Malaria. Parasite Life Cycle

(1)

ANDREW A. LOVER

Malaria Elimination Initiative, Global Health Group, University of California, San Francisco, United States

Malaria is caused by a family of protozoans transmitted by arthropod vectors, which invade red blood cells and cause a range of clinical manifestations, including fever, headache, and malaise; in many host species, this may progress to severe disease, including death.

There are more than 200 species of Plasmod-ium which infect primate, avian, rodent, and saurian (reptilian) hosts. Of these, approximately 50 described species infect primates, all of which are believed to be transmitted by mosquitoes of the Anopheles genus. While approximately 200 Anopheles species are capable of transmission, only 30–40 are important vectors.

Five Plasmodium parasites commonly infect humans: P. falciparum, P. vivax, P. malariae, P. ovalae (two sympatric species), and P. knowlesi (as a zoonosis from Macaca spp.). The health impact on human populations is massive: there were an estimated 214 million cases of malaria (95% CI: 149–303 million) and 438,000 malaria-related deaths (95% CI: 236,000–635,000) globally in 2015 (generally attributed to P. falciparum) (World Health Organization 2015).

Other well-studied primate parasites are those that can infect Macaca species, and include P. cynomolgi, P. innui, and P. fieldi. However, the best-studied parasites in animal systems are the rodent parasites P. berghei, P. yoelii, and P. chabaudi, which are generally well adapted to laboratory animals.

There has been limited study of Plasmodium infections in wild primate populations; however, some evidence exists that indicates pregnant chimpanzees have higher parasitemia due to immune modulation, and that increasing age was associated with lower parasitemia. This suggests human-like responses to repeated malaria infections in wild populations (Nys

The International Encyclopedia of Primatology. Edited by Agustín Fuentes.

captive and laboratory study populations may exhibit overt symptomatic illness. There are currently no data on the morbidity or mortality in wild populations; however, a recent case report found overt symptoms in a wild chimpanzee that closely mimics human malaria infections (Herbert et al. 2015). It is believed that in most host species, multiple lifetime infections confer some level of immunity to symptomatic illness, while allowing for continued asymp-tomatic chronic parasitemia. Generally similar patterns of fever have been observed in Pan and Macaca hosts with human parasites that have been adapted to nonhuman primates and in parasites from nonhuman populations (Coatney, Collins, and Contacos 1971); and some evidence suggests that malarias are less severe in nonhuman primates (Prugnolle et al. 2011).

Parasite Life Cycle

(2)

mosquito stages sexual stage: male or female gametocytes form human blood cell cycle human liver stage late mosquito stage human liver cell human blood cell gametocytes merozoites

The mosquito injects the parasite when it bites the human.

The mosquito consumes the parasite during blood feeding. 4 3 1 2 6 5 ookinete sporozoites gametes oocyst

Figure 1 Life cycle of the malaria parasite. Source: National Institute of Allergy and Infectious Diseases (NIAID).

(gametocytes) have both male and female forms, which then reproduce clonally (asexually) in the new vertebrate host. Another vector then feeds upon the host, ingesting gametocytes that mature in the insect midgut in oocysts, which rupture to release sporozoites, which migrate throughout the arthropod hemolymph to accu-mulate preferentially in the salivary glands; this overall process takes about 8–20 days within the vector.

The inflammatory and immunological responses to free hemozoin and other cellular debris within the bloodstream cause overt febrile illness in the host. The parasites undergo syn-chronized stages of reproduction, which may cause the characteristic periodic fevers associated with clinical illness in humans and primates (quotidian, tertian, or quartan); parasitemia as a

proportion of total red blood cells varies greatly among parasite species and hosts, and largely determines the severity of illness in semi-immune populations (Warrell and Gilles 2002). Anemia often occurs, and may be severe, both during the acute phase of infection and consequent to long-standing repeated infections.

(3)

immune response. In human populations in high transmission areas, young children and pregnant women are at highest risk due to reduced immune responses; similar responses occur in wild chimpanzees (Nys et al. 2014).

