al.Looking under the skin: the first steps in malarial infection and immunity.Nat. Rev. Microbiol. 2013; 11: 701-712Crossref PubMed Scopus (131) Google Scholar, 10Amino R. et al.Quantitative imaging of Plasmodium transmission from mosquito to mammal.Nat. Med. 2006; 12: 220-224Crossref PubMed Scopus (422) Google Scholar]. When arriving at the subcapsular sinus of lymph nodes, they appear to actively glide again and eventually encounter phagocytic cells that appear to clear the vast majority of parasites [10Amino R. et al.Quantitative imaging of Plasmodium transmission from mosquito to mammal.Nat. Med. 2006; 12: 220-224Crossref PubMed Scopus (422) Google Scholar]. Because only few sporozoites are injected into the skin during natural bites, and only about 20% of these enter the lymphatic system [10Amino R. et al.Quantitative imaging of Plasmodium transmission from mosquito to mammal.Nat. Med. 2006; 12: 220-224Crossref PubMed Scopus (422) Google Scholar, 15Yamauchi L.M. et al.Plasmodium sporozoites trickle out of the injection site.Cell. Microbiol. 2007; 9: 1215-1222Crossref PubMed Scopus (159) Google Scholar], it is not clear if there is an immune response to these parasites – and if so whether it would be of a tolerogenic or activating nature [36Chakravarty S. et al.CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes.Nat. Med. 2007; 13: 1035-1041Crossref PubMed Scopus (215) Google Scholar, 37Guilbride D.L. et al.Why functional pre-erythrocytic and bloodstage malaria vaccines fail: a meta-analysis of fully protective immunizations and novel immunological model.PLoS ONE. 2010; 5: e10685Crossref PubMed Scopus (34) Google Scholar]. However, during immunization regimes where sporozoites are used as live attenuated parasite vaccines, the large number of parasites arriving at the lymph node does elicit protective immune responses in mice [36Chakravarty S. et al.CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes.Nat. Med. 2007; 13: 1035-1041Crossref PubMed Scopus (215) Google Scholar, 38Obeid M. et al.Skin-draining lymph node priming is sufficient to induce sterile immunity against pre-erythrocytic malaria.EMBO Mol. Med. 2013; 5: 250-263Crossref PubMed Scopus (30) Google Scholar]. Importantly, RTS,S, the only malaria vaccine candidate that has demonstrated any efficacy in Phase III trials, is a subunit vaccine based on CSP, and follow-up studies generally suggest that protection is correlated to antibody titers [39Campo J.J. et al.Duration of vaccine efficacy against malaria: 5th year of follow-up in children vaccinated with RTS, S/AS02 in Mozambique.Vaccine. 2014; 32: 2209-2216Crossref PubMed Scopus (25) Google Scholar, 40White M.T. et al.A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine.BMC Med. 2014; 12: 117Crossref PubMed Scopus (63) Google Scholar, 41Arama C. Troye-Blomberg M. The path of malaria vaccine development: challenges and perspectives.J. Intern. Med. 2014; 275: 456-466Crossref PubMed Scopus (68) Google Scholar]. It is possible that these antibodies primarily target sporozoites in the skin, where they spend most of their time before invading hepatocytes. Again, it appears important to distinguish between passive transport within the lymphatic vessels, which would not be affected by antibodies, and active motility in the skin and lymph node. The latter could lead to fewer sporozoites arriving in the draining lymph node, and thus lead to an altered immune response during subsequent immunizations. Sporozoites must also travel in the mosquito, and this journey also often suffers from similar confusion between active migration and passive transport [42Sreenivasamurthy S.K. et al.A compendium of molecules involved in vector-pathogen interactions pertaining to malaria.Malar. J. 2013; 12: 216Crossref PubMed Scopus (32) Google Scholar, 43Baton L.A. et al.Genome-wide transcriptomic profiling of Anopheles gambiae hemocytes reveals pathogen-specific signatures upon bacterial challenge and Plasmodium berghei infection.BMC Genomics. 