Ingestion of hemozoin by peripheral blood mononuclear cells alters temporal gene expression of ubiquitination processes

Abstract

Plasmodium falciparum (Pf) malaria is among the leading causes of childhood morbidity and mortality worldwide. During a natural infection, ingestion of the malarial parasite product, hemozoin ( Pf Hz), by circulating phagocytic cells induces dysregulation in innate immunity and enhances malaria pathogenesis. Treatment of cultured peripheral blood mononuclear cells (PBMCs) from healthy, malaria-naïve donors with physiological concentrations of Pf Hz can serve as an in vitro model to investigate cellular processes. Although disruptions in host ubiquitination processes are central to the pathogenesis of many diseases, this system remains unexplored in malaria. As such, we investigated the impact of Pf Hz on the temporal expression patterns of 84 genes involved in ubiquitination processes. Donor PBMCs were cultured in the absence or presence of Pf Hz for 3-, 9-, and 24 h. Stimulation with Pf Hz for 3 h did not significantly alter gene expression. Incubation for 9 h, however, elicited significant changes for 6 genes: 4 were down-regulated ( FBXO4 , NEDD8 , UBE2E3, and UBE2W ) and 2 were up-regulated ( HERC5 and UBE2J1 ). Pf Hz treatment for 24 h significantly altered expression for 14 genes: 12 were down-regulated ( ANAPC11 , BRCC3 , CUL4B , FBXO4 , MIB1 , SKP2 , TP53 , UBA2 , UBA3 , UBE2G1 , UBE2G2 , and WWP1 ), while 2 were up-regulated ( UBE2J1 and UBE2Z ). Collectively, these results demonstrate that phagocytosis of Pf Hz by PBMCs elicits temporal changes in the transcriptional profiles of genes central to host ubiquitination processes. Results presented here suggest that disruptions in ubiquitination may be a previously undiscovered feature of malaria pathogenesis.

Entire Expressed Peripheral Blood Transcriptome in Pediatric Severe Malarial Anemia

“…The transcriptome in children with SMA also revealed dysregulation in proteasome-mediated activity. This finding parallels our earlier studies that were the first to report DEG in ubiquitin-related processes as a feature of SMA 17 , 55 . Canonical pathway analyses showed additional molecular features of SMA including changes in cellular homeostasis, signaling, environmental response, and various molecular mechanisms that regulate cellular and immune stress responses.…”

Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia

“…In children with SMA, impaired protein degradation and autophagy could lead to the accumulation of damaged proteins and organelles, contributing to cellular stress and dysfunction, potentially further impairing erythrocyte production or survival, exacerbating anemia 63 . The observed dysregulation in proteasome-mediated activity parallels our earlier studies that were the first to report DEG in ubiquitin-related processes as a feature of SMA 16 , 64 . Although altered autophagy, to our knowledge, has not been described in human malaria pathogenesis, defects in autophagy are common in an array of other infectious diseases 65 .…”

A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

“…In addition, we examined other disease-associated agents that damage lysosomes. Hemozoin, a crystalline and insoluble material generated during malaria infection, circulates in phagocytes and peripheral tissues, contributing to immunopathological effects(Anyona et al, 2022; Coronado et al, 2014; Guerra et al, 2019; Moore et al, 2004; Schwarzer et al, 1992; Weissbuch et al, 2008). Treatment of human monocytic THP-1 with hemozoin induced lysosomal damage, which was monitored by ALIX puncta formation serving as a lysosomal repair marker(Jia et al, 2020c; Radulovic et al, 2018; Skowyra et al, 2018) (Fig.…”