Warburg Effect in Anopheles Mosquito Anti‐Bacterial Immunity

Abstract

Otto Warburg discovered cancer cells favor increased glycolysis with pyruvate being converted to lactate rather than acetyl‐CoA for the tricarboxylic acid cycle, and this is termed the Warburg effect. Warburg metabolism has been found to occur in mammalian rapidly proliferating cancer and immune cells. Anopheles species mosquitoes, the vectors for malaria, rely on their metabolic system to provide energy and intermediates for their innate immune system, so called immunometabolism. We posited Warburg metabolism is involved in Anopheles sp. mosquito’s immune response. We designed an anti‐bacterial immunity model using intrathoracic inoculations of Escherichia coli K12, avirulent bacterium, and Enterobacter sp. Ag1, virulent bacterium isolated from the Anopheles sp. midgut, to test the immunometabolism response. We found a statistically significant doubling in lactic acid upon Ent sp. immune challenge as compared to injection injury controls using a lactate assay (t‐test, p = 0.0016). This provides evidence to support increased Warburg metabolism in immune challenged mosquitoes. We then fed Anopheles sp. mosquitoes dimethyl fumarate (DMF), a GAPDH inhibitor, and challenged the mosquitoes with E. coli. We found a significant mortality was observed in DMF treated mosquitoes compared to control (Mantel‐Cox, p < 0.001). By inhibiting the utilization of glycolysis and Warburg metabolism, decreased survival related to immune challenge is observed, showing Warburg metabolism is crucial for mosquito immunity. We believe current cancer therapeutics targeting Warburg metabolism can be an effective vector control strategy to prevent mosquito‐borne diseases.