Authors

Discussion

Bacterial pathogens, and some eukaryotic parasites, moderate their growth and density, and this can extend the timeframe of infection in their hosts. A quorum-sensing pathway has been described in bloodstream African trypanosomes, for example, whereby morphological ‘stumpy’ differentiation can be triggered by oligopeptides or cyclic AMP analogues. Here, we describe a distinct environmental sensing mechanism in African trypanosomes. A genome-scale loss-of-function genetic screen revealed a small cohort of knockdowns that increase trypanosome growth, several with domains implicated in calcium-signalling. The dominant hit (Tb927.8.6870) encodes multiple putative calmodulin binding IQ-domains, and we name this protein QIQ1 for Quintuple IQ-domain protein 1, also reflecting the ‘quick’ growth phenotype observed following knockdown. QIQ1 is localized to the parasite flagellum, while the competitive advantage displayed by qiq1-null trypanosomes at high cell density is abolished in the presence of calcium chelators. We show that qiq1-null parasites achieve higher maximum cell density both in vitro and in vivo; in culture and in a mouse model, respectively. Notably, qiq1-nulls maintained morphological differentiation and expressed a ‘stumpy’ cell marker in vivo. Proteomic analysis revealed a specific deficit in mitochondrial ATP-synthase reprogramming at high cell density in the absence of QIQ1. We conclude that African trypanosomes employ multiple mechanisms to modulate growth. We suggest that QIQ1 and other proteins identified here constitute components of a calcium-signalling pathway that reduces growth rate at high density, facilitating energy efficiency in resource-poor environments.