RESUMO
Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2-positive parasites, while LISP2-negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.
Assuntos
Malária Vivax/genética , Plasmodium cynomolgi/genética , Plasmodium vivax/genética , Proteínas de Protozoários/genética , Aminoquinolinas/farmacologia , Animais , Antimaláricos/farmacologia , Biomarcadores/metabolismo , Biomarcadores Farmacológicos , Hepatócitos/metabolismo , Hepatócitos/parasitologia , Interações Hospedeiro-Parasita/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/parasitologia , Macaca mulatta/genética , Macaca mulatta/parasitologia , Malária Vivax/tratamento farmacológico , Malária Vivax/parasitologia , Plasmodium cynomolgi/parasitologia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/patogenicidade , Proteínas de Protozoários/metabolismo , Esporozoítos/genética , Transcriptoma/efeitos dos fármacosRESUMO
Histopathological data collected from patients with severe malaria have been instrumental for studying malaria pathogenesis. Animal models of malaria are critical to complement such studies. Here, the histopathological changes observed in a rhesus macaque with severe and complicated Plasmodium cynomolgi malaria are reported. The animal presented with thrombocytopenia, severe anemia, and hyperparasitemia during the acute infection. The macaque was given subcurative antimalarial treatment, fluid support, and a blood transfusion to treat the clinical complications, but at the time of transfusion, kidney function was compromised. These interventions did not restore kidney function, and the animal was euthanized due to irreversible renal failure. Gross pathological and histological examinations revealed that the lungs, kidneys, liver, spleen, and bone marrow exhibited abnormalities similar to those described in patients with malaria. Overall, this case report illustrates the similarities in the pathophysiological complications that can occur in human malaria and cynomolgi malaria in rhesus macaques.