Immune response pattern in recurrent Plasmodium vivax malaria

Abstract\ud \ud Background\ud \ud Plasmodium vivax is the causative agent of human malaria of large geographic distribution, with 35 million cases annually. In Brazil, it is the most prevalent species, being responsible by around 70 % of the malaria cases.\ud \ud \ud Methods\ud A cross-sectional study was performed in Manaus (Amazonas, Brazil), including 36 adult patients with primary malaria, 19 with recurrent malaria, and 20 endemic controls. The ex vivo phenotypic features of circulating leukocyte subsets (CD4+ T-cells, CD8+ T-cells, NK, NKT, B, B1 and Treg cells) as well as the plasmatic cytokine profile (IL-2, IL-4, IL-6, IL-10, TNF and IFN-γ) were assessed, aiming at establishing patterns of immune response characteristic of primary malaria vs recurrent malaria as compared to endemic controls.\ud \ud \ud Results\ud The proportion of subjects with high levels of WBC was reduced in malaria patients as compared to the endemic control. Monocytes were diminished particularly in patients with primary malaria. The proportion of subjects with high levels of all lymphocyte subsets was decreased in all malaria groups, regardless their clinical status. Decreased proportion of subjects with high levels of CD4+ and CD8+ T-cells was found especially in the group of patients with recurrent malaria. Data analysis indicated significant increase in the proportion of the subjects with high plasmatic cytokine levels in both malaria groups, characterizing a typical cytokine storm. Recurrent malaria patients displayed the highest plasmatic IL-10 levels, that correlated directly with the CD4+/CD8+ T-cells ratio and the number of malaria episodes.\ud \ud \ud Conclusion\ud The findings confirm that the infection by the P. vivax causes a decrease in peripheral blood lymphocyte subsets, which is intensified in the cases of “recurrent malaria”. The unbalanced CD4+/CD8+ T-cells ratio, as well as increased IL-10 levels were correlated with the number of recurrent malaria episodes. These results suggest that the gradual remodelling of the immune response is dependent on the repeated exposure to the parasite, which involves a strict control of the immune response mediated by the CD4+/CD8+ T-cell unbalance and exacerbated IL-10 secretion.Financial support was provided by grants from FAPEAM, CNPq and Programa\ud do Instituto Nacional de Ciência e Tecnologia em Vacinas (INCT-Vacina). YOC\ud was awarded with a fellowship from INCT-Vacina/CNPq and AGC with a fellow‑\ud ship from CAPES (PhD students). AM and ATC are level 2 CNPq research fellow.\ud MVGL and OAMF are level 1 CNPq research fellows. CRFM, OAMF and ATC are\ud FAPEAM research fellows (PVS Programme - PECTI-AM/PG#019/2013). JGCdR\ud received postdoctoral fellowship from CAPES (PNPD/CAPES programme). The\ud funders had no role in study design, data collection and analysis, decision to\ud publish, or preparation of the manuscript