Currently, several methods exist to diagnose infections in humans and other mammalian species. The oldest is a stained blood slide (generally Giemsa stains); these methods have limited sensitivity, but provide rapid results in resource-limited settings and allow some quantification of parasitemia. Rapid cassette-type tests are often used for clinical diagnoses, but also are unable to reliably detect low-parasitemia infections. As such, the current gold standard method for diagnosis is quantitative PCR from blood samples; recent developments allow use of wild-collected fecal specimens, providing an avenue for non-invasive sampling of wild primate populations, but may only capture hosts with active symptomatic infections. Finally, serology can be used to track longer term exposures in primates (IgG and IgM) (Ljungström et al. 2013). Control and Treatment

Malaria control has been a major component of health programs throughout the world since the early nineteenth century, with early successes during the construction of the Panama Canal and throughout the southern United States and Western Europe. These efforts generally relied on control of vector populations by use of insecticides, or removal of vector breeding sites and prompt treatment to remove infected persons from the transmission cycle. Variants of these approaches are used today, along with the key intervention of insecticide-treated nets, and indoor-residual spraying, both of which keep vec-tors from feeding and kill resting vecvec-tors in living spaces. Other pillars of control programs are rapid diagnostic tests and artemisinin-combination treatments (ACTs); chemoprophylaxis is com-mon in some populations (tourists, militaries, etc.), and a vaccine (RTS,S) is currently in final clinical evaluation in humans. Drug regimens differ for P. vivax and P. ovale due to a dormant liver stage (hypnozoite), but ACTs are effective for clinical illness.

Host Species and Speciﬁc Parasites A large body of historical work has focused on morphological and laboratory studies. However, conclusions from many of these reports are uncertain due to difficulties in morphological parasite identification, repeated passages through laboratory hosts, and the potential for submi-croscopic co-infections. In many cases, modern molecular methods have found even greater com-plexity than previously suggested. Little is known about the vectors for most primate malarias, due to inherent difficulties in sampling mosquitoes in close proximity to wild primate populations. Humans

Globally, Plasmodium falciparum (Pf) is respon-sible for most morbidity and mortality, where the majority of the burden occurs in Sub-Saharan Africa. The parasite is limited to tropical and subtropical areas, and may cause high levels of parasitemia in humans (more than 5 percent or 250,000 parasites per μL; levels of 30 percent have been recorded) (Abdalla and Pasvol 2004) and in Aotus laboratory models (Douglas et al. 2015). Plasmodium vivax has a larger geographic range, including some temperate areas, and is widespread in South America, Asia, and the Pacific region. Infections generally cause less severe disease than Pf, but evidence is growing that it may cause severe disease and death in some settings (Baird 2014). Plasmodium malariae and ovale cause milder disease, and are most common in Sub-Saharan Africa and the Pacific. Finally, P. knowlesi is a zoonosis transmitted from Macaca fascicularis and Macaca nemestrina macaques in forested areas of Southeast Asia and the Philippines. Widespread infections in humans were first described in 2008 in Malaysia, and it is believed that habitat change and forest-based activities may be forcing closer overlaps between humans and macaque populations (Lee and Vythilingam 2013).

Other Species

(4)

Cebidae: P. brasilianum and P. simium

Cercopithecidae family (including Macaca): P. coatneyi, P. cynomolgi, P. fieldi, P. fragile, P. gonderi, P. georgesi, P. inui, P. knowlesi, P. shortti, and P. simiovale

Hylobatidae family: P. eylesi, P. hylobati, P. jefferyi, and P. youngi

Eulemur: P. bucki, P. foyeyi, and P. percygarnhami Pan: P. billcollini, P. billbrayii, P. falciparum, P. gabonensi, P. gora, P. gorb, P. reichenowi, P. rodhaini, and P. schwetzi

Pongo: P. pitheci and P. silvaticum

The first parasites observed in wild apes were P. reichenowi and P. schwetzi in Pan and Gorilla; these are generally morphologically similar to human parasites. However, recent surveys of wild great apes in Central Africa suggest that unex-pectedly diverse parasite species assemblages are prevalent in wild populations throughout Sub-Saharan Africa (Boundenga et al. 2015; Prugnolle et al. 2010), and more identifications are likely. Additionally, the human parasites P. falciparum, P. vivax, and P. malariae and closely related subspecies have been identified in wild primate populations.

