Abstract
Malaria represents one of the major life-threatening diseases that poses a huge socio-economic impact, worldwide. Chemoprophylaxis vaccination using a relatively low number of wild-type infectious sporozoites represents an attractive and effective vaccine strategy against malaria. However, the role of immune responses to pre-erythrocytic versus blood-stage parasites in protection against different antimalarial drugs remains unclear. Here, in the present study, we explored the immune responses against the repetitive inoculation of live Plasmodium yoelii (P. yoelii) sporozoites in an experimental Swiss mouse model under antimalarial drug lumefantrine chemoprophylaxis (CPS-LMF). We monitored the liver stage parasitic load, pro/anti-inflammatory cytokines expression, and erythrocytic stage patency, following repetitive cycles of sporozoites inoculations. It was found that repetitive sporozoites inoculation under CPS-LMF results in delayed blood-stage infection during the fourth sporozoites challenge, while sterile protection was produced in mice following the fifth cycle of sporozoites challenge. Intriguingly, we observed a significant up-regulation of pro-inflammatory cytokines (IFN-γ, TNF-α and IL-12) and iNOS response and down-regulation of anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) in the liver HMNC (hepatic mononuclear cells) and spleen cells after 4th and 5th cycle of sporozoites challenge in the CPS-LMF mice. Meanwhile, we also noticed that the liver stage parasites load under CPS-LMF immunization has gradually reduced after 2nd, 3rd, 4th and 5th sporozoites challenge. Overall, our study suggests that chemoprophylaxis vaccination under LMF drug cover develops strong immune responses and confer superior long-lasting protection against P. yoelii sporozoites. Furthermore, this vaccination strategy can be used to study the protective and stage-specific immunity against new protective antigens.
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Acknowledgements
I would like to thank and appreciate all the support and technical assistance provided by Dr. Puri lab at CSIR-CDRI, Lucknow, India during this study. I further extend my gratitude to UoH for graciously providing numerous contributions and making all endeavors possible.
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This research has been funded by Scientific Research Deanship at University of Ha’il, Saudi Arabia through project number RG-20128.
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Conceptualization, AJS, JB, and MG; methodology, WSH, AJ, and SAA; validation, MA MS, RB, SJ, and PS; formal analysis, MA, MG RB, and AJS; investigation, AJ, SAA and JB; data curation, MA, AJ, WSH, SAA and MS; writing—original draft preparation, AJS JB, and MA; writing—review and editing, MG, MA, and PS; visualization, AJ, and WSH; supervision, AJS, MA, and JB; project administration, AJS and JB. All authors have read and agreed to the published version of the manuscript.
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13205_2021_3022_MOESM4_ESM.tif
Supplementary Figure 1 (TIF 346 KB) Residual effect of LMF drug on prophylaxis control. To check the residual activity of LMF drug, blood-stage parasitemia was monitored in mice treated with only LMF (curative dose) without sporozoites inoculation similar to as with CPS-LMF immunization group. Naïve Control and Prophylaxis LMF treated control mice were subsequently infected intravenously with 1×104 P. yoelii sporozoites to check the residual activity of LMF. The y-axis shows the Mean (n=5) % parasitemia of mice from each group, as determined by microscopy of Giemsa-stained thin blood smears, and the x-axis corresponds to days post sporozoites infection. Error bars represent Standard Deviation. Statistical significances between different groups were determined using student’s t test.
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Siddiqui, A.J., Bhardwaj, J., Hamadou, W.S. et al. Chemoprophylaxis under sporozoites-lumefantrine (CPS-LMF) immunization induce protective immune responses against Plasmodium yoelii sporozoites infection in mice. 3 Biotech 11, 465 (2021). https://doi.org/10.1007/s13205-021-03022-0
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DOI: https://doi.org/10.1007/s13205-021-03022-0