Coordination of apicoplast transcription in a malaria parasite by internal and host cues

Kobayashi, Yuki; Komatsuya, Keisuke; Imamura, Sousuke; Nozaki, Tomoyoshi; Watanabe, Yoh-ichi; Sato, Shigeharu; Dodd, Antony N.; Kita, Kiyoshi; Tanaka, Kan

doi:10.1073/pnas.2214765120

Cited by 7 publications

(2 citation statements)

References 51 publications

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“…In contrast, apicoplast RNA levels were strongly reduced upon PfHO knockdown, with a 30% reduction observed in the first cycle and nearly 90% reduction in the second cycle after aTC washout (Figure 5D). This PfHOdependent reduction in RNA abundance was observed for all tested protein-coding and non-coding apicoplast genes spanning all of the currently known or predicted polycistronic apicoplast transcripts (Figure 5 -figure supplement 7) [73][74][75][76] . In contrast to its impact on apicoplast RNA, PfHO knockdown had no measurable impact on RNA transcript abundance for nuclear or mitochondrial genes (Figure 5 -figure supplement 7).…”

Section: Figure Supplement 1 Sequence Homologs Of Pfho Based On Blastmentioning

confidence: 84%

“…The primary subunits of a prokaryotic-like RNA polymerase complex have been identified in Plasmodium . Although associated sigma factors and other interacting proteins are proposed to exist, they have thus far remained difficult to identify 73,75 . We initially considered a model whereby PfHO might function as a sigma factor-like adaptor that directly binds to the multi-subunit prokaryotic RNA polymerase to mediate genomic association and transcription initiation.…”

Section: Discussionmentioning

confidence: 99%

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Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Blackwell,

Jami-Alahmadi,

Nasamu

et al. 2024

Preprint

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Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection,Plasmodium falciparumparasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest thatPlasmodiumrepurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.

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Section: Figure Supplement 1 Sequence Homologs Of Pfho Based On Blastmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Blackwell,

Jami-Alahmadi,

Nasamu

et al. 2024

Preprint

View full text Add to dashboard Cite

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Hormones in malaria infection: influence on disease severity, host physiology, and therapeutic opportunities

Das,

Suar,

Reddy

2024

Bioscience Reports

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Human malaria, caused by Plasmodium parasites, is a fatal disease that disrupts the host’s physiological balance and affects the neuroendocrine system. This review explores how malaria influences and is influenced by hormones. Malaria activates the Hypothalamus-Pituitary-Adrenal axis, leading to increased cortisol, aldosterone, and epinephrine. Cortisol, while reducing inflammation, aids parasite survival, whereas epinephrine helps manage hypoglycemia. The Hypothalamus-Pituitary-Gonad and Hypothalamus-Pituitary-Thyroid axes are also impacted, resulting in lower sex and thyroid hormone levels. Malaria disrupts the renin-angiotensin-aldosterone system (RAAS), causing higher angiotensin-II and aldosterone levels, contributing to edema, hyponatremia and hypertension. Malaria-induced anemia is exacerbated by increased hepcidin, which impairs iron absorption, reducing both iron availability for the parasite and red blood cell formation, despite elevated erythropoietin. Hypoglycemia is common due to decreased glucose production and hyperinsulinemia, although some cases show hyperglycemia due to stress hormones and inflammation. Hypocalcemia, and hypophosphatemia are associated with low Vitamin D3 and parathyroid hormone but high calcitonin. Hormones such as DHEA, melatonin, PTH, Vitamin D3, hepcidin, progesterone, and erythropoietin protects against malaria. Furthermore, synthetic analogs, receptor agonists and antagonists or mimics of hormones like DHEA, melatonin, serotonin, PTH, vitamin D3, estrogen, progesterone, angiotensin, and somatostatin are being explored as potential antimalarial treatments or adjunct therapies. Additionally, hormones like leptin and PCT are being studied as probable markers of malaria infection.

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Melatonin as a Circadian Marker for Plasmodium Rhythms

Dias,

Mohanty,

Garcia

2024

IJMS

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Plasmodium, a digenetic parasite, requires a host and a vector for its life cycle completion. Most Plasmodium species display circadian rhythmicity during their intraerythrocytic cycle within the host, aiding in immune evasion. This rhythmicity, however, diminishes in in vitro cultures, highlighting the importance of host-derived signals for synchronizing the parasite’s asexual cycle. Studies indicate a species–specific internal clock in Plasmodium, dependent on these host signals. Melatonin, a hormone the pineal gland produces under circadian regulation, impacts various physiological functions and is extensively reviewed as the primary circadian marker affecting parasite rhythms. Research suggests that melatonin facilitates synchronization through the PLC-IP3 signaling pathway, activating phospholipase C, which triggers intracellular calcium release and gene expression modulation. This evidence strongly supports the role of melatonin as a key circadian marker for parasite synchronization, presenting new possibilities for targeting the melatonin pathway when developing novel therapeutic approaches.

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Coordination of apicoplast transcription in a malaria parasite by internal and host cues

Cited by 7 publications

References 51 publications

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Hormones in malaria infection: influence on disease severity, host physiology, and therapeutic opportunities

Melatonin as a Circadian Marker for Plasmodium Rhythms

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