When Is a Plasmodium-Infected Mosquito an Infectious Mosquito?
2020; Elsevier BV; Volume: 36; Issue: 8 Linguagem: Inglês
10.1016/j.pt.2020.05.011
ISSN1471-5007
AutoresWouter Graumans, Ella Jacobs, Teun Bousema, Photini Sinnis,
Tópico(s)Insect Pest Control Strategies
ResumoThe discrepancy between exposure to infected mosquito bites and malaria incidence suggests a transmission bottleneck that is currently understudied.Recent studies from non-human malaria models are indicative of a minimum salivary gland sporozoite density that is required to achieve infection following a mosquito bite.Infection-induced alterations in blood-feeding behavior of mosquitoes may influence natural transmission dynamics. Plasmodium parasites experience significant bottlenecks as they transit through the mosquito and are transmitted to their mammalian host. Oocyst prevalence on mosquito midguts and sporozoite prevalence in salivary glands are nevertheless commonly used to confirm successful malaria transmission, assuming that these are reliable indicators of the mosquito's capacity to give rise to secondary infections. Here we discuss recent insights in sporogonic development and transmission bottlenecks for Plasmodium. We highlight critical gaps in our knowledge and frame their importance in understanding the human and mosquito reservoirs of infection. A better understanding of the events that lead to successful inoculation of infectious sporozoites by mosquitoes is critical to designing effective interventions to shrink the malaria map. Plasmodium parasites experience significant bottlenecks as they transit through the mosquito and are transmitted to their mammalian host. Oocyst prevalence on mosquito midguts and sporozoite prevalence in salivary glands are nevertheless commonly used to confirm successful malaria transmission, assuming that these are reliable indicators of the mosquito's capacity to give rise to secondary infections. Here we discuss recent insights in sporogonic development and transmission bottlenecks for Plasmodium. We highlight critical gaps in our knowledge and frame their importance in understanding the human and mosquito reservoirs of infection. A better understanding of the events that lead to successful inoculation of infectious sporozoites by mosquitoes is critical to designing effective interventions to shrink the malaria map. Malaria, the deadliest human vector-borne disease, is caused by parasites of the genus Plasmodium and is transmitted by Anopheles mosquitoes. Transmission of Plasmodium parasites between their mosquito and mammalian hosts is a bottleneck for the parasite and constitutes vulnerabilities that could be leveraged in malaria-elimination efforts (Figure 1). Transmission from humans to mosquitoes starts with sexual commitment following activation of Apatella2-g (PfAP2-G) [1.Sinha A. et al.A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.Nature. 2014; 507: 253-257Crossref PubMed Scopus (179) Google Scholar,2.Kafsack B.F. et al.A transcriptional switch underlies commitment to sexual development in malaria parasites.Nature. 2014; 507: 248-252Crossref PubMed Scopus (188) Google Scholar], that is under epigenetic control of heterochromatin protein 1 (PfHP1) [3.Brancucci N.M.B. et al.Heterochromatin protein 1 secures survival and transmission of malaria parasites.Cell Host Microbe. 2014; 16: 165-176Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] and gametocyte development 1 (GDV1) [4.Filarsky M. et al.GDV1 induces sexual commitment of malaria parasites by antagonizing HP1-dependent gene silencing.Science. 2018; 359: 1259-1263Crossref PubMed Scopus (46) Google Scholar], leading to the development of male and female gametocytes within the human host [5.Inselburg J. 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Spreading the seeds of million-murdering death: metamorphoses of malaria in the mosquito.Trends Parasitol. 2005; 21: 573-580Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Mature sporozoites exit the oocyst into the open circulatory system of the mosquito with a proportion successfully invading the mosquito salivary glands [17.Mueller A.K. et al.Invasion of mosquito salivary glands by malaria parasites: prerequisites and defense strategies.Int. J. Parasitol. 