Asymptomatic Natural Human Infections With the Simian Malaria Parasites Plasmodium cynomolgi and Plasmodium knowlesi

Mallika Imwong, Wanassanan Madmanee, Kanokon Suwannasin, Chanon Kunasol, Thomas J Peto, Rupam Tripura, Lorenz von Seidlein, Chea Nguon, Chan Davoeung, Nicholas P J Day, Arjen M Dondorp, Nicholas J White, Mallika Imwong, Wanassanan Madmanee, Kanokon Suwannasin, Chanon Kunasol, Thomas J Peto, Rupam Tripura, Lorenz von Seidlein, Chea Nguon, Chan Davoeung, Nicholas P J Day, Arjen M Dondorp, Nicholas J White

Abstract

Background: In Southeast Asia, Plasmodium knowlesi, a parasite of long-tailed macaques (Macaca fascicularis), is an important cause of human malaria. Plasmodium cynomolgi also commonly infects these monkeys, but only one naturally acquired symptomatic human case has been reported previously.

Methods: Malariometric studies involving 5422 subjects (aged 6 months to 65 years) were conducted in 23 villages in Pailin and Battambang, western Cambodia. Parasite detection and genotyping was conducted on blood samples, using high-volume quantitative PCR (uPCR).

Results: Asymptomatic malaria parasite infections were detected in 1361 of 14732 samples (9.2%). Asymptomatic infections with nonhuman primate malaria parasites were found in 21 individuals living close to forested areas; P. cynomolgi was found in 11, P. knowlesi was found in 8, and P. vivax and P. cynomolgi were both found in 2. Only 2 subjects were female, and 14 were men aged 20-40 years. Geometric mean parasite densities were 3604 parasites/mL in P. cynomolgi infections and 52488 parasites/mL in P. knowlesi infections. All P. cynomolgi isolates had wild-type dihydrofolate reductase genes, in contrast to the very high prevalence of mutations in the human malaria parasites. Asymptomatic reappearance of P. cynomolgi occurred in 2 subjects 3 months after the first infection.

Conclusions: Asymptomatic naturally acquired P. cynomolgi and P. knowlesi infections can both occur in humans.

Clinical trials registration: NCT01872702.

Keywords: Plasmodium cynomolgi; Asymptomatic; human infections; natural.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Locations of subjects asymptomatically infected with Plasmodium cynomolgi and Plasmodium knowlesi. The inset (bottom right) shows the natural host, Macaca fascicularis (above), and the area in Cambodia under study (below).
Figures 2.
Figures 2.
Cluster analysis of Plasmodium cynomolgi isolates (A) and Plasmodium knowlesi isolates (B). A, Dendrogram of the interstrain relatedness of P. cynomolgi obtained from 13 asymptomatic subjects in Cambodia, including 2 pairs of primary and recurrent infections. Microsatellite types were compared to reference strains [13]. Cluster analysis was based on typing of 8 microsatellites, using genetic similarity indexes obtained by the unweighted pair group method arithmetic averages (UPGMA). The analysis revealed a cluster within the Cambodian infections and 1 very related parasite pair (initial and recurrent infection). Another pair clearly diverged between the primary and recurrent infection. B, Dendrogram based on microsatellite typing of P. knowlesi obtained from 8 asymptomatic subjects in Cambodia, compared with reference strains [14]. Cluster analysis used the same UPGMA method. The analysis revealed a cluster within the Cambodian infections that clearly diverged from reference strains. The upper panels show an unrooted tree, and the lower panels show a rooted tree.
Figure 3.
Figure 3.
Parasite genome densities of Plasmodium cynomolgi and Plasmodium knowlesi in asymptomatic human infections observed in Cambodia between 2013–2016.

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