2009; 10: 257Crossref PubMed Scopus (85) Google Scholar, 44Gunn A. Pitt S.J. Parasitology: An Integrated Approach. John Wiley & Sons, 2012Crossref Google Scholar]. Sporozoites develop in oocysts in the mosquito midgut wall, and must exit into the hemocoel and go to the salivary gland. In the hemocoel, sporozoites are passively transported by the movement of the mosquito hemolymph and, although they are carried throughout the open circulatory system of the mosquito, they appear to preferentially recognize and invade salivary glands [16Ejigiri I. et al.Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity.PLoS Pathog. 2012; 8: e1002725Crossref PubMed Scopus (82) Google Scholar, 32Sultan A.A. et al.TRAP is necessary for gliding motility and infectivity of Plasmodium sporozoites.Cell. 1997; 90: 511-522Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar, 45Kariu T. et al.MAEBL is essential for malarial sporozoite infection of the mosquito salivary gland.J. Exp. Med. 2002; 195: 1317-1323Crossref PubMed Scopus (97) Google Scholar, 46Golenda C.F. et al.The distribution of circumsporozoite protein (CS) in Anopheles stephensi mosquitoes infected with Plasmodium falciparum malaria.J. Histochem. Cytochem. 1990; 38: 475-481Crossref PubMed Scopus (48) Google Scholar, 47Frischknecht F. et al.Using green fluorescent malaria parasites to screen for permissive vector mosquitoes.Malar. J. 2006; 5: 23Crossref PubMed Scopus (18) Google Scholar, 48Akaki M. Dvorak J.A. A chemotactic response facilitates mosquito salivary gland infection by malaria sporozoites.J. Exp. Biol. 2005; 208: 3211-3218Crossref PubMed Scopus (29) Google Scholar]. Similarly to the sporozoites that make it into the bloodstream, the parasites in the hemolymph have the capacity to actively migrate but do not do so in the open circulation of the mosquito. Only once sporozoites attach to the salivary glands do they need to move across the basal membrane and the acinar cells to accumulate in the salivary cavity of these glands [49Sterling C.R. et al.The passage of Plasmodium berghei sporozoites through the salivary glands of Anopheles stephensi: an electron microscope study.J. Parasitol. 1973; 59: 593-605Crossref PubMed Scopus (84) Google Scholar, 50Pimenta P.F. et al.The journey of malaria sporozoites in the mosquito salivary gland.J. Eukaryot. Microbiol. 1994; 41: 608-624Crossref PubMed Scopus (103) Google Scholar, 51Frischknecht F. et al.Imaging movement of malaria parasites during transmission by Anopheles mosquitoes.Cell. Microbiol. 2004; 6: 687-694Crossref PubMed Scopus (146) Google Scholar]. Interestingly, once sporozoites have gained access to the salivary gland acinar cell, little forward motility can be observed. Most parasites move back-and-forth with little productive motility [51Frischknecht F. et al.Imaging movement of malaria parasites during transmission by Anopheles mosquitoes.Cell. Microbiol. 2004; 6: 687-694Crossref PubMed Scopus (146) Google Scholar]. As the infected mosquito probes for blood it ejects sporozoites along with its saliva. Once again, the sporozoites are passively transported by the flow of mosquito saliva. Thus a single parasite stage undergoes several different 'movement transitions' (Figure 1 and Table 1). Importantly, not only the sporozoite stage undergoes cycles of active migration and passive transport. After sporozoite invasion of the host liver, merozoites are formed by the thousands in infected hepatocytes, and these were long thought to get into the bloodstream by simple rupture of the hepatocyte, although it was not clear how they could cross the endothelium to reach the bloodstream [52Meis J.F. et al.Fine structure of exoerythrocytic merozoite formation of Plasmodium berghei in rat liver.J. Protozool. 1985; 32: 694-699Crossref PubMed Scopus (31) Google Scholar, 53Sturm A. Heussler V. Live and let die: manipulation of host hepatocytes by exoerythrocytic Plasmodium parasites.Med. Microbiol. Immunol. 2007; 196: 127-133Crossref PubMed Scopus (31) Google Scholar, 54Graewe S. et al.Chronicle of a death foretold: Plasmodium liver stage parasites decide on the fate of the host cell.FEMS Microbiol. Rev. 2012; 36: 111-130Crossref PubMed Scopus (32) Google Scholar]. Active migration was one possibility, because merozoites possess the necessary gliding machinery; however, it was discovered that small bags of merozoites bud off as merosomes from the infected cells [55Sturm A. et al.Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids.Science. 2006; 313: 1287-1290Crossref PubMed Scopus (387) Google Scholar]. Merosomes rupture to release merozoites [56Baer K. et al.Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature.PLoS Pathog. 2007; 3: e171Crossref PubMed Scopus (164) Google Scholar] that presumably are passively carried in the blood until they attach to and invade a red blood cell (Figure 1). In observed static conditions, merozoites enter red blood cells by actively migrating across a junction they establish between the two cells [57Baum J. et al.Host-cell invasion by malaria parasites: insights from Plasmodium and Toxoplasma.Trends Parasitol. 2008; 24: 557-563Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar]. After invasion, growth, and schizogony, new merozoites are explosively released from the red blood cell [58Abkarian M. et al.A novel mechanism for egress of malarial parasites from red blood cells.Blood. 2011; 117: 4118-4124Crossref PubMed Scopus (74) Google Scholar], and are briefly transported again within the blood before attaching to and invading an uninfected blood cell (Figure 1 and Table 1). Attachment to and invasion of red blood cells are thought of as good targets for vaccines and possibly also drugs [59Rodriguez L.E. et al.Intimate molecular interactions of P. falciparum merozoite proteins involved in invasion of red blood cells and their implications for vaccine design.Chem. Rev. 2008; 108: 3656-3705Crossref PubMed Scopus (88) Google Scholar, 60Chandramohanadas R. et al.Small molecule targeting malaria merozoite surface protein-1 (MSP-1) prevents host invasion of divergent plasmodial species.J. Infect. Dis. 2014; 210: 1616-1626Crossref PubMed Scopus (31) Google Scholar]. Several proteins involved in either or both processes are at different stages of subunit vaccine development with the hope that antibodies against these proteins could protect infected people by blocking the access of the parasite to the red blood cell [61O'Donnell R.A. et al.Antibodies against merozoite surface protein (MSP)-1(19) are a major component of the invasion-inhibitory response in individuals immune to malaria.J. Exp. Med. 2001; 193: 1403-1412Crossref PubMed Scopus (235) Google Scholar, 62Barry A.E. Arnott A. Strategies for designing and monitoring malaria vaccines targeting diverse antigens.Front. Immunol. 2014; 5: 359Crossref PubMed Scopus (75) Google Scholar, 63Wright G.J. Rayner J.C. Plasmodium falciparum erythrocyte invasion: combining function with immune evasion.PLoS Pathog. 2014; 10: e1003943Crossref PubMed Scopus (110) Google Scholar]. Apical membrane antigen 1 (AMA1) and merozoite surface protein 1 (MSP1) are such candidates. The role of MSP1 (the major surface antigen of merozoites) in mediating initial attachment to target erythrocytes appears to be clear [64Kadekoppala M. Holder A.A. Merozoite surface proteins of the malaria parasite: the MSP1 complex and the MSP7 family.Int. J. Parasitol. 2010; 40: 1155-1161Crossref PubMed Scopus (58) Google Scholar]. However, the role played by AMA1 is contested – initial data suggest a role in invasion whereas more recent data indicate a role in attachment [65Giovannini D. et al.Independent roles of apical membrane antigen 1 and rhoptry neck proteins during host cell invasion by apicomplexa.Cell Host Microbe. 2011; 10: 591-602Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 66Bargieri D.Y. et al.Apical membrane antigen 1 mediates apicomplexan parasite attachment but is dispensable for host cell invasion.Nat. Commun. 2013; 4: 2552Crossref PubMed Scopus (107) Google Scholar]. For our discourse, understanding whether AMA1 functions in invasion or attachment will determine when antibodies need to act to prevent infection. Not all merozoites that successfully invade proceed to undergo schizogony and produce more merozoites. A fraction of invaded parasites transform into male and female gametocytes – parasites under cell cycle arrest that are prepared for transmission back to the mosquito [67Kuehn A. Pradel G. The coming-out of malaria gametocytes.J. Biomed. Biotechnol. 