A systematic review of honey bee (Apis mellifera, Linnaeus, 1758) infections and available treatment options

Abstract

Background

Honey bees and honeycomb bees are very valuable for wild flowering plants and economically important crops due to their role as pollinators. However, these insects confront many disease threats (viruses, parasites, bacteria and fungi) and large pesticide concentrations in the environment. Varroa destructor is the most prevalent disease that has had the most negative effects on the fitness and survival of different honey bees (Apis mellifera and A. cerana). Moreover, honey bees are social insects and this ectoparasite can be easily transmitted within and across bee colonies.

Objective

This review aims to provide a survey of the diversity and distribution of important bee infections and possible management and treatment options, so that honey bee colony health can be maintained.

Methods

We used PRISMA guidelines throughout article selection, published between January 1960 and December 2020. PubMed, Google Scholar, Scopus, Cochrane Library, Web of Science and Ovid databases were searched.

Results

We have collected 132 articles and retained 106 articles for this study. The data obtained revealed that V. destructor and Nosema spp. were found to be the major pathogens of honey bees worldwide. The impact of these infections can result in the incapacity of forager bees to fly, disorientation, paralysis, and death of many individuals in the colony. We find that both hygienic and chemical pest management strategies must be implemented to prevent, reduce the parasite loads and transmission of pathogens. The use of an effective miticide (fluvalinate‐tau, coumaphos and amitraz) now seems to be an essential and common practice required to minimise the impact of Varroa mites and other pathogens on bee colonies. New, alternative biofriendly control methods, are on the rise, and could be critical for maintaining honey bee hive health and improving honey productivity.

Conclusions

We suggest that critical health control methods be adopted globally and that an international monitoring system be implemented to determine honey bee colony safety, regularly identify parasite prevalence, as well as potential risk factors, so that the impact of pathogens on bee health can be recognised and quantified on a global scale.

This review provides a comprehensive survey of the diversity and distribution of some of the important pathogens affecting bee health and summarises the available treatments currently being used to mitigate and control bee infections.

1. INTRODUCTION

Honey bees and honeycomb bees are originally from Asia and Europe that have great environmental and economic importance. These insects are very valuable for both wild flowering plants and economically important crops, due to their pollination services (Gallai et al., 2009). However, bees face multiple pathogenic threats, including viruses, parasites (endo‐ and ectoparasites) bacterial diseases, high doses of environmental pesticides, and insufficient access to quality food (Retschnig et al., 2015). It has been reported that many bee colonies are managed as pollinators, harbour fungi, and other infections, including microsporidians (Sphaerius sp.), and trypanosomiases infections (Matthijs et al., 2020; Ngor et al., 2020). However, little information is known about the diversity of most bee species' microbial (virus, parasites etc.) diseases (Ngor et al., 2020). Recently, the loss of managed colonies of the western honey bee Apis mellifera (Linnaeus, 1758) has led researchers to investigate the factors that could have caused colony mortality (Dead, 2008; Aizen et al., 2009). Fungi, viruses and parasites such as Nosema spp. are one of the major contributors to their decline (Ngor et al., 2020; Goulson et al., 2015). Moreover, most of these organisms are easily transmitted, due to the social behaviour of the honey bee, living in large colonies, which could consequently shorten the lifespan of individual bees or cause the collapse of the entire bee colony (Higes et al., 2008).

The mechanism of pathogen transmission is typically vertical, going from an infected queen to her offspring, but there is also the horizontal transmission, when infected worker bees come into contact with other individuals in the hive or exchange food. This phenomenon, called trophallaxis, increases the physical contact between bees in the hive, this process transfers food or nutrients, but can also accelerate disease transmission (Chen et al., 2006). Transmission can occur from vectors as well, such as Varroa destructor mites, transmitting the ‘Deformed Wing Virus’ (DWV) for example, which has the potential to devastate entire colonies (Beaurepaire et al., 2020; Amiri et al., 2016). Infected drones can also transmit viruses during mating (Chen et al., 2006). Furthermore, there is increasing evidence that honey bee pathogens can infect other insect species and plants (Pattemore et al., 2014), thus, posing a destabilising threat to entire local and regional ecosystems.

There is an increasing global concern about the decline in bee colony health. The scientific community is recommending several control and preventive methods (synthetic and natural chemicals: essential oils, ban of insecticides, reduction of bee density and increased hive hygiene) to minimise the impact of these diseases. Additionally, pathogens that are present in bee colonies worldwide are affecting the economy of food‐producing countries and are also threatening dozens of native insect species as well (Matthijs et al., 2020; Dead et al., 2008). Most of the health strategies to be initiated depend on food producers’ initiatives or local governmental rules, which may vary considerably from country to country. This review aims to provide a comprehensive survey of the diversity and distribution of some of the important pathogens affecting bee health and summarise the available treatments currently being used to mitigate and control bee infections. A few promising therapeutic alternatives are emerging, which may be valuable for an integrated pest management strategy to control bee infections.