Recent Evolutionary and Genetic Studies Use of genomic and phylogenetic approaches has allowed exploration of the evolutionary relationships between parasite species, and a range of recent studies suggest several sets of host switching events. However, these studies have in some cases produced contradictory results, and proper choice of sequence technology, sampled loci, and statistical methodology is critical for robust results.

There has been recent work studying the parasite populations in wild primate species with the advent of sampling methods that allow the identification of malaria parasites from fecal material. These studies have suggested extensive “parasite chatter” between human populations and nonhuman primates in areas where there is sufficient geographical overlap. In Sub-Saharan Africa, P. falciparum from human populations has been found in nonhuman primates, and parasites very closely related to nonhuman

primate strains have been found in wild and peridomestic nonhuman primates (Rayner et al. 2011). This emerging body of work has also identified multiple species of Plasmodium that are very closely related but distinct from the known human and primate parasites species. In summary, these results suggest very complex coevolutionary trajectories between Plasmodium and primate hosts which require multiple sets of transfers between host species, but the number, timing, and direction of these transfers are still being resolved (Di Fiore et al. 2009).

Additionally, a parasite P. knowlesi that com-monly infects Macaca populations in Southeast Asia has caused extensive infections in rural human populations in the region, causing mor-bidity and mortality; the vectors for transmission are believed to be members of the forest-dwelling species complex Anopeheles leucosphyrus. There is also evidence for coevolution of parasite subspecies with different Macaca hosts (Divis et al. 2015).

Conclusions

Malaria is an important issue in human health, and likely also impacts primate populations. Large-scale land changes in many parts of the world are forcing increasingly closer overlaps between humans and primate populations in the presence of vectors species, and have important impacts on the risk of emerging zoonoses and anthroponoses (Wolfe et al. 1998). This has led to the potential emergence of simian species in humans (P. knowlesi and P. cynomolgi), and suggests the potential for other emerging diseases (Ramasamy 2014).

SEE ALSO: Chimpanzee and Bonobo (Pan); Emerging Infectious Disease; Gorilla (Gorilla); Habitat Use; Macaque (Macaca); Molecular Diversity; Non-Invasive Techniques:

Vocalizations; Sympatry; Vaccination; Zoonoses

REFERENCES

Abdalla, Saad H., and Geoffrey Pasvol. 2004. Malaria: A

Hematological Perspective. London: Imperial College

(5)

Baird, J. Kevin 2014. “Editorial: Pernicious and Threat-ening Plasmodium vivax as Reality.” American

Jour-nal of Tropical Medicine and Hygiene, 91(1): 1–2.

Boundenga, L., B. Ollomo, V. Rougeron, L. Mouele, B. Mve-Ondo, L. M. Delicat-Loembet, N. Moukodoum, A. Okouga, C. Arnathau, E. Elguero, P. Durand, F. Liégeois, V. Boué, P. Motsch, G. Le Flohic, A. Ndoun-gouet, C. Paupy, C. Ba, F. Renaud, and F. Prugnolle. 2015. “Diversity of Malaria Parasites in Great Apes in Gabon.” Malaria Journal, 14(1): 111.

Coatney, G. R., W. E. Collins, and P. G. Contacos. 1971.

The Primate Malarias. Washington: US Government

Printing Office.

Di Fiore, A., T. Disotell, P. Gagneux, and F. J. Ayala. 2009. “Primate Malarias: Evolution, Adaptation, and Species Jumping.” In Primate Parasite Ecology. The

Dynamics and Study of Host–Parasite Relationships,

edited by Michael A. Huffman and Colin A. Chap-man, 141–182. Cambridge: Cambridge University Press.

