Overview
Honey bees, which provide pollination services of critical importance to humans in both agricultural and ecological settings, have recently suffered from increased mortality at the colony level, likely due to a complex set of interacting stresses. Key stresses thought to be involved include nutritional stress due to loss of appropriate forage, chemical poisoning from pesticides, changes to natural living conditions brought about through large-scale beekeeping practices, myriad environmental changes due to climate change, and infection by insect parasites and pathogenic microbes.
I. Honey bee cellular stress responses
There seems to be no single cause for the recent increase in honey bee disease. Rather, stresses likely interact at the cellular level to cause tissue pathology, disease and mortality. One major focus of my research is to characterize the common cellular processes triggered by these disparate stressors, that include nutritional deficiencies due to loss of appropriate forage, chemical poisoning from pesticides, changes to normal living conditions brought about through large-scale beekeeping practices, myriad environmental changes due to climate change, and infection by insect parasites and pathogenic microbes. The various pathways that make up cellular stress responses provide logical and compelling processes to examine for interactions between these stressors. Diverse stresses, including those implicated in honey bee disease, are known to disrupt proteostasis, which refers to the homeostasis of protein synthesis, folding, function, and degradation both within a cell and in an organism as a whole. Dysfunctional proteostasis leads to pathological cellular changes, including a build-up of unfolded proteins, and triggers a suite of responses that limit damage to the cell and return it to homeostasis. Within individual cells, proteostasis is maintained by the responses of the proteostatic network, including the Heat Shock Response (HSR), responding to proteostatic disruption in the cytoplasm, the Unfolded Protein Response (UPR), responding to proteostatic perturbation in the endoplasmic reticulum, the Amino Acid Response (AAR), responding to amino acid limitation, and the Proteasome Recovery Pathway (PRP), responding to proteasome dysfunction. In other organisms, these stress response pathways have been shown to influence cellular and organismal outcomes to exposures to the very environmental stressors suspected of playing a part in recent honey bee losses (see above). However, these stress response pathways have not been fully characterized at the molecular level in honey bees. One major research goal of my lab is to characterize these pathways to define features shared with other species and to elucidate novel elements that provide new insight into how disparate stresses impact honey bee biology. We can then utilize this information to discover common components to help understand how these pathways and the stresses that induce them interact.
II. N. ceranae infection in bees
Among the environmental stressors implicated in honey bee disease, researchers have intensified focus on the role of microbial attack. The microsporidian species N. ceranae and Nosema apis can cause individual mortality in honey bees and have been implicated in colony collapse. Microsporidia constitute a group of spore-forming unicellular, obligate intracellular parasites which have recently been reclassified as fungi. Currently, approximately 1500 species are known. Microsporidian infections are widespread in nature, but are relatively understudied compared to other fungal groups. Midgut infection by N. ceranae, now one of the most common pathogens of the honey bee, causes energetic stress, epithelial damage, and when untreated, death. Furthermore, infection is associated with a number of physiological and behavioral changes that likely affect individual contribution to the colony. The Snow lab has developed novel methods for diagnosing and studying honey bee infection by this pathogen, utilizing broadly applicable cellular dyes. N. ceranae infection has traditionally been controlled by treatment with the drug Fumagillin, a methionine aminopeptidase 2 inhibitor. Yet, the effectiveness of Fumagillin treatment in controlling N. ceranae at the colony level appears limited in scope and duration. High doses of this drug affect host cell function and evidence suggests that N. ceranae can evade suppression in some circumstances. Most critically, future availability of Fumagillin is uncertain, making efforts to find alternative treatment strategies critical to protect honey bees from this parasite. Eukaryotic pathogens can be challenging to combat using chemical antibiotics because of the phylogenetic closeness with their hosts and microsporidia are no exception. However, comparative genomics indicates that microsporidia have undergone a major genome compaction relative to other fungi and have lost many of the cellular processes and pathways found in free-living eukaryotes. Thus, we hypothesized that they would have reduced resilience to cellular stresses. In support of this, Fumagillin itself works by interfering with protein synthesis, thereby disrupting proteostasis. We have begun to characterize the cellular responses to stresses in this key pathogen of the honey bee, focusing again on the pathways of the proteostatic network. The ultimate goal is to uncover differences in the cell physiology of the responses to stresses between the host and pathogen. These differences could then be exploited to develop treatments that minimize effects on the host.