2. METHOD

2.1. Strategy to find and select articles

The method used to conduct this systematic review was based on the one used by Akinla et al. (2018), but with some modifications. The PRISMA guidelines were observed strictly throughout the search.

2.2. Data extraction, exclusion and inclusion criteria

The most relevant articles on honey bee parasites, fungi and their treatment, published between January 1960 and December 2020, were selected based on the keywords searched, the rigor of the methodology used, and the conclusions drawn. Articles had to be written in English and published in journals with an impact factor greater than 1.0. The databases targeted were PubMed, Google Scholar, Scopus, Cochrane Library, Web of science and Ovid. Equations were designed based on the keywords to search the databases. The collected data were taken as is, without any confirmation from the investigators.

2.3. Keywords

Equations were designed from the following keywords to carry out the research ‘Honey bee’ AND ‘parasites’ AND ‘current treatments’; ‘Honey bee’ AND ‘Fungus’; ‘Honey bee’ AND ‘parasites’ AND ‘Parasites’ AND ‘current treatments’ OR ‘parasites and fungus’ AND ‘honey bee’ AND ‘treatments’ etc.

2.4. Inclusion criteria

Inclusion criteria were:

• (1)Articles about honey bee parasites during the period of January 1960 to December 2020.
• (2)Articles about honey bee fungal infections during the period of January 1960 to December 2020.
• (3)Articles about the current treatment of honey bee parasites and fungal infections during the period of January 1960 to December 2020.

2.5. Exclusion criteria

Exclusion criteria were:

• (1)Lack of sufficient descriptions about the parasites and fungal infections.
• (2)Duplicated contents within the article.
• (3)Lack of information on the therapies that were used.

2.6. Analysis and processing of articles

At the end of the process, a total of 106 articles were retained.

3. RESULTS AND DISCUSSION

The present systematic review is the result of data collection carried out in different databases. After the first sort, a total of 132 full articles were identified, which made it possible to eliminate duplicated articles, in which we retained 125 articles for analysis. An in‐depth reading of the articles led to the second selection of 106 articles for this study. Figure 1 shows the selection diagram according to the PRISMA statement.

FIGURE 1.

PRISMA model study design process.

3.1. General information and potential pathogens

Bees are social insects playing a very important role in pollination services and agriculture productivity. One third of the food consumed in the world is linked to the pollinating activity of bees (Gallai et al., 2009). Honey bees produce honey and other products such as propolis, royal jelly and wax (Aizen et al., 2009; Amakpe, 2010). Like all organisms, the honey bee has been undergoing a lot of pressure lately due to various unfavourable environmental conditions, namely pollution, exotic diseases, nanoplastics, loss of forage areas, climate change (i.e. long cold weather, droughts, floods, fires) and major El Nino effects (i.e. high temperatures). Various pathogens, stressful beekeeping practices, and high doses of crop insecticides (Gallai et al., 2009; Amakpe, 2010) have been also related to the reduction of flying periods and bee populations. For this last point, the use of certain pesticides (clothianidin, imidacloprid and thiamethoxam) were prohibited by law of the European Union, as they represent a danger for the bees at sublethal levels, attacking the nervous system of the insects (Lundin et al., 2015).

Diseases, such as varroosis, are adding a lot of stress to bee colonies (Meixner, 2010). Indeed, what makes this disease more damaging is the fact that the mite not only feeds on the bee's haemolymph and fat body, but also serves as a vector for viruses. Moreover, there are also other common honey bee pathogens such as bacteria (American/European foulbrood) (Forsgren et al., 2005), tracheal mites (Acarapis woodi) and other mites (Tropilaelaps spp.), fungi (Aspergilus spp., Ascosphera apis sp., and Nosema spp.), nematodes, and conopid flies that are parasitoids of bees (Reynaldi et al., 2015; Anderson & Truemann, 2000; Arab et al., 2018).

3.2. Reviewed geographical distribution and ecology of bees

The species A. mellifera has a wide natural range, extending from sub‐Saharan Africa, Northern Europe, Middle East to Central and North Asia (Ruttner, 2013; Bertrand, 2013). The amplification of this distribution was also the result of human migration. Nowadays, A. mellifera is currently present around the world (Sheppard et al., 1996). The other species within the genus Apis are distributed in Asia and in particular in South‐East Asia, coinciding with tropical climates (Whitfield et al., 2006).

