Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modelling vivax malaria pathology and relapse infections

Abstract

Background: Plasmodium vivax infections in humans or in new world monkeys pose research challenges that necessitate the use of alternative model systems. Plasmodium cynomolgi is a closely related species that shares genetic and biological characteristics with P. vivax, including relapses. Here, the haematological dynamics and clinical presentation of sporozoite-initiated P. cynomolgi infections in Macaca mulatta (rhesus macaques) are evaluated over a 100-day period.Methods: Five M. mulatta were inoculated with 2000 P. cynomolgi B strain sporozoites. Parasitological and haematological data were collected daily to study the clinical presentations of primary infections and relapses. Peripheral blood and bone marrow aspirates were collected at specific time points during infection for future and retrospective systems biology analyses.Results: Patent infections were observed between days 10 and 12, and the acute, primary infection consisted of parasitaemias ranging from 269,962 to 1,214,842 parasites/µl (4.42-19.5 % parasitaemia). All animals presented with anaemia, ranging from moderate (7-10 g/dl) to severe (<7 g/dl), based on peripheral haemoglobin concentrations. Minimum haemoglobin levels coincided with the clearance of parasites and peripheral reticulocytosis was evident at this time. Mild thrombocytopaenia (<150,000 platelets/µl) was observed in all animals, but unlike haemoglobin, platelets were lowest whenever peripheral parasitaemia peaked. The animals' conditions were classified as non-severe, severe or lethal (in one case) based upon their clinical presentation. The lethal phenotype presented uniquely with an exceptionally high parasitaemia (19.5 %) and lack of a modest reticulocyte release, which was observed in the other animals prior to acute manifestations. One or two relapses were observed in the four surviving animals, and these were characterized by significantly lower parasitaemias and minimal changes in clinical parameters compared to preinfection values.Conclusions: Rhesus macaque infections initiated by P. cynomolgi B strain sporozoites recapitulated pathology of human malaria, including anaemia and thrombocytopaenia, with inter-individual differences in disease severity. Importantly, this study provides an in-depth assessment of clinical and parasitological data, and shows that unlike the

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…3). Of interest, malaria has been characterized by hemolysis of both infected and uninfected erythrocytes (Fonseca et al, 2016; Joyner et al, 2016; Severe Malaria, 2014), leading to the release of cell-free hemoglobin and further heme prosthetic groups (Pamplona et al, 2007). The relatively low parasitemia observed in infections with P. vivax , and their preference to reticulocytes questions the relative contributions of parasite burden to hemolysis, especially of uninfected RBCs.…”

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

“…Clustering features across all omics data and organizing samples by infection time point shows that acute infection was characterized by the broadest scope and greatest magnitude of changes in omic profiles (Figure S1A), a result that was expected given the lower parasite burden during relapse infection (Joyner et al, 2016). Acute infections led to significantly upregulated transcripts for many genes (differentially expressed genes; DEG) compared to baseline (Figure 1B-C).…”

“…Samples spanned pre-infection, acute primary infection, post-peak, and relapse infection time points. Comprehensive details on the longitudinal experimental design, clinical parameters relating to parasitemia and anemia, as well as the sampling time points have been described previously (Joyner et al, 2016).…”

“…A better understanding of relapse infection biology is thus critical for current malaria control and eradication efforts. The Plasmodium cynomolgi – rhesus macaque ( Macaca mulatta ) infection model for vivax malaria holds great potential for studying host responses and pathogenesis during acute and relapsing Plasmodium infections (Joyner et al, 2016). Macaque infections allow for more tractable longitudinal sampling of peripheral blood (PB) and bone marrow (BM) than in human studies, and macaque and human immune systems are highly similar, making this an excellent model system.…”

Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi

“…2 The striking similarity to P vivax, and in particular its ability to cause relapse infections, has and still makes P cynomolgi a model of choice for chemotherapeutic and biological investigations. [3][4][5][6] Indeed, the exoerythrocytic cycle of mammalian Plasmodium parasites was first uncovered by using P cynomolgi, 7 as was the discovery of the dormant liver stages responsible for relapses, the hypnozoites. 8 Early attempts to inoculate P cynomolgi sporozoites or infected blood failed to yield an infection in neurosyphilis patients (paretics) undergoing malaria therapy, 9,10 but in the early 1960s, accidental infections with P cynomolgi through infected mosquito bites were recorded in staff members from 2 distinct groups in the United States (1group from Tennessee and the other from Ohio).…”