bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2023–01–29
seven papers selected by
Lakesh Kumar, BITS Pilani
  1. Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii.
  2. Invasion of Toxoplasma gondii bradyzoites: Molecular dissection of the moving junction proteins and effective vaccination targets.
  3. Treatments of Mycobacterium tuberculosis and Toxoplasma gondii with Selenium Nanoparticles.
  4. Complement-dependent loss of inhibitory synapses on pyramidal neurons following Toxoplasma gondii infection.
  5. Acetylation of Cyclic AMP Receptor Protein by Acetyl Phosphate Modulates Mycobacterial Virulence.
  6. Pre-existing Toxoplasma gondii infection increases susceptibility to pentylenetetrazol-induced seizures independent of traumatic brain injury in mice.
  7. Host-parasite interactions during Plasmodium infection: Implications for immunotherapies.
  1. Nat Commun. 2023 Jan 26. 14(1): 422
    Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii.
    Yaqiong Li, Zhipeng Niu, Jichao Yang, Xuke Yang, Yukun Chen, Yingying Li, Xiaohan Liang, Jingwen Zhang, Fuqiang Fan, Ping Wu, Chao Peng, Bang Shen.
      The ubiquitous pathogen Toxoplasma gondii has a complex lifestyle with different metabolic activities at different stages that are intimately linked to the parasitic environments. Here we identified the eukaryotic regulator of cellular homeostasis AMP-activated protein kinase (AMPK) in Toxoplasma and discovered its role in metabolic programming during parasite's lytic cycle. The catalytic subunit AMPKα is quickly phosphorylated after the release of intracellular parasites to extracellular environments, driving energy-producing catabolism to power parasite motility and invasion into host cells. Once inside host cells, AMPKα phosphorylation is reduced to basal level to promote a balance between energy production and biomass synthesis, allowing robust parasite replication. AMPKγ depletion abolishes AMPKα phosphorylation and suppresses parasite growth, which can be partially rescued by overexpressing wildtype AMPKα but not the phosphorylation mutants. Thus, through the cyclic reprogramming by AMPK, the parasites' metabolic needs at each stage are satisfied and the lytic cycle progresses robustly.
    DOI:  https://doi.org/10.1038/s41467-023-36084-0
  2. Proc Natl Acad Sci U S A. 2023 Jan 31. 120(5): e2219533120
    Invasion of Toxoplasma gondii bradyzoites: Molecular dissection of the moving junction proteins and effective vaccination targets.
    Rania Najm, Margarida T Grilo Ruivo, Diana Marcela Penarete-Vargas, Maguy Hamie, Thomas Mouveaux, Mathieu Gissot, Martin J Boulanger, Hiba El Hajj, Maryse Lebrun.
      Toxoplasmosis is a neglected parasitic disease necessitating public health control. Host cell invasion by Toxoplasma occurs at different stages of the parasite's life cycle and is crucial for survival and establishment of infection. In tachyzoites, which are responsible for acute toxoplasmosis, invasion involves the formation of a molecular bridge between the parasite and host cell membranes, referred to as the moving junction (MJ). The MJ is shaped by the assembly of AMA1 and RON2, as part of a complex involving additional RONs. While this essential process is well characterized in tachyzoites, the invasion process remains unexplored in bradyzoites, which form cysts and are responsible for chronic toxoplasmosis and contribute to the dissemination of the parasite between hosts. Here, we show that bradyzoites invade host cells in an MJ-dependent fashion but differ in protein composition from the tachyzoite MJ, relying instead on the paralogs AMA2 and AMA4. Functional characterization of AMA4 reveals its key role for cysts burden during the onset of chronic infection, while being dispensable for the acute phase. Immunizations with AMA1 and AMA4, alone or in complex with their rhoptry neck respective partners RON2 and RON2L1, showed that the AMA1-RON2 pair induces strong protection against acute and chronic infection, while the AMA4-RON2L1 complex targets more selectively the chronic form. Our study provides important insights into the molecular players of bradyzoite invasion and indicates that invasion of cyst-forming bradyzoites contributes to cyst burden. Furthermore, we validate AMA-RON complexes as potential vaccine candidates to protect against toxoplasmosis.
    Keywords:  Toxoplasma; bradyzoite; invasion; moving-junction; vaccine
    DOI:  https://doi.org/10.1073/pnas.2219533120
  3. Bionanoscience. 2023 Jan 11. 1-29
    Treatments of Mycobacterium tuberculosis and Toxoplasma gondii with Selenium Nanoparticles.
    Ikhazuagbe H Ifijen, Best Atoe, Raphael O Ekun, Augustine Ighodaro, Ifeanyi J Odiachi.
