Development of the malaria parasite in the skin of the mammalian host

Abstract

The first step of Plasmodium development in vertebrates is the transformation of the sporozoite, the parasite stage injected by the mosquito in the skin, into merozoites, the stage that invades erythrocytes and initiates the disease. The current view is that, in mammals, this stage conversion occurs only inside hepatocytes. Here, we document the transformation of sporozoites of rodentinfecting Plasmodium into merozoites in the skin of mice. After mosquito bite, ∼50% of the parasites remain in the skin, and at 24 h ∼10% are developing in the epidermis and the dermis, as well as in the immunoprivileged hair follicles where they can survive for weeks. The parasite developmental pathway in skin cells, although frequently abortive, leads to the generation of merozoites that are infective to erythrocytes and are released via merosomes, as typically observed in the liver. Therefore, during malaria in rodents, the skin is not just the route to the liver but is also the final destination for many inoculated parasites, where they can differentiate into merozoites and possibly persist.intravital imaging | Plasmodium | schizogony M alarial infection starts with the inoculation of Plasmodium sporozoites by mosquitoes probing the vertebrate skin for blood. The highly motile sporozoites eventually invade host target cells where they differentiate and divide into numerous merozoites, the parasite form that invades erythrocytes and initiates the pathogenic phase of malarial infection. The host cell type in which sporozoites transform into merozoites, however, differs between Plasmodium species. In species that infect birds, sporozoites differentiate inside macrophages primarily in the skin but also in the spleen, liver, and bone marrow (1). In species that infect mammals, sporozoites are known to differentiate only inside hepatocytes in the liver (2-4).The first demonstration that sporozoites of mammal-infecting Plasmodium species develop inside hepatocytes was made in 1948 after i.v. inoculation of sporozoites of P. cynomologi into rhesus monkeys (2). In addition to reporting fully mature parasites inside hepatocytes, the authors also documented the persistence of immature and dormant forms of the parasite in the liver several months after the initial inoculation, which they proposed to be the cause of relapses (5), and were later called hypnozoites (6). Subsequent work indicated that sporozoites of species that infect humans (7) also undergo complete development inside hepatocytes.Since these early studies, P. berghei and the related P. yoelii species, which infect rodents, have been used as practical and safe models for studying the pre-erythrocytic phase of malaria. These parasites were shown to differentiate in the liver of laboratory rodents (8), and the P. berghei/rodent system was used to demonstrate that the majority of sporozoites were inoculated by mosquitoes in the skin rather than directly into the blood circulation (9), as traditionally assumed. More recently, the generation of fluorescent P. berghei parasites, alo...

Early skin immunological disturbance after Plasmodium-infected mosquito bites

“…Presumably, transverse dermal cell movements by sporozoites (from the invasion of host cells that cause disruption of the plasma membrane) [9] are important for future establishment of liver stage infection, since it is the mechanism by which these parasites can escape from the dermal phagocytes [10]. More recently, it was reported that a small proportion of the dermal sporozoites can continue their development into merozoite forms (as they usually do inside liver cells) by infecting hair follicle cells [11]. Nonetheless, the contribution of these dermal merozoite forms compared to the entire host infection appears to be either inexistent or minimal [11].…”

“…More recently, it was reported that a small proportion of the dermal sporozoites can continue their development into merozoite forms (as they usually do inside liver cells) by infecting hair follicle cells [11]. Nonetheless, the contribution of these dermal merozoite forms compared to the entire host infection appears to be either inexistent or minimal [11]. Sporozoites injected by infected mosquitoes into actively immunized mice (animals pre-treated with irradiated sporozoites), or passively immunized animals (mice that received mAbs against sporozoites), stop moving and are rapidly destroyed [7,12], thereby inferring that immune system pre-activation by the first parasite inoculation can prevent future infections by new sporozoites.…”

New approaches in antimalarial drug discovery and development: a review

“…When available, the tests are useful tools to investigate drug activity against pre-erythrocytic stages of the parasites , Mazier et al 2009). The use of GFP sporozoites would be useful in protocols because this approach would allow the parasite route to be followed from the site of inoculation to the liver cells (Gueirard et al 2010), thus elucidating where the parasite is targeted by the antimalarials. The anti-sporozoite activity of two medicinal plants, Ampelozyziphus amazonicus and Strychnopsis thouarsii, has been demonstrated; these drugs were used in malaria-endemic areas of Brazil (AndradeNeto et al 2008, Krettli et al 2001 and Madagascar (Carraz et al 2006), as discussed below.…”

Malária: Dos velhos fármacos aos novos alvos moleculares

“…Cerca de 15 a 200 esporozoítos são injetados por um único mosquito infectado (AMINO et al, 2006;GUEIRARD et al, 2010;SILVIE et al, 2007). No sistema circulatório, após cerca de 60 minutos os esporozoítos invadem os hepatócitos, iniciando assim o ciclo exoeritrocítico.…”