The unicellular parasite Toxoplasma gondii infects warm-blooded animals and humans, and it is highly prevalent throughout the world. Infection of immunocompetent hosts is usually asymptomatic or benign but leads to long-term parasite persistence mainly within neural and muscular tissues. The transition from acute primary infection towards chronic toxoplasmosis is accompanied by a developmental switch from fast replicating and metabolically highly active tachyzoites to slow replicating and largely dormant bradyzoites within tissue cysts. Such developmental differentiation is critical for T. gondii in order to complete its life cycle and for pathogenesis. Herein, we summarize accumulating evidence indicating a major impact of the host cell physiology on stage conversion between the tachyzoite and the bradyzoite stage of the parasite. Withdrawal from cell cycle progression, proinflammatory responses, reduced availability of nutrients and extracellular adenosine can indeed induce tachyzoite-to-bradyzoite differentiation and tissue cyst formation. In contrast, high glycolytic activity as indicated by increased lactate secretion can inhibit bradyzoite formation. These examples argue for the intriguing possibility that after dissemination within its host, T. gondii can sense its cellular microenvironment to initiate the developmental program towards the bradyzoite stage in distinct cells. This may also explain the predominant localization of T. gondii in neural and muscular tissues during chronic toxoplasmosis.

The cellular transcriptome is shaped by both the rates of mRNA synthesis in the nucleus and mRNA degradation in the cytoplasm under a specified condition. The last decade witnessed an exciting development in the field of post-transcriptional regulation of gene expression which underscored a strong functional coupling between the transcription and mRNA degradation. The functional integration is principally mediated by a group of specialized promoters and transcription factors that govern the stability of their cognate transcripts by “marking” them with a specific factor termed “coordinator.” The “mark” carried by the message is later decoded in the cytoplasm which involves the stimulation of one or more mRNA-decay factors, either directly by the “coordinator” itself or in an indirect manner. Activation of the decay factor(s), in turn, leads to the alteration of the stability of the marked message in a selective fashion. Thus, the integration between mRNA synthesis and decay plays a potentially significant role to shape appropriate gene expression profiles during cell cycle progression, cell division, cellular differentiation and proliferation, stress, immune and inflammatory responses, and may enhance the rate of biological evolution.

Presence of pathogens within a eukaryotic cell is apt to generate stress. Such stress eventually leads to host defense responses, which includes, but is not limited to, apoptosis induction and subsequent destruction of the host cell and the pathogen. Obligate intracellular pathogens such as Chlamydia trachomatis are dependent on the survival of the host cell owing to their unique replication niche within a membrane-bound inclusion. Furthermore, being energy parasites, chlamydial development is strictly dependent on the host metabolism. Over the past decade the role of the small non-coding RNAs called microRNAs (miRNAs) have come into focus with respect to the regulation of apoptotic signaling, metabolic homeostasis and bacterial pathogenesis. Effect of Chlamydia infection on the host miRNA profile was hitherto unknown. In our recent work we demonstrated that Chlamydia infection induces and requires an upregulation of the host miRNA, miR-30c-5p (miR-30c) to ameliorate infection induced stress on the host mitochondrial architecture and hinders induction of apoptosis.

Vector-borne trypanosomatid parasite infections in tropical and sub-tropical countries constitute a major threat to humans and livestock. Trypanosoma brucei parasites are transmitted by tsetse fly and lead to African sleeping sickness in humans and Nagana in cattle. In Latin American countries, Trypanosoma cruzi infections spread by triatomine kissing bugs lead to Chagas disease. Various species of Leishmania transmitted to humans by phlebotomine sandflies manifest in a spectrum of diseases termed Leishmaniasis. 20 million people are currently infected with trypanosomatid parasites, leading to over 30,000 deaths annually and half billion people at risk of the infection. It is estimated that 300,000 Chagas infected people reside in the United States and 100,000 in Europe. Glycosomes are peroxisome-like organelles found only in trypanosomatids. Glycolysis occurs in the cytosol in all other organisms, but glycolytic enzymes and other metabolic pathways are compartmentalized inside glycosomes in trypanosomatids. Glycosomes are essential for the parasite survival and hence thought to be an attractive drug target. Our recent study [Dawidowski et al. Science (2017)] is the first to report small molecule inhibitors of glycosomal protein import. Using structure-based drug design, we developed small molecule inhibitors of the Trypanosoma PEX5-PEX14 protein-protein interaction that disrupt glycosomal protein import and kill the parasites. Oral treatment of T. brucei infected mice with PEX14 inhibitor significantly reduced the parasite levels with no adverse effect on mice. The study provides the grounds for further development of the glycosome inhibitors into clinical candidates and validates the parasite protein-protein interactions as drug targets.