Malaria-derived hemozoin alters chromatin remodelling and skews dendritic cell responses to subsequent bacterial infections

Hemozoin (HZ), the malaria pigment, is released together with the with the parasite merozoites during the blood stage of the disease, which is connected with the pro-inflammatory response to induce T-cells and B-cells. Co-infections with bacteria lead to a more severe disease progression and the underlying mechanisms are poorly understood. Here, we investigated the impact of HZ on the early response of monocyte-derived dendritic cells (moDC) to a common bacterial component, LPS. A short-term HZ exposure for two hours did not induce an inflammatory response, but it did alter the transcriptional response to LPS. In moDC co-exposed to HZ and LPS, the induction of HLA-DR and PD-L1 gene expression was reduced and associated with decreased binding of RELA compared to LPS-stimulated cells. These gene promoters recruited the silencing chromatin remodelling complex NuRD upon co-exposure, instead of the PBAF complex at the promoter in LPS-stimulated cells. Further, HZ maintained transcription of C-type lectin receptors associated to an immature DC phenotype, DC-SIGN (CD209) and macrophage mannose receptor (MMR/CD206). Here, activated RELA and IRF3 were recruited in a PBAF and ncBAF dependent manner. Upon LPS co-exposure, NuRD was replacing these complexes to allow for a reduced transcriptional level of these immature markers. The association of chromatin remodelling complexes did not alter the chromatin state at the promoters, which was changed during differentiation to DCs or even at an earlier point. In conclusion, HZ exposure primes specific gene promoters at an early time point, which results in a different transcriptional response and may also lead to a changed immune reaction to bacterial co-infections. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/585548v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1573c58org.highwire.dtl.DTLVardef@3aeb6forg.highwire.dtl.DTLVardef@36f4bdorg.highwire.dtl.DTLVardef@1fddcd2_HPS_FORMAT_FIGEXP M_FIG C_FIG