Disentangling the Drivers and Dangers of Toxic Cyanobacteria Biosynthetic Heterogeneity in Cyanobacterial Harmful Algal Blooms

Proposal Summary Harmful algal blooms (cyanoHABs), dense proliferations of toxic cyanobacterial metabolites due to eutrophication of freshwater, are a leading threat towards drinking water. CyanoHABs impact human health in a multifaceted way through acute and chronic exposure, aerosolization, economic loss, and reduction in access to natural resources. Some metabolites produced in cyanoHABs are well known such as microcystins and saxitoxins, yet countless others remain unidentified. Advances in DNA sequencing and biosynthetic gene cluster (BGC) mining have revealed the genomic basis and origin of a novel suite of metabolites amongst cyanoHABs, yet current research remains focused on canonical cyanotoxins. Additionally, recent work indicates that many commonly produced cyanopeptides have unknown toxic synergistic effects when produced in combination. These insights suggest that studies of individual cyanotoxins and cyanopeptides on human health do not reflect the composite health risk associated with natural bloom samples. Thus, unanswered questions remain about the effects of toxic cyanobacterial metabolites when produced as mixtures in cyanoHABs. Moreover, the environmental factors driving the production of these toxic metabolites remains poorly understood. Our goal is to identify the effects of cyanopeptide mixtures on an array of human cell lines and identify the mechanistic basis for toxin production in cyanoHABs using a nine-year, multi-omic time series from Western Lake Erie (WLE), where cyanoHABs have threatened the drinking water supply for decades. Determining conserved cyanobacterial biosynthetic patterns in the field through metagenomic, metatranscriptomic, and metabolomic analysis will enable improved monitoring strategies to protect public health in and around WLE and globally. Furthermore, we plan to model these data to identify environmental and physiochemical parameters that stimulate the production of toxic cyanobacterial metabolites in WLE cyanoHABs. We anticipate these efforts will catalyze the production of enhanced risk assessment models that consider the combined risks of other toxic metabolites beyond common cyanotoxins like microcystins. Throughout this study, we will bridge field and laboratory studies using multi-omic and bioassay techniques to redefine “toxicity” in cyanoHABs by identifying additional metabolites and metabolite combinations that pose unrecognized threats to human health. Overall, we hypothesize that changes in toxic metabolite composition across spatiotemporal gradients correspond with fluctuating cyanobacterial communities within cyanoHABs, representing biosynthetic adaptations and novel threats towards human health. Ultimately, the development of such models and frameworks for cyanoHABs have the potential to produce highly resolved risk assessment models for cyanoHABs around the world, thereby protecting people and natural resources from the effects of these catastrophic events and informing prevention and management strategies.