bims-toxgon 2023-01-01 papers

Issue of 2023–01–01
five papers selected by
Lakesh Kumar, BITS Pilani

Parasit Vectors. 2022 Dec 24. 15(1): 487

Chronic Toxoplasma gondii infection contributes to perineuronal nets impairment in the primary somatosensory cortex.

Ramayana Morais de Medeiros Brito, Ywlliane da Silva Rodrigues Meurer, Jully Anne Lemos Batista, Andréa Lima de Sá, Cássio Ricardo de Medeiros Souza, Janeusa Trindade de Souto, Valter Ferreira de Andrade-Neto.

Toxoplasma gondii is able to manipulate the host immune system to establish a persistent and efficient infection, contributing to the development of brain abnormalities with behavioral repercussions. In this context, this work aimed to evaluate the effects of T. gondii infection on the systemic inflammatory response and structure of the primary somatosensory cortex (PSC). C57BL/6 and BALB/c mice were infected with T. gondii ME49 strain tissue cysts and accompanied for 30 days. After this period, levels of cytokines IFN-γ, IL-12, TNF-α and TGF-β were measured. After blood collection, mice were perfused and the brains were submitted to immunohistochemistry for perineuronal net (PNN) evaluation and cyst quantification. The results showed that C57BL/6 mice presented higher levels of TNF-α and IL-12, while the levels of TGF-β were similar between the two mouse lineages, associated with the elevated number of tissue cysts, with a higher occurrence of cysts in the posterior area of the PSC when compared to BALB/c mice, which presented a more homogeneous cyst distribution. Immunohistochemistry analysis revealed a greater loss of PNN labeling in C57BL/6 animals compared to BALB/c. These data raised a discussion about the ability of T. gondii to stimulate a systemic inflammatory response capable of indirectly interfering in the brain structure and function.

Keywords: Brain infection; Inflammation; Perineuronal nets; Primary somatosensory cortex; Toxoplasma gondii

DOI: https://doi.org/10.1186/s13071-022-05596-x

Elife. 2022 Dec 28. pii: e82207. [Epub ahead of print]11

A choline-releasing glycerophosphodiesterase essential for phosphatidylcholine biosynthesis and blood stage development in the malaria parasite.

Abhinay Ramaprasad, Paul-Christian Burda, Enrica Calvani, Aaron J Sait, Susana Alejandra Palma-Duran, Chrislaine Withers-Martinez, Fiona Hackett, James Macrae, Lucy Collinson, Tim Wolf Gilberger, Michael J Blackman.

The malaria parasite Plasmodium falciparum synthesizes significant amounts of phospholipids to meet the demands of replication within red blood cells. De novo phosphatidylcholine (PC) biosynthesis via the Kennedy pathway is essential, requiring choline that is primarily sourced from host serum lysophosphatidylcholine (lysoPC). LysoPC also acts as an environmental sensor to regulate parasite sexual differentiation. Despite these critical roles for host lysoPC, the enzyme(s) involved in its breakdown to free choline for PC synthesis are unknown. Here we show that a parasite glycerophosphodiesterase (PfGDPD) is indispensable for blood stage parasite proliferation. Exogenous choline rescues growth of PfGDPD-null parasites, directly linking PfGDPD function to choline incorporation. Genetic ablation of PfGDPD reduces choline uptake from lysoPC, resulting in depletion of several PC species in the parasite, whilst purified PfGDPD releases choline from glycerophosphocholine in vitro. Our results identify PfGDPD as a choline-releasing glycerophosphodiesterase that mediates a critical step in PC biosynthesis and parasite survival.

Keywords: P. falciparum; biochemistry; chemical biology; infectious disease; microbiology

DOI: https://doi.org/10.7554/eLife.82207

J Inorg Biochem. 2022 Dec 10. pii: S0162-0134(22)00387-7. [Epub ahead of print]240 112098

The two-electron reduced A cluster in acetyl-CoA synthase: Preparation, characteristics and mechanistic implications.

Simonida Gencic, Evert C Duin, David A Grahame.