Divis, P. C. S., B. Singh, F. Anderios, S. Hisam, A. Matu-sop, C. H. Kocken, S. A. Assefa, C. W. Duffy, and D. J. Conway. 2015. “Admixture in Humans of Two Divergent Plasmodium knowlesi Populations Asso-ciated with Different Macaque Host Species.” PLoS

Pathogens, 11(5): e1004888.

Douglas, A. D., G. C. Baldeviano, C. M. Lucas, L. A. Lugo-Roman, C. Crosnier, S. J. Bartholdson, A. Diouf, K. Miura, L. E. Lambert,J. A. Ventocilla, K. P. Leiva, K. H. Milne, J. J. Illingworth, A. J. Spencer, K. A. Hjerrild, D. G. W. Alanine, A. V. Turner, J. T. Moorhead, K. A. Edgel, Y. Wu, C. A. Long, G. J. Wright, A. G. Lescano, and S. J. Draper, 2015. “A PfRH5-Based Vaccine Is Efficacious Against Heterol-ogous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys.” Cell Host & Microbe, 17(1): 130–139.

Herbert, A., L. Boundenga, A. Meyer, D. N. Moukodoum, A. P. Okouga, C. Arnathau, P. Durand, J. Magnus, B. Ngoubangoye, E. Willaume, C. T. Ba, V. Rougeron, R. Renaud, B. Ollomo, and F. Prugnolle. 2015. “Malaria-Like Symptoms Associated with a Natural Plasmodium reichenowi Infection in a Chimpanzee.” Malaria Journal, 14(1): 220.

Lee, K.-S., and I. Vythilingam. 2013. “Plasmodium

knowlesi: Emergent Human Malaria in Southeast

Asia.” In Parasites and their Vectors, edited by Y. A. L. Lim and I. Vythilingam, 5–31. Vienna: Springer. Ljungström, I., K. Moll, H. Perlmann, A. Scherf, and

M. Wahlgren. 2013. Methods in Malaria Research, 6th ed. Virginia: MR4/ATCC.

Nys, H. M. D., S. Calvignac-Spencer, C. Boesch, P. Dorny, R. M. Wittig, R. Mundry, and F. H. Leendertz. 2014. “Malaria Parasite Detection Increases During

Pregnancy in Wild Chimpanzees.” Malaria Journal, 13(1): 413.

Prugnolle, F., P. Durand, C. Neel, B. Ollomo, F. J. Ayala, C. Arnathau, L. Etienne, E. Mpoudi-Ngole, D. Nkoghe, E. Leroy, E. Delaporte, M. Peeters, and F. Renaud. 2010. “African Great Apes Are Natural Hosts of Multiple Related Malaria Species, Including

Plasmodium falciparum.” Proceedings of the National Academy of Sciences of the United States of America,

107(4): 1458–1463.

Prugnolle, F., B. Ollomo, P. Durand, E. Yalcindag, C. Arnathau, E. Elguero, A. Berry, X. Pourrut, J.-P. Gon-zalez, D. Nkoghe, J. Akiana, D. Verrier, E. Leroy, F. J. Ayala, and F. Renaud. 2011. “African Monkeys Are Infected by Plasmodium falciparum Nonhuman Primate-Specific Strains.” Proceedings of the National

Academy of Sciences of the United States of America,

108(29): 11948–11953.

Ramasamy, R. 2014. “Zoonotic Malaria—Global Overview and Research and Policy Needs.” Frontiers

in Public Health, 2: 123.

Rayner, J. C., W. Liu, M. Peeters, P. M. Sharp, and B. H. Hahn. 2011. “A Plethora of Plasmodium Species in Wild Apes: A Source of Human Infection?” Trends in

Parasitology, 27(5): 222–229.

Warrell, D. A., and H. M. Gilles, eds. 2002. Essential

Malariology, 4th ed. London: Hodder Arnold.

Wolfe, N. D., A. A. Escalante, W. B. Karesh, A. Kil-bourn, A. Spielman, and A. A. Lal. 1998. “Wild Pri-mate Populations in Emerging Infectious Disease Research: The Missing Link?” Emerging Infectious

Diseases, 4(2): 149–158.

World Health Organization. 2015. World Malaria

Report 2015. Geneva: World Health Organization.