Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

Abstract

Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense.

Large-Scale Phylogenetic Analysis of Trypanosomatid Adenylate Cyclases Reveals Associations with Extracellular Lifestyle and Host–Pathogen Interplay

“…The BLAST output showed a remarkable expansion of the RAC family in T. b. brucei , retrieving a total of 88 sequences, which is in agreement with previous results ( Salmon 2018 ). In the livestock-dwelling Trypanosoma congolense and T. evansi , RACs showed a similar degree of expansion, with 69 members each, whereas the human-dwelling T. b. gambiense carries 51 identified RACs ( supplementary table S1 , Supplementary Material online).…”

“…2013 ; Salmon 2018 ). But in mammalian cells, the G protein-coupled receptors are physically separated from the effector AC domains, in the trypanosomatids RACs, both the ectodomain (ED) and the AC domain are on the same polypeptide chain, separated by the central transmembrane domain (TMD) that allows the protein to be properly embedded in the plasma membrane ( Salmon 2018 ). A highly variable ED may facilitate the binding of yet unknown host-derived compounds ( Saada et al.…”

“…Interestingly, the T. brucei genome encodes ∼80 RACs ( Salmon 2018 ), a prominent expansion when compared with other trypanosomatids, for which complete genomes are available ( Lukeš et al. 2018 ).…”

“…2015 ). PDEs act as negative regulators of cAMP signaling by converting cAMP into AMP ( Salmon 2018 ). In T. brucei , RNAi-mediated depletion of PDE led to the defect in social behavior directly correlated with an increase in the intracellular cAMP levels ( Oberholzer et al.…”

Comparative transcriptomics and host-specific parasite gene expression profiles inform on drivers of proliferative kidney disease

“…Cyclic nucleotide balance is also crucial for parasite development, host-to-host transmission, target tissue recognition, and immune evasion, enabling rapid adaptation to different host environments 56,57 . The bryozoan-specific nature of GC/NPR-A in this study may imply similar roles in regulating developmental events leading to transmission and invasion of T.…”