Bacteria-mediated hypoxia functions as a signal for mosquito development

Mosquitoes host communities of microbes in their digestive tract that consist primarily of bacteria. We previously reported that several mosquito species, including <i>Aedes aegypti</i>, do not develop beyond the first instar when fed a nutritionally complete diet in the absence of a gut microbiota. In contrast, several species of bacteria, including <i>Escherichia coli</i>, rescue development of axenic larvae into adults. The molecular mechanisms underlying bacteria-dependent growth are unknown. Here, we designed a genetic screen around <i>E. coli</i> that identified high-affinity cytochrome <i>bd</i> oxidase as an essential bacterial gene product for mosquito growth. Bioassays showed that bacteria in nonsterile larvae and gnotobiotic larvae inoculated with wild-type <i>E. coli</i> reduced midgut oxygen levels below 5%, whereas larvae inoculated with <i>E. coli</i> mutants defective for cytochrome <i>bd</i> oxidase did not. Experiments further supported that hypoxia leads to growth and ecdysone-induced molting. Altogether, our results identify aerobic respiration by bacteria as a previously unknown but essential process for mosquito development.