2010; 40: 1229-1235Crossref PubMed Scopus (19) Google Scholar,18.Sinden R.E. et al.Progression of Plasmodium berghei through Anopheles stephensi is density-dependent.PLoS Pathog. 2007; 3e195Crossref PubMed Scopus (87) Google Scholar]. Sporozoites remain in the salivary glands and may render adult mosquitoes infectious for the remainder of their lifespan [16.Beier J.C. Malaria parasite development in mosquitoes.Annu. Rev. Entomol. 1998; 43: 519-543Crossref PubMed Scopus (0) Google Scholar]. The rate at which sporozoites are inoculated into the next host, how this is related to the density of gametocytes in the human host, oocyst burden and salivary gland sporozoite burden are matters of current debate [19.Churcher T.S. et al.Probability of transmission of malaria from mosquito to human is regulated by mosquito parasite density in naive and vaccinated hosts.PLoS Pathog. 2017; 13e1006108Crossref PubMed Scopus (42) Google Scholar, 20.Walk J. et al.Mosquito infectivity and parasitemia after controlled human malaria infection.Am. J. Trop. Med. Hyg. 2018; 98: 1705-1708Crossref PubMed Scopus (2) Google Scholar, 21.Stone W.J. et al.The relevance and applicability of oocyst prevalence as a read-out for mosquito feeding assays.Sci. Rep. 2013; 3: 3418Crossref PubMed Google Scholar]. It is, however, evident that sporogonic development in mosquitoes involves several bottlenecks where Plasmodium parasites are present in vulnerably low numbers (Figure 1). Here, we review the available literature on developmental bottlenecks in mosquitoes with a focus on recent manuscripts on the transition from salivary gland sporozoites to skin sporozoites. We argue that this understudied area of malaria transmission is of key importance to better appreciate the dynamics of malaria transmission in natural settings, quantify the contribution of different populations of infected individuals (e.g. high- and low-density gametocyte carriers) to onward transmission and predict the impact of malaria interventions. Oocysts are typically detected by microscopy on the Anopheles mosquito's midgut wall 7–9 days after an infectious bloodmeal, although some markers allow much earlier oocyst detection [22.Itsara L.S. et al.PfCap380 as a marker for Plasmodium falciparum oocyst development in vivo and in vitro.Malar. J. 2018; 17: 135Crossref PubMed Scopus (0) Google Scholar]. The density of oocysts is strongly determined by the gametocyte density in the peripheral blood of the infectious human host that formed the source of the mosquito's infection [23.Bradley J. et al.Predicting the likelihood and intensity of mosquito infection from sex specific Plasmodium falciparum gametocyte density.eLife. 2018; 7e34463Crossref PubMed Scopus (22) Google Scholar,24.Kiattibutr K. et al.Infectivity of symptomatic and asymptomatic Plasmodium vivax infections to a Southeast Asian vector, Anopheles dirus.Int. J. Parasitol. 2017; 47: 163-170Crossref PubMed Scopus (28) Google Scholar]. Following the formation of oocysts on the mosquito's midgut basal wall, a massive expansion of parasite numbers occurs through a replication process known as schizogony. This is a syncytial mode of replication in which genomic DNA replication, after multiple rounds of mitotic nuclear division, precedes cytoplasmic compartmentalization into individual sporozoites by the formation of cytoplasmic islands [15.Baton L.A. Ranford-Cartwright L.C. Spreading the seeds of million-murdering death: metamorphoses of malaria in the mosquito.Trends Parasitol. 2005; 21: 573-580Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], called sporoblasts, from which sporozoites bud, each containing one nucleus and the appropriate number of individual organelles, ultimately filling the oocyst with thousands of crescent-shaped sporozoites (10–15 μm by 1 μm in diameter). One successful oocyst produces between 1500 and 5000 individual sporozoites [25.Wang C.Y.T. et al.Assessing Plasmodium falciparum transmission in mosquito-feeding assays using quantitative PCR.Malar. J. 2018; 17: 249Crossref PubMed Scopus (5) Google Scholar,26.Rosenberg R. Rungsiwongse J. The number of sporozoites produced by individual malaria oocysts.Am. J. Trop. Med. Hyg. 