Abstract
A recently developed humanized mouse has been used to assess the immune response evoked against the isolated attenuated C9 parasite clone (C9-M; carrying a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500) of Plasmodium falciparum. Significant human RBC engraftment was achieved by ameliorating the residual non-adaptive immune response using clodronate-loaded liposome treatment. Controlled reactive professional phagocytic leukocytes in immunodeficient mice allowed for sizeable human blood chimerism and injected huRBCs acted as bona fide host cells for P. falciparum. huRBC-reconstituted immunodeficient mice received infectious challenge with attenuated P. falciparum C9 parasite mutants (C9-M), complemented (C9-C), and wild type (NF54) progenitors to study the role of immune effectors in the clearance of the parasite from mouse circulation. C9-M and NF54 parasites grew and developed in the huRBC-reconstituted humanized NSG mice. Further, the presence of mutant parasites in deep-seated tissues suggests the escape of parasites from the host's immune responses and thus extended the survival of the parasite. Our results suggest an evasion mechanism that may have been employed by the parasite to survive the mouse's residual non-adaptive immune responses. Collectively, our data suggest that huRBCs reconstituted NSG mice infected with attenuated P. falciparum is a valuable tool to explore the role of C9 mutation in the growth and survival of parasite mutants and their response to the host's immune responses. This mouse might help in identifying novel chemotherapeutic targets to develop new anti-malarial drugs.
Highlights
The human malaria parasite was accountable for 4,45,000 deaths in the 2016 [1]
Experiments were performed in NSG mice using 650 μl of Human Red Blood Cells (huRBC) pellets mixed with 25% de-complemented human serum intravenously injected three times every week, and reconstituted NSG mice were infected with P. falciparum through an intravenous route
The present study shows that P. falciparum huRBC/NSG-IV model may be useful to study the immune responses evoked against the grafted parasite, and possible survival mechanisms employed by the parasites
Summary
The human malaria parasite was accountable for 4,45,000 deaths in the 2016 [1]. The in vitro findings do not replicate the in vivo findings and a laboratory animal model is needed. The study of human malaria parasites in animal models is severely limited by ethical and technical constraints, since only a few primate species have been found to be receptive to P. falciparum infection [2,3,4]. A human blood chimeric mouse could serve to harmonize in vitro P. falciparum cultivation and in vivo studies carried out in rodent animal models. Introduction of several mouse strains with genetic immune deficiencies has greatly benefited the development of a small laboratory animal model [7,8,9,10,11,12,13,14,15] to study the asexual blood stage infection of P. falciparum. The late entry into the S/M phase coincides with the timing for the peak expression of PF13_0027, suggesting that the deficiency in the mutant cycle can be correlated with the gene expression pattern [26]
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