Control Methods of Nosemosis: Comparison
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Nosemosis is a serious microsporidian disease of adult European honey bees caused by the spore-forming unicellular fungi Nosema apis and Nosema ceranae.

  • nosemosis
  • antibiotic treatments
  • fumagillin

1. Introduction

N. ceranae is a microsporidium firstly isolated in the Asian bee Apis cerana, and then found in Apis mellifera [3,15][1][2]. It is currently endemic worldwide [16][3], as well as the other well-known Nosema species: N. apis [13][4]. However, in some regions, usually with colder climates, N. apis is still prevalent. N. apis has a low prevalence in Southern Europe [16,17,18,19][3][5][6][7] while N. ceranae is widely present in Southern Europe, specifically in areas with a temperate-warm climate [3,20][1][8]. N. ceranae infection has important differences with N. apis control due to the microsporidium biology and because N. ceranae tends to persist throughout the year [3][1].

2. Control Methods

2.1. Antibiotic Treatments

Given that honey bees are food-producing animals [53[9][10],54], the use of antibiotic treatments in beekeeping should consider the impact on the hive products, mainly in terms of residues [54][10].
Nosemosis control with antibiotics has been mainly based on fumagillin administration. Depending on the geographical location and colony conditions (e.g., weather, stress, strength, etc.), it is advised to treat infested colonies from once (in autumn during feeding) to twice a year (in autumn and in spring, in the case of severe infections) [55,56,57,58][11][12][13][14]. While the autumn treatment aims to keep the colony alive during the cold season, the spring treatment is focused on improving the health status of adult bees that will be able to properly take care of the next generation of bees that are raised in spring.
While efficacy of fumagillin against N. apis has long since been proven [59][15], recent evidence indicates that fumagillin is effective against N. ceranae in western honey bees too [60][16]. Nevertheless, the use of fumagillin in heavily infected colonies with N. ceranae did not improve the size or increase the survival rate of colonies during winter, regardless of the dose or administration strategy adopted [61,62][17][18]. Moreover, the study carried out by Li et al. (2017) suggested that the elimination of gut bacteria by an antibiotic treatment weakened the immune function and made honey bees more susceptible to Nosema infection.
Treating colonies with 120 mg/colony of fumagillin in four applications (total amount of syrup 250 mL, each application 62.5 mL) was effective against depopulation and colony death, although relapses were detectable 4 months after treatment ended [7][19]. The total amount of active fumagillin ingested by a bee is the key to effectiveness. Administration of fumagillin with sucrose syrup gave better results than with medicated patties, which were not entirely consumed by the bees during field trials [7][19].
The use of fumagillin is not authorized in Europe due to the lack of a maximum residue limit definition in honey and of a registered veterinary medicine with this active substance. Its use in the EU may be admitted only under exceptional circumstances. Fumagillin is registered for use in Canada to treat Nosema disease. It is available in the commercial product as a salt, dicyclohexylamine (DCH). This chemical contaminant is a potential hazard for human health, as it is five times more toxic than fumagillin according to studies conducted on rats, and it is a genotoxic and oncogenic compound [61][17]. DCH is significantly more resistant to degradation in honey than fumagillin. Observed half-lives for DCH ranged from a minimum of 368 days, when stored at 34 °C in darkness, to a maximum of 852 days, when stored at 21 °C in darkness. A maximum half-life of 246 days was observed for fumagillin in samples kept in darkness at a temperature of 21 °C, while the observed half-life of fumagillin was estimated to be 3 days when exposed to light at 21 °C, and complete degradation was observed after 30 days under the same conditions. The stability of DCH, combined with its toxicity, make it an important hazard to be considered regarding hive products for human consumption safety [62][18].
The effectiveness of commercial product Fumagilin B® showed to be influenced by several factors, such as storage conditions (e.g., temperature and RH), dosage, dilution and UV exposure. High temperatures inside the hive can drastically reduce the initial concentration of fumagillin within a few hours.
Moreover, the effect of low fumagillin concentrations were tested. At lower fumagillin concentrations, significantly more pathogenic spores of N. ceranae were produced in treated bees than in untreated infected bees. Protein profiles of bees fed with fumagillin confirmed the hypothesis that fumagillin affects bee physiology when administered at concentrations lower than those that are effective against N. ceranae. In the case of mixed infections, the prevalence of N. ceranae may increase due to the use of fumagillin, replacing N. apis, which is more sensitive to the treatment [63][20].
A novel mass spectrometry allows the determination of traces of fumagillin and its degradation products in honey [7][19].
As an alternative to fumagillin, in vitro tests performed on the lepidopteran cell line showed that tinidazole and metronidazole can completely inhibit N. ceranae infection and were as effective as fumagillin. However, both substances cannot be used for the control of Nosema spp., as they belong to the active ingredients not allowed in the EU (Reg. 37/2010). The use of nitroimidazoles in dairy animals is prohibited in many countries [64][21].