1991; 45: 574-577Crossref PubMed Scopus (51) Google Scholar]. Sporozoite egress is required for sporozoite release in the mosquito's hemocoel and is actively established by parasite-dependent proteolysis. In this process, reviewed by Kojin et al. [27.Kojin B.B. Adelman Z.N. The sporozoite's journey through the mosquito: a critical examination of host and parasite factors required for salivary gland invasion.Front. Ecol. Evol. 2019; 7 (Published online August 14, 2019. https://doi.org/10.3389/fevo.2019.00284)Crossref Scopus (0) Google Scholar], a parasite-derived cysteine protease plays a central role in rupture of the capsule [28.Aly A.S. Matuschewski K. A malarial cysteine protease is necessary for Plasmodium sporozoite egress from oocysts.J. Exp. Med. 2005; 202: 225-230Crossref PubMed Scopus (120) Google Scholar] – together with the circumsporozoite protein (CSP), which can be found on the oocyst plasma membrane and the inner surface of the capsule [29.Wang Q. et al.Exit of Plasmodium sporozoites from oocysts is an active process that involves the circumsporozoite protein.PLoS Pathog. 2005; 1: 72-79Crossref Scopus (30) Google Scholar]. Recently two essential proteins were identified, oocyst rupture protein (ORP) 1 and 2, that promote heterodimer formation in the oocyst after maturation, possibly leading directly or indirectly to destabilization and the activation of the cysteine protease [30.Curra C. et al.Release of Plasmodium sporozoites requires proteins with histone-fold dimerization domains.Nat. Commun. 2016; 7: 13846Crossref PubMed Scopus (6) Google Scholar,31.Siden-Kiamos I. et al.Identification of Plasmodium berghei oocyst rupture protein 2 (ORP2) domains involved in sporozoite egress from the oocyst.Int. J. Parasitol. 2018; 48: 1127-1136Crossref PubMed Scopus (2) Google Scholar]. Since rupture occurs for the majority of oocysts in low-infected mosquitoes [21.Stone W.J. et al.The relevance and applicability of oocyst prevalence as a read-out for mosquito feeding assays.Sci. Rep. 2013; 3: 3418Crossref PubMed Google Scholar], it is generally assumed that oocyst positivity is a reliable indicator of later infectivity of mosquitoes. This, however, depends on the migration of sporozoites into salivary glands. Upon exit from the oocyst, sporozoites enter the open circulatory system of the mosquito, which consists of a dorsal vessel, spanning the length of the mosquito, that contracts to generate waves of directional flow. Released sporozoites can enter the abdominal portion of the dorsal vessel through openings, called ostia, and be passively carried anteriorly with the flow, exiting the vessel in the thoracic cavity near the salivary glands [32.Hillyer J.F. Pass G. The insect circulatory system: structure, function, and evolution.Annu. Rev. Entomol. 2020; 65: 121-143Crossref PubMed Scopus (0) Google Scholar, 33.Hillyer J.F. et al.Efficiency of salivary gland invasion by malaria sporozoites is controlled by rapid sporozoite destruction in the mosquito haemocoel.Int. J. Parasitol. 2007; 37: 673-681Crossref PubMed Scopus (0) Google Scholar, 34.Glenn J.D. et al.Structural mechanics of the mosquito heart and its function in bidirectional hemolymph transport.J. Exp. Biol. 2010; 213: 541-550Crossref PubMed Scopus (60) Google Scholar]. Sporozoites that do not enter the dorsal vessel are carried with the flow of hemolymph throughout the mosquito body, and while a proportion likely enter salivary glands, many can be found trapped in the mosquito's appendages, the alary muscle, and other locations [33.Hillyer J.F. et al.Efficiency of salivary gland invasion by malaria sporozoites is controlled by rapid sporozoite destruction in the mosquito haemocoel.Int. J. Parasitol. 2007; 37: 673-681Crossref PubMed Scopus (0) Google Scholar,35.Golenda 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 Google Scholar]. The hemolymph contains immune factors and phagocytic cells, called hemocytes, and one study found evidence of sporozoite degradation in the hemolymph [33.Hillyer J.F. et al.Efficiency of salivary gland invasion by malaria sporozoites is controlled by rapid sporozoite destruction in the mosquito haemocoel.Int. J. Parasitol. 