Yolanda Corbett1,2, Silvia Parapini3,4, Federica Perego5, Valeria Messina6, Serena Delbue5, Paola Misiano7, Mario Falchi8, Francesco Silvestrini6,4, Donatella Taramelli7,4, Nicoletta Basilico5,4, Sarah D'Alessandro9,10,11. 1. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Pascal 36, 20133, Milan, Italy. ycorbett179@gmail.com. 2. Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network, Milan, Italy. ycorbett179@gmail.com. 3. Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy. 4. Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network, Milan, Italy. 5. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, via Pascal 36, 20133, Milan, Italy. 6. Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy. 7. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Pascal 36, 20133, Milan, Italy. 8. AIDS-Ricerca e sviluppo, Istituto Superiore di Sanità, Rome, Italy. 9. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, via Pascal 36, 20133, Milan, Italy. sarah.dalessandro@unimi.it. 10. Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network, Milan, Italy. sarah.dalessandro@unimi.it. 11. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Pascal 36, 20133, Milan, Italy. sarah.dalessandro@unimi.it.
Abstract
BACKGROUND: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. METHODS: Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. RESULTS: The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. CONCLUSIONS: These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.
BACKGROUND: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. METHODS: Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. RESULTS: The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. CONCLUSIONS: These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.
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