Immune response pattern in recurrent Plasmodium vivax malaria

Abstract

BackgroundPlasmodium 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.MethodsA 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.ResultsThe 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.ConclusionThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1501-5) contains supplementary material, which is available to authorized users.

Vivax infection alters peripheral B‐cell profile and induces persistent serum IgM

“…By contrast, several other studies report that malarial infection affects B‐cell lymphopoiesis with an attendant decrease in the total number of B cells in peripheral blood of mice and humans similar to what we have observed . Although the studies by Figueiredo et al and Chaves et al are situated in Brazil and investigate the effect of primary vivax infection in adults, the median parasitemia is an order of magnitude higher in the Chaves et al study and our study, suggesting that apart from parasite and host genetics, other factors such as parasitemia levels may also affect B‐cell lymphopoiesis. The decrease in total B cells in the peripheral pool has been linked to an increase in proinflammatory cytokines and increased serum BAFF levels .…”

“…However, both malaria and dengue patients exhibited significant leucopenia and thrombocytopenia in the acute phase of the infection (Table ) as has been reported earlier . Unlike what was observed for first‐time malaria sufferers in Brazil, there was no change in the number of monocytes in our malaria cohort (Table ) neither did we observe lymphopenia in our cohort as reported . All these changes were transient and reverted to baseline at day 30 (Table ).…”

Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study

“…In addition, the cohorts, especially the healthy controls, were not perfectly age‐matched. However, the observed KYN/TRP ratio increase in patients might be explained by the acute inflammation that accompanies Plasmodium infection, as noted by elevated Th1 and Th2 cytokines, a well‐documented phenomenon also observed by others . We also acknowledge that other concomitant infections can produce similar cytokines and serum kynurenines responses as observed in our cohort, and we cannot exclude other infectious causes for these responses.…”

“…Blood canonical Th1 and Th2 cytokines were markedly increased in acute P vivax and P falciparum malaria infections and exposure or parasite load‐dependent strong association with activation of proinflammatory responses and cytokine imbalance was observed . Murine and human Plasmodium infections have demonstrated that early in infection IFN‐γ is produced by innate activation of Natural Killer (NK) cells that is subsequently taken over by CD4+ and CD8+ T cells over the course of infection .…”

Exposure to Plasmodium vivax is associated with the increased expression of exhaustion markers on γδ T lymphocytes

“…An effective and balanced immune response by the host is required for the control of P. vivax and its associated symptoms. Adaptive αβ T cells that include CD4 + and CD8 + T cells have been demonstrated to contribute to host immunity against P. vivax replication . In addition, a fraction of unconventional T cells, known as γδ T cells, is also important in providing protection against Plasmodium infections .…”