2007; 37: 673-681Crossref PubMed Scopus (0) Google Scholar]. Nonetheless, the degree to which this occurs and the mechanism(s) by which this occurs remain understudied. There is a paucity of studies that have looked at the efficiency with which oocyst sporozoites colonize salivary glands [26.Rosenberg R. Rungsiwongse J. The number of sporozoites produced by individual malaria oocysts.Am. J. Trop. Med. Hyg. 1991; 45: 574-577Crossref PubMed Scopus (51) Google Scholar,33.Hillyer J.F. et al.Efficiency of salivary gland invasion by malaria sporozoites is controlled by rapid sporozoite destruction in the mosquito haemocoel.Int. J. Parasitol. 2007; 37: 673-681Crossref PubMed Scopus (0) Google Scholar]. Rosenberg et al. counted the sporozoites in single oocysts of Plasmodium falciparum- and Plasmodium vivax-infected mosquitoes and compared these numbers with a previous study in which salivary-gland sporozoites were enumerated; they estimated that 20% of oocyst sporozoites successfully enter salivary glands [26.Rosenberg R. Rungsiwongse J. The number of sporozoites produced by individual malaria oocysts.Am. J. Trop. Med. Hyg. 1991; 45: 574-577Crossref PubMed Scopus (51) Google Scholar]. In another study, using mosquitoes heavily infected with the rodent malaria parasite Plasmodium berghei, a 10-fold lower efficiency of salivary gland entry by sporozoites was estimated [18.Sinden R.E. et al.Progression of Plasmodium berghei through Anopheles stephensi is density-dependent.PLoS Pathog. 2007; 3e195Crossref PubMed Scopus (87) Google Scholar]. Upon arrival at the glands, entry is dependent on recognition events between sporozoites and salivary-gland proteins, a process reviewed in detail by Ghosh and Jacobs-Lorena [36.Ghosh A.K. Jacobs-Lorena M. Plasmodium sporozoite invasion of the mosquito salivary gland.Curr. Opin. Microbiol. 2009; 12: 394-400Crossref PubMed Scopus (32) Google Scholar], Mueller et al. [17.Mueller A.K. et al.Invasion of mosquito salivary glands by malaria parasites: prerequisites and defense strategies.Int. J. Parasitol. 2010; 40: 1229-1235Crossref PubMed Scopus (19) Google Scholar], and Kojin et al. [27.Kojin B.B. Adelman Z.N. The sporozoite's journey through the mosquito: a critical examination of host and parasite factors required for salivary gland invasion.Front. Ecol. Evol. 2019; 7 (Published online August 14, 2019. https://doi.org/10.3389/fevo.2019.00284)Crossref Scopus (0) Google Scholar]. On the sporozoite side, CSP, thrombospondin-related anonymous protein (TRAP), TRAP-related protein (TREP), and apical membrane antigen/erythrocyte binding-like protein (MAEBL) have been shown to be involved in this process [37.Kariu T. et al.MAEBL is essential for malarial sporozoite infection of the mosquito salivary gland.J. Exp. Med. 2002; 195: 1317-1323Crossref PubMed Scopus (81) Google Scholar,38.Combe A. et al.TREP, a novel protein necessary for gliding motility of the malaria sporozoite.Int. J. Parasitol. 2009; 39: 489-496Crossref PubMed Scopus (31) Google Scholar]. CSP is known to bind to heparan sulfate proteoglycans and this may constitute the basis for the initial recognition event as these glycans are found on salivary glands [39.Sinnis P. et al.Mosquito heparan sulfate and its potential role in malaria infection and transmission.J. Biol. Chem. 2007; 282: 25376-25384Crossref PubMed Scopus (58) Google Scholar,40.Frevert U. et al.Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes.J. Exp. Med. 1993; 177: 1287-1298Crossref PubMed Google Scholar]. On the host side, several salivary-gland proteins involved in sporozoite invasion have been identified – CSP-binding protein (CSPBP), salivary gland surface protein 1 (SGS1), and Saglin being the best characterized [41.Wang J. et al.Anopheles gambiae circumsporozoite protein-binding protein facilitates Plasmodium infection of mosquito salivary glands.J. Infect. Dis. 2013; 208: 1161-1169Crossref PubMed Scopus (18) Google Scholar,42.Ghosh A.K. et al.Malaria parasite invasion of the mosquito salivary gland requires interaction between the Plasmodium TRAP and the Anopheles saglin proteins.PLoS Pathog. 