Transferrin-mediated iron sequestration suggests a novel therapeutic strategy for controlling Nosema disease in the honey bee, Apis mellifera

Authors: RODRIGUEZ-GARCIA, CRISTINA - Non ARS Employee; Heerman, Matthew; Cook, Steven; Evans, Jay; Hoffman, Gloria; Banmeke, Olubukola; ZHANG, ZI - Non ARS Employee; HUANG, SHAOKANG - Non ARS Employee; Hamilton, Michele; Chen, Yanping

Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/4/2021
Publication Date: 2/18/2021
Citation: Rodriguez-Garcia, C., Heerman, M.C., Cook, S.C., Evans, J.D., Hoffman, G.D., Banmeke, O.A., Zhang, Z., Huang, S., Hamilton, M.C., Chen, Y. 2021. Transferrin-mediated iron sequestration suggests a novel therapeutic strategy for controlling Nosema disease in the honey bee, Apis mellifera. PLoS Pathogens. 17(2):e1009270. https://doi.org/10.1371/journal.ppat.1009270.
DOI: https://doi.org/10.1371/journal.ppat.1009270

Interpretive Summary: Nosema disease is an adult honey bee disease caused by a small parasite named Nosema ceranae (N. cerenae) that lives in the digestive tract of honeybees and is linked to colony losses worldwide. Iron is an essential nutrient for both pathogenic microbes and their hosts, and relies largely on an iron transporter protein, transferrin. In this study, we found that N. ceranae infection could cause iron deficiency in infected bees. We also found that N. ceranae infection led to elevated levels of transferrin, allowing the parasite, N. ceranae, to scavenge more iron from the host for its survival. As a result, we employed a genetic method to interfere with the production of transferrin in N. ceranae-infected honeybees. The reduction of transferrin production and activity was found to accompany reduced iron loss and to improve the survival of N. ceranae-infected bees. This study suggests a novel strategy for bee disease treatment and should be of interest to researchers, graduate students, beekeepers and policymakers worldwide.

Technical Abstract: Nosemosis C, a Nosema disease caused by microsporidia parasite Nosema ceranae, is a significant disease burden of the European honey bee Apis mellifera which is one of the most economically important insect pollinators. Nevertheless, there is no effective treatment currently available for Nosema disease and the disease mechanisms underlying the pathological effects of N. ceranae infection in honey bees are poorly understood. Iron is an essential nutrient for growth and survival of hosts and pathogens alike. The iron tug-of-war between host and pathogen is a central battlefield at the host-pathogen interface which determines the outcome of an infection and, however, has not been explored in honey bees. To fill the gap, we conducted a study to investigate the impact of N. ceranae infection on iron homeostasis in honey bees. The expression of transferrin, an iron binding and transporting protein that is one of the key players of iron homeostasis, in response to N. ceranae infection was analysed. Further, the functional roles of transferrin in iron homeostasis and honey bee host immunity were characterized using a RNA interference (RNAi)-based method. The results showed that N. ceranae infection causes iron deficiency and upregulation of the A. mellifera transferrin (AmTrf) mRNA in honey bees, implying that higher expression of AmTsf allows N. ceranae to scavenge more iron from the host for its proliferation and survival. The suppressed expression levels of AmTsf via RNAi could lead to reduced N. ceranae transcription activity, alleviated iron loss, enhanced immunity, and improved survival of the infected bees. The intriguing multifunctionality of transferrin illustrated in this study is a significant contribution to the existing body of literature concerning iron homeostasis in insects. The uncovered functional role of transferrin on iron homeostasis, pathogen growth and honey bee's ability to mount immune responses may hold the key for the development of novel strategies to treat or prevent diseases in honey bees.