2010; 2010: 976827Crossref PubMed Scopus (84) Google Scholar]. After gametogenesis, the male gamete actively swims within the bolus of the blood-meal in the mosquito stomach and fuses with the female gamete [68Sinden R.E. Croll N.A. Cytology and kinetics of microgametogenesis and fertilization in Plasmodium yoelii nigeriensis.Parasitology. 1975; 70: 53-65Crossref PubMed Scopus (54) Google Scholar]. Transmission-blocking approaches can target multiple aspects: gamete maturation, the active motility of the male gamete, or the docking of the two cells [69Gwadz R.W. Successful immunization against the sexual stages of Plasmodium gallinaceum.Science. 1976; 193: 1150-1151Crossref PubMed Scopus (135) Google Scholar, 70Carter R. et al.Plasmodium gallinaceum: transmission-blocking immunity in chickens. II. The effect of antigamete antibodies in vitro and in vivo and their elaboration during infection.Exp. Parasitol. 1979; 47: 194-208Crossref PubMed Scopus (42) Google Scholar, 71Healer J. et al.Transmission-blocking immunity to Plasmodium falciparum in malaria-immune individuals is associated with antibodies to the gamete surface protein Pfs230.Parasitology. 1999; 119: 425-433Crossref PubMed Scopus (60) Google Scholar, 72Hirai M. Mori T. Fertilization is a novel attacking site for the transmission blocking of malaria parasites.Acta Trop. 2010; 114: 157-161Crossref PubMed Scopus (17) Google Scholar, 73Ojo K.K. et al.Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors.J. Clin. Invest. 2012; 122: 2301-2305Crossref PubMed Scopus (89) Google Scholar]. Finally, after fertilization and zygote formation, a motile egg cell, the ookinete, forms and actively penetrates the peritrophic matrix surrounding the blood meal and the underlying epithelial cells of the mosquito midgut. Before attaching to the matrix, the ookinete may not actively move in the mosquito midgut because this environment provides little traction for gliding motility. However, once attached to the mosquito midgut, the ookinete actively moves across this cell layer [74Angrisano F. et al.Malaria parasite colonisation of the mosquito midgut – placing the Plasmodium ookinete centre stage.Int. J. Parasitol. 2012; 42: 519-527Crossref PubMed Scopus (44) Google Scholar] (Figure 1). Secreted or surface proteins of the ookinetes that assist in traversal again could serve as targets for transmission-blocking antibodies or peptides, and thus prevent oocyst formation in the mosquito [75Barr P.J. et al.Recombinant Pfs25 protein of Plasmodium falciparum elicits malaria transmission-blocking immunity in experimental animals.J. Exp. Med. 1991; 174: 1203-1208Crossref PubMed Scopus (176) Google Scholar, 76Shahabuddin M. et al.Transmission-blocking activity of a chitinase inhibitor and activation of malarial parasite chitinase by mosquito protease.Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 4266-4270Crossref PubMed Scopus (239) Google Scholar, 77Birkett A.J. et al.Malaria vaccine R&D in the Decade of Vaccines: breakthroughs, challenges and opportunities.Vaccine. 2013; 31: B233-B243Crossref PubMed Scopus (57) Google Scholar]. The complexities of the Plasmodium life cycle provide many challenges in fully understanding how the parasite proliferates and disseminates, but also offer us multiple opportunities for intervention. Indeed, developing drug or vaccine combinations that could target multiple proteins and stages is desirable [1Flannery E.L. et al.Antimalarial drug discovery – approaches and progress towards new medicines.Nat. Rev. Microbiol. 2013; 11: 849-862Crossref PubMed Scopus (229) Google Scholar]. It is our intention in this article to point out that blocking the ability of the parasite to actively move and/or interact with host factors for invasion opens up both therapeutic and preventive opportunities. The skin serves as the first mammalian barrier for the sporozoite, and is thus the first site where preventive agents can be employed. The skin phase is a significant bottleneck for the parasite both in terms of numbers and exposure to antibody-mediated responses. Studies in mice have supported the idea that antibody-mediated responses can halt active movement and/or result in complement-mediated cytotoxicity of sporozoites in the skin to prevent infection [23Sack B.K. et al.Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum.Infect. Immun. 