2009; 5e1000265Crossref PubMed Scopus (59) Google Scholar]. CSPBP and Saglin were identified in screens using CSP or TRAP, respectively. CSPBP- or SGS1-specific antibodies and peptides inhibiting the TRAP–Saglin interaction decrease invasion of the salivary glands by sporozoites. However, the specific role of Saglin, as an essential salivary-gland receptor for sporozoite invasion, was recently doubted when no protein expression was observed in the distal lateral lobes of the salivary gland, a primary sporozoite invasion site [43.O'Brochta D.A. et al.Is Saglin a mosquito salivary gland receptor for Plasmodium falciparum?.Malar. J. 2019; 18: 2Crossref PubMed Scopus (1) Google Scholar]. Together, these studies suggest that entry into salivary glands is a complex process involving several sporozoite proteins as well as mosquito glycans and proteins. Indeed, visualization of this process by detailed, sequential electron micrographs suggests that there is an initial recognition event between the sporozoite surface coat and the salivary gland basal lamina, followed by tighter adhesion and entry into the cells [44.Pimenta P.F. et al.The journey of malaria sporozoites in the mosquito salivary gland.J. Eukaryot. Microbiol. 1994; 41: 608-624Crossref PubMed Google Scholar]. Additional binding studies, as well as in vivo knockdown studies in the mosquito using RNAi, are needed to further elucidate the molecular events involved in this process [45.Okulate M.A. et al.Identification and molecular characterization of a novel protein Saglin as a target of monoclonal antibodies affecting salivary gland infectivity of Plasmodium sporozoites.Insect Mol. Biol. 2007; 16: 711-722Crossref PubMed Scopus (0) Google Scholar,46.Brennan J.D.G. et al.Anopheles gambiae salivary gland proteins as putative targets for blocking transmission of malaria parasites.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13859-13864Crossref PubMed Scopus (0) Google Scholar]. Experiments that directly examined the number of ruptured oocysts in relation to salivary gland sporozoite load suggest that, on average, 1250 sporozoites reach the salivary gland per ruptured oocyst [21.Stone W.J. et al.The relevance and applicability of oocyst prevalence as a read-out for mosquito feeding assays.Sci. Rep. 2013; 3: 3418Crossref PubMed Google Scholar]; other studies estimate higher sporozoite numbers per oocyst but do not directly relate this to oocyst rupture [25.Wang C.Y.T. et al.Assessing Plasmodium falciparum transmission in mosquito-feeding assays using quantitative PCR.Malar. J. 2018; 17: 249Crossref PubMed Scopus (5) Google Scholar,26.Rosenberg R. Rungsiwongse J. The number of sporozoites produced by individual malaria oocysts.Am. J. Trop. Med. Hyg. 1991; 45: 574-577Crossref PubMed Scopus (51) Google Scholar]. Whilst these numbers are deemed sufficient to render a mosquito infectious for the remainder of her life, there are data suggesting that infectiousness decreases as sporozoites age, further complicating assessments of a mosquito's infectious potential in the field [47.Porter R.J. et al.Studies on malarial sporozoites. II. Effect of age and dosage of sporozoites on their infectiousness.Exp. Parasitol. 1954; 3: 267-274Crossref PubMed Google Scholar,48.Boyd M.F. et al.On the duration of infectiousness in anophelines harboring Plasmodium falciparum1.Am. J. Trop. Med. Hyg. 1936; s1-16: 157-158Crossref Google Scholar]. The salivary glands of female mosquitoes are paired organs, one on each side of the esophagus, with each gland consisting of three lobes, two lateral lobes, and a shorter median lobe. Each lobe is organized as a single layer of cup-shaped epithelial cells surrounding a large secretory cavity and a central salivary canal. In the distal portion of the glands, the salivary duct is continuous with the secretory cavity; however, as one moves anteriorly towards the proboscis, the ducts narrow, to about 1 μm in diameter, which is slightly wider than a single sporozoite, and become chitinized, eventually joining with the duct from the opposite gland to form the common salivary duct [49.Clements A.N. The Biology of Mosquitoes: Development, Nutrition, and Reproduction. Chapman & Hall, 1992Google Scholar]. Several studies have found that sporozoites preferentially enter the distal portions of the lateral and median lobes where the ducts are continuous with the secretory cavity [45.Okulate M.A. et al.Identification and molecular characterization of a novel protein Saglin as a target of monoclonal antibodies affecting salivary gland infectivity of Plasmodium sporozoites.Insect Mol. Biol. 2007; 16: 711-722Crossref PubMed Scopus (0) Google Scholar,50.Sinden R.E. The biology of Plasmodium in the mosquito.Experientia. 