Summary eIF2B is the guanine nucleotide exchange factor (GEF) required for cytoplasmic protein synthesis initiation in eukaryotes and its regulation within the integrated stress response (ISR). It activates its partner factor eIF2, thereby promoting translation initiation. Here we provide evidence through biochemical and genetic approaches that eIF2B can bind directly to GTP and this can enhance its rate of GEF activity toward eIF2–GDP in vitro . GTP binds to a subcomplex of the eIF2Bγ and ε subunits. The eIF2Bγ amino-terminal domain shares structural homology with hexose sugar phosphate pyrophosphorylase enzymes that bind specific nucleotides. A K66R mutation in eIF2Bγ is especially sensitive to guanine or GTP in a range of functional assays. Taken together, our data suggest eIF2Bγ may act as a sensor of purine nucleotide availability and thus modulate eIF2B activity and protein synthesis in response to fluctuations in cellular nucleotide levels.

Trypanosomatids are a diverse family of protozoan parasites, some of which cause devastating human and livestock diseases. There are two distinct infection life-cycles in trypanosomatids; some species complete their entire life-cycle in a single host (monoxenous) while others infect two hosts (dixenous). Dixenous trypanosomatids are mostly vectored by insects, and the human trypanosomatid diseases are transmitted mainly by vectored parasites. While infection prevalence has been described for subsets of hosts and trypanosomatids, little is known about whether monoxenous and dixenous trypanosomatids differ in infection prevalence. Here, we use meta-analyses to synthesise all published evidence of trypanosomatid infection prevalence for the last two decades. We employed a semi-automated screening protocol, using machine learning algorithms and natural language processing, resulting in the qualitative inclusion of 569 citations and quantitative inclusion of 261 citations. We find striking difference in infection prevalence with monoxenous species having twice the infection prevalence (19.8%) than dixenous species (8.68%) in both insect and non-insect hosts and are more than three-fold more prevalent in insects (20.9%) compared to their dixenous kins (6.61%). We also find that dixenous trypanosomatids have lower infection prevalence among insects compared to their definitive hosts, which is consistent across dixenous genera. Within the monoxenous trypanosomatids, genera infecting bees are characterised with the highest prevalence, which does not vary between wild and managed bees. To our knowledge, these results reveal for the first time, a fundamental difference in infection prevalence according to host specificity where vectored species suffer from lower infection prevalence as a result of a ‘jack of all trades, master of none’ style trade-off between the vector and definitive host.

Trypanosomatids are a diverse family of protozoan parasites, some of which cause devastating human and livestock diseases. There are two distinct infection life-cycles in trypanosomatids; some species complete their entire life-cycle in a single host (monoxenous) while others infect two hosts (dixenous). Dixenous trypanosomatids are mostly vectored by insects, and the human trypanosomatid diseases are caused mainly by vectored parasites. While infection prevalence has been described for subsets of hosts and trypanosomatids, little is known about whether monoxenous and dixenous trypanosomatids differ in infection prevalence. Here, we use meta-analyses to synthesise all published evidence of trypanosomatid infection prevalence for the last two decades, encompassing 931 unique host-trypansomatid systems. In examining 584 studies that describe infection prevalence, we find, strikingly, that monoxenous species are two-fold more prevalent than dixenous species across all hosts. We also find that dixenous trypanosomatids have significantly lower infection prevalence in insects than their non-insect hosts. To our knowledge, these results reveal for the first time, a fundamental difference in infection prevalence according to host specificity where vectored species might have lower infection prevalence as a result of a potential ‘jack of all trades, master of none’ style trade-off between the vector and subsequent hosts.

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