      Toxoplasma gondii and Mycobacterium tuberculosis are pathogens that are harmful to humans. When these diseases interact in humans, the result is typically fatal to the public health. Several investigations on the relationship between M. tuberculosis and T. gondii infections have found that there is a strong correlation between them with each infection having a reciprocal effect on the other. TB may contribute to the reactivation of innate toxoplasmosis or enhance susceptibility to a new infection, and toxoplasma co-infection may worsen the severity of pulmonary tuberculosis. As a consequence, there is an earnest and urgent necessity to generate novel therapeutics that can subdue these challenges. Selenium nanostructures' compelling properties have been shown to be a successful treatment for Mycobacterium TB and Toxoplasma gondii. Despite the fact that selenium (Se) offers many health advantages for people, it also has a narrow therapeutic window; therefore, consuming too much of either inorganic or organic compounds based on selenium can be hazardous. Compared to both inorganic and organic Se, Se nanoparticles (SeNPs) are less hazardous. They are biocompatible and excellent in selectively targeting specific cells. As a consequence, this review conducted a summary of the efficacy of biogenic Se NPs in the treatment of tuberculosis (TB) and toxoplasmosis. Mycobacterium tuberculosis, Toxoplasma gondii, and their co-infection were all briefly described.
    Keywords:  Infections; Mycobacterium tuberculosis; Pathogens; Selenium nanoparticles; Toxoplasma gondii
    DOI:  https://doi.org/10.1007/s12668-023-01059-4
  4. J Neurochem. 2023 Jan 23.
    Complement-dependent loss of inhibitory synapses on pyramidal neurons following Toxoplasma gondii infection.
    Gabriela L Carrillo, Jianmin Su, Mikel L Cawley, Derek Wei, Simran K Gill, Ira J Blader, Michael A Fox.
      The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, non-human primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. These observations and associations raise questions about how this parasitic infection may alter neural circuits. We previously demonstrated that T. gondii infection triggers the loss of inhibitory perisomatic synapses, a type of synapse whose dysfunction or loss has been linked to neurological and neuropsychiatric disorders. We showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons and not those on cortical interneurons. Moreover, we show that infection induces an increased expression of the complement C3 gene, including by populations of these excitatory neurons. Infecting C3-deficient mice with T. gondii revealed that C3 is required for the loss of perisomatic inhibitory synapses. Interestingly, loss of C1q did not prevent the loss of perisomatic synapses following infection. Together, these findings provide evidence that T. gondii induces changes in excitatory pyramidal neurons that trigger selective removal of inhibitory perisomatic synapses and provide a role for a non-classical complement pathway in the remodeling of inhibitory circuits in the infected brain.
    Keywords:  Toxoplasma gondii; complement; inhibitory synapse; microglia; parvalbumin interneuron; pyramidal neuron
    DOI:  https://doi.org/10.1111/jnc.15770
  5. Microbiol Spectr. 2023 Jan 26. e0400222
    Acetylation of Cyclic AMP Receptor Protein by Acetyl Phosphate Modulates Mycobacterial Virulence.
    Yuchang Di, Siyue Xu, Mingzhe Chi, Youwei Hu, Xiao Zhang, Honghai Wang, Wenhong Zhang, Xuelian Zhang.
      The success of Mycobacterium tuberculosis (Mtb) as a pathogen is partly attributed to its ability to sense and respond to dynamic host microenvironments. The cyclic AMP (cAMP) receptor protein (CRP) is closely related to the pathogenicity of Mtb and plays an important role in this process. However, the molecular mechanisms guiding the autoregulation and downstream target genes of CRP while Mtb responds to its environment are not fully understood. Here, it is demonstrated that the acetylation of conserved lysine 193 (K193) within the C-terminal DNA-binding domain of CRP reduces its DNA-binding ability and inhibits transcriptional activity. The reversible acetylation status of CRP K193 was shown to significantly affect mycobacterial growth phenotype, alter the stress response, and regulate the expression of biologically relevant genes using a CRP K193 site-specific mutation. Notably, the acetylation level of K193 decreases under CRP-activating conditions, including the presence of cAMP, low pH, high temperature, and oxidative stress, suggesting that microenvironmental signals can directly regulate CRP K193 acetylation. Both cell- and murine-based infection assays confirmed that CRP K193 is critical to the regulation of Mtb virulence. Furthermore, the acetylation of CRP K193 was shown to be dependent on the intracellular metabolic intermediate acetyl phosphate (AcP), and deacetylation was mediated by NAD+-dependent deacetylases. These findings indicate that AcP-mediated acetylation of CRP K193 decreases CRP activity and negatively regulates the pathogenicity of Mtb. We believe that the underlying mechanisms of cross talk between transcription, posttranslational modifications, and metabolites are a common regulatory mechanism for pathogenic bacteria. IMPORTANCE Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, and the ability of Mtb to survive harsh host conditions has been the subject of intensive research. As a result, we explored the molecular mechanisms guiding downstream target genes of CRP when Mtb responds to its environment. Our study makes a contribution to the literature because we describe the role of acetylated K193 in regulating its binding affinity to target DNA and influencing the virulence of mycobacteria. We discovered that mycobacteria can regulate their pathogenicity through the reversible acetylation of CRP K193 and that this reversible acetylation is mediated by AcP and a NAD+-dependent deacetylase. The regulation of CRPMtb by posttranslational modifications, at the transcriptional level, and by metabolic intermediates contribute to a better understanding of its role in the survival and pathogenicity of mycobacteria.
