Serotonin and melatonin, neurohormones for homeostasis, as novel inhibitors of infections by the intracellular parasite Chlamydia

Yamaguchi University, Yamaguti, Yamaguchi, Japan
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.31). 12/2005; 56(5):861-8. DOI: 10.1093/jac/dki331
Source: PubMed


Chlamydiae are obligate intracellular bacteria, causing a variety of diseases, i.e. pneumonia, sexually transmitted disease, conjunctivitis and zoonosis. Tryptophan depletion by interferon-gamma (IFN-gamma) is the most important host defence system against chlamydial infection. Thus chlamydial tryptophan metabolism is thought to play key roles for IFN-gamma resistance, persistent infection and host/tissue tropisms. We tested tryptophan derivatives for activity against chlamydia-infected cells.
Rates of chlamydial infection and sizes of the inclusions were evaluated by in vitro infection using three Chlamydiaceae species, Chlamydia trachomatis, Chlamydophila pneumoniae and Chlamydophila felis, which show significant divergence of tryptophan synthesis genes and different susceptibilities to IFN-gamma.
Melatonin and serotonin, which are recognized as neural hormones for maintenance of organism homeostasis, reduced chlamydial infection but not other bacterial growth tested here. Unlike IFN-gamma, melatonin limited infection of all three chlamydiae and the effects were not recovered by tryptophan supplementation. Melatonin treatment only of host cells could diminish infection and the infection reduction was neutralized by a pertussis toxin, an inhibitor of G proteins. Ligands of melatonin and serotonin receptors also hampered infection.
Inhibition mechanisms of chlamydial infection by melatonin and serotonin appear to be different from those of IFN-gamma and involve specific G-protein-coupled receptors. Melatonin is deemed to inhibit early progression of the chlamydial development cycle, such as establishment of intracellular infection and/or conversion from elementary body to reticulate body. Utilization of melatonin, serotonin or their derivatives may be advantageous for harmless prevention of chlamydial infection.