2014; 82: 808-817Crossref PubMed Scopus (67) Google Scholar, 24Vanderberg J.P. Frevert U. Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes.Int. J. Parasitol. 2004; 34: 991-996Crossref PubMed Scopus (257) Google Scholar, 25Kebaier C. et al.Kinetics of mosquito-injected Plasmodium sporozoites in mice: fewer sporozoites are injected into sporozoite-immunized mice.PLoS Pathog. 2009; 5: e1000399Crossref PubMed Scopus (85) Google Scholar, 78Yilmaz B. et al.Gut microbiota elicits a protective immune response against malaria transmission.Cell. 2014; 159: 1277-1289Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar]. Hence, while one could contemplate strategies to activate complement or immune cells that stop the passively transported parasites in the blood, it might also be sensible to develop strategies to block active migration. For example, if one targets a conserved motility mechanism by a drug, this could likewise block active migration of sporozoites, invasion of erythrocytes by merozoites, or ookinete motility [79Baum J. et al.Regulation of apicomplexan actin-based motility.Nat. Rev. Microbiol. 2006; 4: 621-628Crossref PubMed Scopus (131) Google Scholar]. There are indeed suggestions in the literature that low molecular weight molecules could be used to stop active parasite movement [80Hellmann J.K. et al.Synergistic and additive effects of epigallocatechin gallate and digitonin on Plasmodium sporozoite survival and motility.PLoS ONE. 2010; 5: e8682Crossref PubMed Scopus (43) Google Scholar, 81Lentz C.S. et al.In vitro activity of wALADin benzimidazoles against different life cycle stages of Plasmodium parasites.Antimicrob. Agents Chemother. 2015; 59: 654-658Crossref PubMed Scopus (4) Google Scholar, 82Liehl P. et al.Phosphothioate oligodeoxynucleotides inhibit Plasmodium sporozoite gliding motility.Cell. Microbiol. 2010; 12: 506-515Crossref PubMed Scopus (11) Google Scholar, 83Miller L.H. et al.Interaction between cytochalasin B-treated malarial parasites and erythrocytes. Attachment and junction formation.J. Exp. Med. 1979; 149: 172-184Crossref PubMed Scopus (263) Google Scholar, 84Siden-Kiamos I. et al.Involvement of actin and myosins in Plasmodium berghei ookinete motility.Mol. Biochem. Parasitol. 2006; 150: 308-317Crossref PubMed Scopus (38) Google Scholar, 85Munter S. et al.Plasmodium sporozoite motility is modulated by the turnover of discrete adhesion sites.Cell Host Microbe. 2009; 6: 551-562Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 86Mizuno Y. et al.Effect of jasplakinolide on the growth, invasion, and actin cytoskeleton of Plasmodium falciparum.Parasitol. Res. 2002; 88: 844-848Crossref PubMed Scopus (41) Google Scholar]. Perhaps potent and parasite-selective inhibitors could be developed for formulation in topical insect-repellant creams that would serve as a malaria prophylaxis strategy. Compound libraries such as those made available by Medicines for Malaria Venture could accelerate the discovery and development of such molecules [87Spangenberg T. et al.The open access malaria box: a drug discovery catalyst for neglected diseases.PLoS ONE. 2013; 8: e62906Crossref PubMed Scopus (267) Google Scholar]. The malaria parasite undergoes alternating phases of active and passive migration in different tissues during its life cycle. The life cycle can be subdivided into at least seven actively-motile stages and six stages in which it is passively carried by the mosquito or mammalian host, each presenting different opportunities as drug or vaccine targets. Appreciating the full complexity of this fascinating parasite would allow for more targeted therapeutic interventions. R.D. was funded by a fellowship from the CellNetworks – Cluster of Excellence (EXC81) at Heidelberg University and a European Research Council starting grant (ERC-StG-281719) to F.F. R.A. is supported by the French National Agency for Research (IM3alaria) and the Institut Pasteur. F.F. is a member of the European Commission Framework Program 7 network EVIMalaR and the Collaborative Research Center 1129 of the German Research Foundation. P.S. is supported by the US National Institutes of Health (AI056840) and The Bloomberg Family Foundation.
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