    Keywords:  CRP; Mycobacterium tuberculosis; cAMP; cAMP receptor protein; cyclic AMP; lysine acetylation; virulence
    DOI:  https://doi.org/10.1128/spectrum.04002-22
  6. Front Mol Neurosci. 2022 ;15 1079097
    Pre-existing Toxoplasma gondii infection increases susceptibility to pentylenetetrazol-induced seizures independent of traumatic brain injury in mice.
    Tamara L Baker, Alessandro D Uboldi, Christopher J Tonkin, David K Wright, Anh Vo, Trevor Wilson, Richelle Mychasiuk, Stuart J McDonald, Bridgette D Semple, Mujun Sun, Sandy R Shultz.
       Introduction: Post-traumatic epilepsy (PTE) is a debilitating chronic outcome of traumatic brain injury (TBI), and neuroinflammation is implicated in increased seizure susceptibility and epileptogenesis. However, how common clinical factors, such as infection, may modify neuroinflammation and PTE development has been understudied. The neurotropic parasite, Toxoplasma gondii (T. gondii) incurably infects one-third of the world's population. Thus, many TBI patients have a pre-existing T. gondii infection at the time of injury. T. gondii infection results in chronic low-grade inflammation and altered signaling pathways within the brain, and preliminary clinical evidence suggest that it may be a risk factor for epilepsy. Despite this, no studies have considered how a pre-existing T. gondii infection may alter the development of PTE.
    Methods: This study aimed to provide insight into this knowledge gap by assessing how a pre-existing T. gondii infection alters susceptibility to, and severity of, pentylenetetrazol (PTZ)-induced seizures (i.e., a surrogate marker of epileptogenesis/PTE) at a chronic stage of TBI recovery. We hypothesized that T. gondii will increase the likelihood and severity of seizures following PTZ administration, and that this would occur in the presence of intensified neuroinflammation. To test this, 6-week old male and female C57BL/6 Jax mice were intraperitoneally injected with 50,000 T. gondii tachyzoites or with the PBS vehicle only. At 12-weeks old, mice either received a severe TBI via controlled cortical impact or sham injury. At 18-weeks post-injury, mice were administered 40 mg/kg PTZ and video-recorded for evaluation of seizure susceptibility. Fresh cortical tissue was then collected for gene expression analyses.
    Results: Although no synergistic effects were evident between infection and TBI, chronic T. gondii infection alone had robust effects on the PTZ-seizure response and gene expression of markers related to inflammatory, oxidative stress, and glutamatergic pathways. In addition to this, females were more susceptible to PTZ-induced seizures than males. While TBI did not impact PTZ responses, injury effects were evident at the molecular level.
    Discussion: Our data suggests that a pre-existing T. gondii infection is an important modifier of seizure susceptibility independent of brain injury, and considerable attention should be directed toward delineating the mechanisms underlying this pro-epileptogenic factor.
    Keywords:  epileptogenesis; immune response; neuroinflammation; oxidative stress; post-traumatic epilepsy (PTE)
    DOI:  https://doi.org/10.3389/fnmol.2022.1079097
  7. Front Immunol. 2022 ;13 1091961
    Host-parasite interactions during Plasmodium infection: Implications for immunotherapies.
    Pankaj Chandley, Ravikant Ranjan, Sudhir Kumar, Soma Rohatgi.
      Malaria is a global infectious disease that remains a leading cause of morbidity and mortality in the developing world. Multiple environmental and host and parasite factors govern the clinical outcomes of malaria. The host immune response against the Plasmodium parasite is heterogenous and stage-specific both in the human host and mosquito vector. The Plasmodium parasite virulence is predominantly associated with its ability to evade the host's immune response. Despite the availability of drug-based therapies, Plasmodium parasites can acquire drug resistance due to high antigenic variations and allelic polymorphisms. The lack of licensed vaccines against Plasmodium infection necessitates the development of effective, safe and successful therapeutics. To design an effective vaccine, it is important to study the immune evasion strategies and stage-specific Plasmodium proteins, which are targets of the host immune response. This review provides an overview of the host immune defense mechanisms and parasite immune evasion strategies during Plasmodium infection. Furthermore, we also summarize and discuss the current progress in various anti-malarial vaccine approaches, along with antibody-based therapy involving monoclonal antibodies, and research advancements in host-directed therapy, which can together open new avenues for developing novel immunotherapies against malaria infection and transmission.
    Keywords:  Plasmodium; antibody therapy; host-directed therapy; immune evasion; immunotherapeutics; vaccine candidates
    DOI:  https://doi.org/10.3389/fimmu.2022.1091961
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