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    • "Melatonin is pleiotropic and affects multiple systems with remarkable functional versatility, including immunostimulatory (Guerrero and Reiter, 2002; Carrillo-Vico et al., 2005), anti-inflammatory (Jung et al., 2010; Szczepanik, 2007; Chahbouni et al., 2010), and antioxidant (Galano et al., 2011; Suzen, 2013) roles. In addition, melatonin protects the host from pathogens, such as retroviruses (Zhang et al., 1999), Chlamydia (Rahman et al., 2005), Plasmodium (Hotta et al., 2003) and T. cruzi (Oliveira et al., 2010). The anti-inflammatory properties of melatonin can be explained by its effect on NF-␬␤ because this transcription factor regulates numerous genes involved in the immune response and inflammation . "
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    ABSTRACT: Chronic cardiomyopathy is the most important clinical form of Chagas disease, and it is characterised by myocarditis that is associated with fibrosis and organ dysfunction. Alternative treatment options are important tools to modulate host immune responses. The main goal of this work was to evaluate the anti-inflammatory actions of melatonin during the chronic phase of Chagas disease. TNF-α, IL-10 and nitrite concentrations were evaluated as predictive factors of immune modulation. Creatine phosphokinase-MB (CK-MB), cardiac inflammatory foci and heart weight were assessed to evaluate the efficacy of the melatonin treatment. Male Wistar rats were infected with 1X10(5) blood trypomastigotes of the Y strain of T. cruzi and kept untreated for 60 days to mimic chronic infection. After this period, the rats were orally treated with melatonin 50mg/kg/day, and the experiments were performed 90, 120, and 180 days post-infection. Melatonin treatment significantly increased the concentration of IL-10 and reduced the concentrations of NO and TNF-α produced by cardiomyocytes. Furthermore, it led to decreased heart weight, serum CK-MB levels and inflammatory foci when compared to the untreated and infected control groups. We conclude that melatonin therapy is effective at protecting animals against the harmful cardiac inflammatory response that is characteristic of chronic T. cruzi infection.
    Acta tropica 09/2013; 128(3). DOI:10.1016/j.actatropica.2013.09.014 · 2.27 Impact Factor
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    • "Therefore, at the cellular level, both endogenous and exogenous melatonin induced IL‐2 production. Melatonin can also decrease genital infection (Rahman et al., 2005), suggesting relevance in both the early developmental etiology of schizophrenia, as well as in the management of adult manifestations (Anderson and Maes, 2012), including the emergence of tardive dyskinesia (Shamir et al., 2001). "
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    ABSTRACT: In 1995, the macrophage-T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered that activated immuno-inflammatory pathways may account for the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N-methyl d-aspartate receptor (NMDAr) and glutamate production. The aim of the present paper is to review the current state-of-the art regarding the role of the above pathways in schizophrenia. Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, in driving an early developmental etiology to schizophrenia. Models of prenatal rodent infection show maintained activation of immuno-inflammatory pathways coupled to increased microglia activation. The ensuing activation of immuno-inflammatory pathways in schizophrenia may activate the TRYCAT pathway, including increased kynurenic acid (KA) and neurotoxic TRYCATs. Increased KA, via the inhibition of the α7 nicotinic acetylcholine receptor, lowers gamma-amino-butyric-acid (GABA)ergic post-synaptic current, contributing to dysregulated glutamatergic activity. Hypofunctioning of the NMDAr on GABAergic interneurons will contribute to glutamatergic dysregulation. Many susceptibility genes for schizophrenia are predominantly expressed in early development and will interact with these early developmental driven changes in the immuno-inflammatory and TRYCAT pathways. Maternal infection and subsequent immuno-inflammatory responses are additionally associated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations in neurogenesis and myelination. In such a scenario a) a genetic or epigenetic potentiation of immuno-inflammatory pathways may constitute a double hit on their own, stimulating wider immuno-inflammatory responses and thus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; and b) antipsychotic-induced changes in immuno-inflammatory, TRYCAT and O&NS pathways would modulate the CNS glia-neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2012; 42. DOI:10.1016/j.pnpbp.2012.06.014 · 3.69 Impact Factor
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    • "Melatonin (N-acetyl-5-methoxytryptamine; MLT) is a naturally occurring compound belonging to the indoleamines. It is involved in many biological activities in animals, among them sleep, temperature homeostasis, inhibition of parasite infection, development of tumors, and antioxidative activity (Tan et al., 2002; Rahman et al., 2005; Garcia et al., 2006; Yang et al., 2007). "
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    ABSTRACT: The presence and role of melatonin in plants are still under debate owing to difficulties of identification and quantification. Accordingly, although it has been frequently proposed that melatonin acts as an antioxidant in phototrophic organisms, experimental data on its physiological role are scarce. This study describes the use of a rapid and simple new method for quantification of melatonin in the marine macroalga Ulva sp., organisms routinely exposed to tide-related environmental stresses and known for their high tolerance to abiotic conditions. The method was used here to show that exposure to oxidative stress-inducing environmental conditions (elevated temperature and heavy metals) induced a rise in melatonin level in the algae. Addition of exogenous melatonin alleviated the algae from cadmium-induced stress. Interestingly, although the algae were taken from a culture growing free floating and kept under constant photoperiod and water level, they exhibited a semi-lunar rhythm of melatonin levels that correlated with predicted spring tides. The correlation can probably be interpreted as reflecting preparation for predicted low tides, when the algae are exposed to increasing temperature, desiccation, and salinity, all known to induce oxidative stress. Given the simplicity of the described method it can easily be adapted for the study of melatonin in many other phototrophic organisms. These results provide, for the first time, experimental data that support both an antioxidant role for melatonin and its semi-lunar rhythm in macroalgae.
    Journal of Experimental Botany 03/2011; 62(6):1903-10. DOI:10.1093/jxb/erq378 · 5.53 Impact Factor
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