Lower expression of GATA3 and T‐bet correlates with downregulated IL‐10 in severe falciparum malaria

Abstract

Interleukin (IL)-10, a non-redundant anti-inflammatory cytokine is produced by different cells and its production involves activation of cell-specific transcriptional regulatory machinery in response to specific pathogen. We have previously demonstrated downregulated levels of IL-10 in severe falciparum malaria. The present study investigated transcriptional regulation of IL-10 in severe malaria. Comparative expression analysis of cell-specific signalling proteins and transcription factors for IL-10 production during the stage of active infection and with resolution of parasitaemia was performed. Interestingly, T-bet and GATA3, the Th1 and Th2 transcription factors, respectively, were downregulated in severe malaria with fold change values of 0.59 and 0.86. Increase in the levels of both the factors with resolution of parasitaemia implicated a role for parasite in depressed levels of these factors. Further support for probable parasite manipulation of GATA3 was obtained from negative correlation of GATA3 with parasitaemia. In addition, a role for interferon-α in suppressing IL-10 transcription was evident from its negative correlation with GATA3 and IL-10 levels. In summary, IL-10 transcription in Th1 and Th2 is defective and appears to have major contribution to low levels in severe malaria.

Transcriptional Modulation of the Host Immunity Mediated by Cytokines and Transcriptional Factors in Plasmodium falciparum-Infected Patients of North-East India

“…The balance between pro- and anti-inflammatory responses in malaria progression could be best characterized by the expression levels of IL-12 and IL-10 in malaria clinical forms and are equivocally debated too. In contrast to previous reports of higher levels of IL-12 [25,26], IFN-γ [25,27] and lower IL-10 [25,28] expressions in uncomplicated and SM, a lower level of IL-12 in uncomplicated malaria was observed which got further depressed in SM. Further, elevated levels of IL-10 in uncomplicated malaria with a high peak during SM were seen.…”

Cytokine Effects on the Entry of Filovirus Envelope Pseudotyped Virus-Like Particles into Primary Human Macrophages

“…During the 2014–2016 EBOV outbreak, both increased [104,105] or decreased [106,107] survival rates were reported in patients co-infected with malaria species. Malaria is known to exert variable effects on IL-10, depending on the severity of infection (lower IL-10 in complicated cases, compared to asymptomatic subjects [108,109,110,111]), but cytokine levels, including IL-10, have not been evaluated in the currently published studies on EBOV and malaria co-infection.…”

Integrative Approaches to Understand the Mastery in Manipulation of Host Cytokine Networks by Protozoan Parasites with Emphasis on Plasmodium and Leishmania Species

“…Plasmodium -derived PAMPs that include GPI anchors, CpG motifs, AT-rich motifs, and haemazoin are sensed by PRRs of host that include TLRs, NLRs, and AIM2 on cells of monocyte/macrophage lineage and on DCs ( 61 , 63 – 65 ). These ligand–receptor interactions initiate MyD88 and STING-IRF3 mediated downstream signaling leading to activation of NF-κB and IRF3 pathways and synthesis of pro-inflammatory cytokines and interferon α/β ( 55 , 65 – 68 ). It is the exaggerated activation of these pathways “mediated by IFN-γ pro-inflammatory priming with extreme levels of pro-inflammatory mediators” with concomitant loss of regulatory cytokines that drives malaria pathogenesis ( 46 , 57 , 68 ).…”

“…These ligand–receptor interactions initiate MyD88 and STING-IRF3 mediated downstream signaling leading to activation of NF-κB and IRF3 pathways and synthesis of pro-inflammatory cytokines and interferon α/β ( 55 , 65 – 68 ). It is the exaggerated activation of these pathways “mediated by IFN-γ pro-inflammatory priming with extreme levels of pro-inflammatory mediators” with concomitant loss of regulatory cytokines that drives malaria pathogenesis ( 46 , 57 , 68 ). It has also been proposed that in addition to driving inflammation, P. falciparum by downregulating GATA3 expression suppresses IL-10 and SOCS3 that are necessary to control inflammation, possibly by exploiting the IFNα/β pathway as summarized in Figure 1 .…”

“…High load of Pf AT rich DNA would lead to increased levels of TRAF3 and of IFN-α. And IFN-α, in turn, suppresses GATA3 expression in Th2 cells resulting in low levels of IL-10 and hence down regulated SOCS3 ( 68 ). In addition, low levels of IL-2 and T-bet fail to mediate switch from IFN-γ+/IL-10− to IFN-γ+/IL-10+ Th1 cells that requires T-bet and IL-2 levels, also explain low levels of IL-10.…”