Lessons Learned for Pathogenesis, Immunology, and Disease of Erythrocytic Parasites: Plasmodium and Babesia

Abstract

Malaria caused by Plasmodium species and transmitted by Anopheles mosquitoes affects large human populations, while Ixodes ticks transmit Babesia species and cause babesiosis. Babesiosis in animals has been known as an economic drain, and human disease has also emerged as a serious healthcare problem in the last 20-30 years. There is limited literature available regarding pathogenesis, immunity, and disease caused by Babesia spp. with their genomes sequenced only in the last decade. Therefore, using previous studies on Plasmodium as the foundation, we have compared similarities and differences in the pathogenesis of Babesia and host immune responses. Sexual life cycles of these two hemoparasites in their respective vectors are quite similar. An adult Anopheles female can take blood meal several times in its life such that it can both acquire and transmit Plasmodia to hosts. Since each tick stage takes blood meal only once, transstadial horizontal transmission from larva to nymph or nymph to adult is essential for the release of Babesia into the host. The initiation of the asexual cycle of these parasites is different because Plasmodium sporozoites need to infect hepatocytes before egressed merozoites can infect erythrocytes, while Babesia sporozoites are known to enter the erythrocytic cycle directly. Plasmodium metabolism, as determined by its two- to threefold larger genome than different Babesia, is more complex. Plasmodium replication occurs in parasitophorous vacuole (PV) within the host cells, and a relatively large number of merozoites are released from each infected RBC after schizogony. The Babesia erythrocytic cycle lacks both PV and schizogony. Cytoadherence that allows the sequestration of Plasmodia, primarily P. falciparum in different organs facilitated by prominent adhesins, has not been documented for Babesia yet. Inflammatory immune responses contribute to the severity of malaria and babesiosis. Antibodies appear to play only a minor role in the resolution of these diseases; however, cellular and innate immunity are critical for the clearance of both pathogens. Inflammatory immune responses affect the severity of both diseases. Macrophages facilitate the resolution of both infections and also offer cross-protection against related protozoa. Although the immunosuppression of adaptive immune responses by these parasites does not seem to affect their own clearance, it significantly exacerbates diseases caused by coinfecting bacteria during coinfections.

Keywords: Babesia; Plasmodium; babesiosis; hemoparasite; immune responses; malaria; pathogenesis; vector borne protozoa.

Figure 1

Life cycles of Plasmodium and Babesia species. After acquiring Plasmodium gametocytes from infected hosts, gametogenesis followed by fusion of gametes to produce zygote occurs in the midgut of Anopheles females. Ookinete passes through the midgut wall, and sporozoites are released from the oocyte into salivary glands that are transmitted to the host during blood meal. Similar steps are followed by Babesia species in ticks except it requires transstadial horizontal transmission of parasites from one stage of the tick developmental cycle to the next. After deposition in skin dermis, the haploid sporozoites of Plasmodium travel to the liver through blood and infect hepatocytes. After a single replication cycle, the merozoites released from hepatocytes enter the erythrocytic cycle. Invasion of hepatocytes is absent in the Babesia cycle. In addition, the Babesia cycle in RBCs differs from Plasmodium because unlike Plasmodium, it does not replicate in the parasitophorous vacuole, lacks PTEX secretion apparatus, and does not undergo schizogony. (Image of different stages of Ixodes scapularis ticks was generously provided by James Occi of Rutgers University at New Brunswick, NJ, USA.)

Figure 2

Differential morphological forms of B. microti during replication in RBCs of C3H mouse and in vitro culture of P. falciparum. (A) Clearly defined rings, pleomorphic trophozoites and pyriforms, and tetrads are observed during the replication of B. microti, while (B) rings, trophozoites, and schizonts are clearly observed during the erythrocytic cycle of P. falciparum.

Figure 3

Summary of host immune responses stimulated during Plasmodium and Babesia species infection that help in the clearance of parasites, cause death of the host due to excessive inflammation, or allow protozoan survival in the host for long periods of time. Uninfected individuals or animals were included as controls for comparison in various previous studies that formed the foundation of this figure.