Tryp-ing Up Metabolism: Role of Metabolic Adaptations in Kinetoplastid Disease Pathogenesis.

Today, more than a billion people-one-sixth of the world's population-are suffering from neglected tropical diseases. Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected tropical diseases caused by protozoan parasites belonging to the genera Trypanosoma and Leishmania About half a million people living in tropical and subtropical regions of the world are at risk of contracting one of these three infections. Kinetoplastids have complex life cycles with different morphologies and unique physiological requirements at each life cycle stage. This review covers the latest findings on metabolic pathways impacting disease pathogenesis of kinetoplastids within the mammalian host. Nutrient availability is a key factor shaping in vivo parasite metabolism; thus, kinetoplastids display significant metabolic flexibility. Proteomic and transcriptomic profiles show that intracellular trypanosomatids are able to switch to an energy-efficient metabolism within the mammalian host system. Host metabolic changes can also favor parasite persistence, and contribute to symptom development, in a location-specific fashion. Ultimately, targeted and untargeted metabolomics studies have been a valuable approach to elucidate the specific biochemical pathways affected by infection within the host, leading to translational drug development and diagnostic insights.

Duress without stress: Cryptobia infection results in HPI axis dysfunction in rainbow trout.

Despite clear physiological duress, rainbow trout (Oncorhynchus mykiss) infected with the pathogenic haemoflagellate Cryptobia salmositica do not appear to mount a cortisol stress response. Therefore, we hypothesized that the infection suppresses the stress response by inhibiting the key effectors of the hypothalamic-pituitary-interrenal (HPI) axis. To test this, we characterized the basal activity of the HPI axis and the cortisol response to air exposure in saline- and parasite-injected fish. All fish were sampled at 4 and 6 weeks post-injection (wpi). While both the treatment groups had resting plasma cortisol levels, the parasite-infected fish had lower levels of plasma ACTH than the control fish. Relative to the control fish, the infected fish had higher mRNA levels of brain pre-optic area corticotrophin-releasing factor (CRF) and pituitary CRF receptor type 1, no change in pituitary POMC-A1, -A2 and -B gene expression, higher and lower head kidney melanocortin 2 receptor mRNA levels at 4 and 6 wpi respectively and reduced gene expression of key proteins regulating interrenal steroidogenesis: StAR, cytochrome P450scc and 11ß-hydroxylase. The parasite-infected fish also had a reduced plasma cortisol response to a 60-s air exposure stressor. Superfusion of the head kidney tissues of the parasite-infected fish led to significantly lower ACTH-stimulated cortisol release rates than that observed in the control fish. These novel findings show that infection of rainbow trout with C. salmositica results in complex changes in the transcriptional activity of both central and peripheral regulators of the HPI axis and in a reduction in the interrenal capacity to synthesize cortisol.

Nitrosative stress during infection-induced inflammation in fish: lessons from a host-parasite infection model.

The inflammatory response should be considered a protective immune reaction of the host aimed at the removal of pathogens, sometimes irrespective of negative side-effects. In this review we discuss the differential contribution of macrophages and neutrophilic granulocytes to nitrosative stress in vivo and discuss how the timing and concentration of nitric oxide (NO·) are important factors determining the degree of nitrosative stress during parasite-induced inflammation. Infections of common carp (Cyprinus carpio) with the extracellular protozoan parasite Trypanoplasma borreli provide an excellent example of how adaptation and homeostasis are essential elements of the host-pathogen relationship. On the one hand, host-derived NO· interferes with clearance of IgM from the parasite surface and thus can be considered a protective immune reaction of the host. On the other hand, it is essential that the host limits the risks associated with the production of NO·, preventing suppressive effects on lymphocyte proliferation. We review, for both host and parasite, the role of oxygen and nitrogen radicals in the induction of nitrosative stress and the importance of antioxidant compounds for protection against these radicals. Finally, mediators of inflammation such as cytokines, chemokines or alarmins that are involved in the inflammatory response will be discussed in the context of the carp-T. borreli infection model.