Acetyl-CoA synthase (ACS) is a central enzyme in the carbon and energy metabolism of certain anaerobic species of bacteria and archaea that catalyzes the direct synthesis and cleavage of the acetyl CC bond of acetyl-CoA by an unusual enzymatic mechanism of special interest for its use of organonickel intermediates. An Fe4S4 cluster associated with a proximal, reactive Nip and distal spectator Nid comprise the active site metal complex, known as the A cluster. Experimental and theoretical methods have uncovered much about the ACS mechanism, but have also opened new unanswered questions about the structure and reactivity of the A cluster in various intermediate forms. Here we report a method for large scale isolation of ACS with its A cluster in the acetylated state. Isolated acetyl-ACS and the two-electron reduced ACS, produced by acetyl-ACS reaction with CoA, were characterized by UV-visible and EPR spectroscopy. Reactivity with electron acceptors provided an assessment of the apparent Em for two-electron reduction of the A cluster. The results help to distinguish between alternative electronic states of the reduced cluster, provide evidence for a role of the Fe/S cluster in catalysis, and offer an explanation of why one-electron reductive activation is observed for a reaction cycle involving 2-electron chemistry.

Keywords: A cluster; Acetogens and methanogens; Acetyl-CoA synthase; CO dehydrogenase; Iron sulfur clusters; Nickel

DOI: https://doi.org/10.1016/j.jinorgbio.2022.112098

EBioMedicine. 2022 Dec 28. pii: S2352-3964(22)00600-4. [Epub ahead of print]87 104418

Acylations in cardiovascular biology and diseases, what's beyond acetylation.

Xin Sun, Yang Zhang, Xiao-Feng Chen, Xiaoqiang Tang.

Metabolism regulates cardiovascular biology through multiple mechanisms, including epigenetic modifications. Over the past two decades, experimental and preclinical studies have highlighted the critical roles of histone modifications in cardiovascular development, homeostasis, and diseases. The widely studied histone acetylation is critical in cardiovascular biology and diseases, and inhibitors of histone deacetylases show therapeutic values. In addition to lysine acetylation, a series of novel non-acetyl lysine acylations have recently been recognized. These non-acetyl lysine acylations have been demonstrated to have physiological and pathological functions, and recent studies have analyzed the roles of these non-acetyl lysine acylations in cardiovascular biology. Herein, we review the current advances in the understanding of non-acetyl lysine acylations in cardiovascular biology and discuss open questions and translational perspectives. These new pieces of evidence provide a more extensive insight into the epigenetic mechanisms underlying cardiovascular biology and help assess the feasibility of targeting acylations to treat cardiovascular diseases.

Keywords: Cardiovascular biology; Cardiovascular disease; Epigenetics; Metabolism; Metabolite; Non-acetyl acylation

DOI: https://doi.org/10.1016/j.ebiom.2022.104418

Parasitol Res. 2022 Dec 26.

Transcriptional changes during metacyclogenesis of a Colombian Trypanosoma cruzi strain.

Paola García-Huertas, Yesid Cuesta-Astroz, Valentina Araque-Ruiz, Nora Cardona-Castro.

During its life cycle, Trypanosoma cruzi undergoes physiological modifications in order to adapt to insect vector and mammalian host conditions. Metacyclogenesis is essential, as the parasite acquires the ability to infect a variety of mammalian species, including humans, in which pathology is caused. In this work, the transcriptomes of metacyclic trypomastigotes and epimastigotes were analyzed in order to identify differentially expressed genes that may be involved in metacyclogenesis. Toward this end, in vitro induction of metacyclogenesis was performed and metacyclic trypomastigotes obtained. RNA-Seq was performed on triplicate samples of epimastigotes and metacyclic trypomastigotes. Differential gene expression analysis showed 513 genes, of which 221 were upregulated and 292 downregulated in metacyclic trypomastigotes. The analysis showed that these genes are related to biological processes relevant in metacyclogenesis. Within these processes, we found that most of the genes associated with infectivity and gene expression regulation were upregulated in metacyclic trypomastigotes, while genes involved in cell division, DNA replication, differentiation, cytoskeleton, and metabolism were mainly downregulated. The participation of some of these genes in T. cruzi metacyclogenesis is of interest, as they may be used as potential therapeutic targets in the design of new drugs for Chagas disease.

Keywords: Differentiation; Metacyclogenesis; RNA-Seq; T. cruzi; Transcriptome

DOI: https://doi.org/10.1007/s00436-022-07766-3