1984; 40: 1330-1343Crossref PubMed Google Scholar]. After their entry, sporozoites move into the secretory cavity and a few can be found in the salivary duct, awaiting their inoculation into the mammalian host [44.Pimenta P.F. et al.The journey of malaria sporozoites in the mosquito salivary gland.J. Eukaryot. Microbiol. 1994; 41: 608-624Crossref PubMed Google Scholar]. Sporozoites that enter the more proximal portions of the gland appear to be 'landlocked' and may not be able to enter the salivary canal [51.Sterling 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 Google Scholar]. Thus, the process of localization to the salivary glands and entry into the secretory cavities of the glands presents many barriers to transmission [52.Wells M.B. Andrew D.J. Anopheles salivary gland architecture shapes Plasmodium sporozoite availability for transmission.mBio. 2019; 10e01238-19Crossref PubMed Scopus (1) Google Scholar]. Plasmodium parasites take advantage of the obligate blood-feeding behavior of the mosquito to enter their mammalian host. After the mosquito stylet pierces the skin it commences to search for blood, the labrum thrusting and bending to survey the entire area within its reach. Release of saliva occurs during probing [53.Griffiths R.B. Gordon R.M. An apparatus which enables the process of feeding by mosquitoes to be observed in the tissues of a live rodent; together with an account of the ejection of saliva and its significance in malaria.Ann. Trop. Med. Parasitol. 1952; 46: 311-319Crossref PubMed Scopus (44) Google Scholar], contributing to the mosquito's ability to find blood due to saliva proteins that counteract the hemostatic and inflammatory responses of the host. The probing phase ends when the mosquito locates blood, having cannulated a vessel or created a hematoma from the rupture of capillaries. There is no evidence of significant salivation during imbibement of blood [49.Clements A.N. The Biology of Mosquitoes: Development, Nutrition, and Reproduction. Chapman & Hall, 1992Google Scholar,53.Griffiths R.B. Gordon R.M. An apparatus which enables the process of feeding by mosquitoes to be observed in the tissues of a live rodent; together with an account of the ejection of saliva and its significance in malaria.Ann. Trop. Med. Parasitol. 1952; 46: 311-319Crossref PubMed Scopus (44) Google Scholar], though, if it does occur, the difference in the flow rate of saliva compared with the counter flow of blood into the mosquito, estimated to be 104–105 times faster, would result in reingestion of the saliva secreted during blood feeding. Indeed, sporozoites have been found in the midguts of blood-fed mosquitoes [54.Beier M.S. et al.Ingestion of Plasmodium falciparum sporozoites during transmission by anopheline mosquitoes.Am. J. Trop. Med. Hyg. 1992; 47: 195-200Crossref PubMed Scopus (18) Google Scholar,55.Kebaier C. Vanderberg J.P. Re-ingestion of Plasmodium berghei sporozoites after delivery into the host by mosquitoes.Am. J. Trop. Med. Hyg. 2006; 75: 1200-1204Crossref PubMed Google Scholar]. The physiology of blood feeding suggests that sporozoites are predominately inoculated into the extravascular tissue. Experiments in which the bite site was removed, transplanted to naïve animals, or artificially heated, and in vivo visualization of the process of sporozoite inoculation, all support the notion that the majority of sporozoites are inoculated into the skin [56.Matsuoka 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 (0) Google Scholar, 57.Lloyd O.C. Sommerville T. The fate of sporozoites of Plasmodium cynomolgi injected into the skin of Rhesus monkeys.J. Pathol. Bacteriol. 1949; 61: 144-146Google Scholar, 58.Sidjanski 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 (111) Google Scholar, 59.Medica D.L. 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