2.2. Organic Control Methods

In Europe, wresearchers consider as organic methods the veterinary treatments allowed for organic beekeeping production [65][22]. A veterinary treatment is defined as “all courses of a curative or preventive treatment against one occurrence of a specific disease” [66][23].
Organic control methods can be identified with phytotherapeutics, organic acids, essential oils, polysaccharides, bacteria and metabolites. Their frequent common advantages are: their availability in many countries; the low risk for consumers to contaminate bee products; their low toxicity for the environment and the absence of demonstrated resistance of nosema. As a possible disadvantage, they could demonstrate high variability in reducing the infection levels of nosema in bees [21][24].

2.2.1. Phytotherapeutics

Other natural compounds have been tested with promising results in laboratory conditions. Among these are thymol showing a Nosema-inhibiting effect and thymol and resveratrol showing a positive impact in increasing bee longevity [67][25].
Herbal supplements (with or without C vitamin), have shown to reduce the N. ceranae infection levels in affected honey bee colonies enhancing their strength [68][26] and reducing the winter mortality [69][27]. Feeds containing Brassica nigra and Eruca sativa, with different amounts of glucosinolates (GSLs), reduced the N. ceranae infection [70][28]. Additionally, Agaricus blazei extract [71][29], Andrographis paniculate, Asteraceae (Artemisia dubia, Aster scaber, Helianthus annuus) and Eleuthereococcus senticosus may have a positive effect against nosemosis [69][27].
Piperine (an alkaloid in the roots of the Piperaceae family) and curcumin (a natural phenol produced by Curcuma longa) are potential candidates regarding antinosemosis therapy too, being able to increase the activity of the antioxidant system in honey bees [69][27].
Another product derived from plants that have demonstrated activity against N. ceranae infection is propolis. This product administrated to bees before or after the Nosema infection reduced significantly mortality, infectivity and infection rates [72][30].
The control of Nosema has also been focused on causing limitations to the gut cell invasion. That is the objective of the phyto-pharmacological preparation of Nozevit, a preparation that includes plant polyphenols, vitamins, minerals and amino acids. Histological studies showed that Nozevit induces the production of mucous from the epithelial layer of treated bees and provides an additional effect of coating the peritrophic membrane to form a firmer envelope that ensures protection from new invasions of Nosema spores [73][31]. Similar data had been previously observed in field experiments by the reduction of bee count spores [74][32] and by the reduction in the number of infected house and forager worker honey bees [52][33], although with lower efficacies than in the fumagillin control hives.
Other tested products such as Nosestat (a.i. Iodine 4 g.—Formic Acid 5 g. in 100 mL. of product), Phenyl salicylate or Vitafeed Gold (extract of Beta vulgaris) gave good results, highly related with low consumption of the different doses by bees in field conditions [21][24]. Concerning the essential oils, Porrini [75][34] and Damiani [76][35] observed significant antiparasitic activity of Laurus nobilis alcoholic extract, similarly, and found that different extracts of the same plant inhibited N. ceranae spore development, having the best results with ethanol extracts. More recently, Origanum vulgare and Rosmarinus officinalis alcoholic extracts (0.7% g/g, volatile oils) reduced the number of spores after three consecutive treatments without being related with bee mortality [77][36]. Bravo [78][37] found the essential oils of Cryptocarya alba to be effective in controlling N. ceranae development in vitro.

2.2.2. Bacteria and Their Metabolite

Acetobacteraceae are able to suppress the development of N. ceranae reducing the spore load [69][27].
Porrini [79][38] obtained good results with a bacterial metabolite and, specifically, surfactin, both in reduction of infectivity and in parasitosis development.

2.2.3. Organic Acids

Maggi [80][39] evaluated the effects of organic acids produced by Lactobacillus johnsonii CRL1647 (lactic acid, phenyl-lactic acid and acetic acid). A reduction on Nosema intensity was observed after two treatments, as well as the enhancement of fumagillin efficiency. No toxic effects were found in vitro, observing an increase of the beehive population and in the size of fat bodies in the bees. It is a clear example of the possibilities of natural new molecules on Nosema control.
Nanetti [81][40] tested the use of oxalic acid to control N. ceranae both in laboratory and in field conditions. They found that those oral applications interfered with the increase of artificial infections, and that two topical administrations in field conditions decreased the prevalence in the colony, finding a significant difference with untreated colonies and concluding that oxalic acid is a valid substance to be used to control N. ceranae infections.

2.3. Other Control Methods: RNA Interference (RNAi)

The oral application of double-stranded RNA (dsRNA) in N. ceranae infected bees can activate the immune response, suppress the reproduction of N. ceranae and improve honey bees’ health status [82][41]. The results obtained from the use of RNAi technology demonstrated the prospects of its applications in anti-nosemosis therapy, but more research is needed in order to be widely implemented in beekeeping practice [69][27].

References

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