To date, 29 subspecies of honey bees have been recognised and described on the basis of morphological, behavioural, ecological and geographic distribution characteristics (Ruttner, 2013; Bertrand, 2013; Sheppard et al., 1996). Bees have an agronomic and ecological importance in nature. Flowers provide bees with food (nectar and pollen) and medicinal resources (propolis etc.). The majority of phanerogams could not accomplish their reproduction without the intervention of these pollinators, which play an important and dominating role in their perpetuation (Whitfield et al., 2006; Paraïso et al., 2011). Bees by transporting pollen from the male reproductive part of the plant, the anther, to the female reproductive part, the stigma, facilitate the fertilisation of flowering plants and thus help maintain plant biodiversity (Meixner, 2010; Bertrand, 2013; Danforth et al., 2013).

The honey bee A. mellifera lives in an organised society in the hive that is based on two principles: the differentiation or distribution of work among the different members, and the coordination or direction of all individual faculties. Honey bees are eusocial insects, characterised by the overlapping of generations, the cooperation in the care of immatures, and contains the division of reproductive work (Ruttner, 2013; Sheppard et al., 1996). An average honey bee colony has between 10,000 and 80,000 bees and is organised around two distinct castes: the reproducers (queens and drones) and the sterile workers. The function of the males is limited to the fertilisation of virgin queens, as they generally die after mating (Danforth et al., 2013).

3.3. The bee development cycle

Bees are holometabolous insects, having a complete metamorphosis. They are completely different in the larval state than in the adult state (Paraïso et al., 2011; Danforth et al., 2013). The development cycle of an adult bee, passes through three stages: egg, larval and pupal stage and then to the adult stage (Collet et al., 2006; Özdil et al., 2009). The duration of development is variable, the queen has the shortest cycle, the drones have the longest cycle, and the workers have an intermediate cycle (Collet et al., 2006). These life‐spans may be different among the subspecies and according to environmental conditions (i.e. temperature, humidity and brood nutrition). The ideal nest temperature for brood development is 35°C (Paraïso et al., 2011; Danforth et al., 2013).

3.4. Brief socioeconomic importance of bees

Bees, especially honey bees, are known for their role as pollinators (Klein et al., 2007). They participate in the pollination of cultivated plants such as fruit trees, vegetables and fodder, as well as plants that can be used in the manufacturing of biofuels (Klein et al., 2007). From an environmental point of view, pollination ensures the maintenance of plant biodiversity (Ruttner, 2013). In agriculture, pollination improves the quality and quantity of food production (Rose et al., 2007). Bees contribute to more than 80% of the pollination services of the world's agriculture, which have been estimated at $153 billion euros per year (Goulson et al., 2015). For industrial crops, an increase in production has been demonstrated when more hives are present per hectare. Thus, farmers rent and install beehives in their fields to increase yield during harvesting (Rose et al., 2007). The honey bee is also known for the production of honey and other beekeeping products, hence its nomenclature A. mellifera or honey bee.

3.5. Natural predators of bees

Most of the health‐related problems that affect bees and beekeeping worldwide are from causal agents such as V. destructor and this has become one of the main problems, while fungi and viruses are active contributors as well (Rose et al., 2007; Z'Hor et al., 2020).

3.6. Parasites of the honey bee

Bees can harbour several pathogens, which are summarised below and in Table 1.

TABLE 1.

Summary of the most important pathogens of the honey bee.

Pathogen	Disease or common name	Nature of the agent	Type of population affected		Characteristics
			Adult bees	Brood
Varroa destructor	Varroosis	Mesostigma mite	Yes	Yes	Straggling bees with atrophied wings, high winter mortality, transmission pathogens.
Acarapis woodi	Acariosis	Trombidiform mite	Yes	No	Paralysed and flightless bees, increased spring mortality, high winter mortality.
Braula caeca	Bee lice	Diptera	Yes (queen)	No	Ectoparasites are present primarily on the thorax of the queen.
Malpighamoeba mellificae	Amoebiasis	Protozoan	Yes	No	Bees unable to fly, swollen abdomen, diarrhoea, yellowish round faecal spots on flight board

3.6.1. Varroosis

The disease varroosis is caused by a mite infection. The organism was collected for the first time by the entomologist Edward Jacobson, from A. cerana, from the Island of Java, Indonesia. Dr. Oudemans, a Dutch acarologist, made its first description in 1904 and gave the name of V. jacobsoni, as a tribute to its discoverer (Z'HOR et al., 2020; Topolska, 2001). The first observation of Varroa in the brood of A. mellifera L. is believed to have taken place in Korea in 1950. Anderson and Truemann (2000) separated the mite species, originally known as V. jacobsoni, into two separate species. The name of the species that include the mites infesting the honey bee A. mellifera L. is now referred to as V. destructor. V. jacobsoni and V. destructor are sister species characterised by short, tightly coiled peritreme, fewer endopod setae, and the presence of one seta on the trochanter per palpal (Topolska, 2001; 34); the size is 1063.8 μm by 26.4 μm for V. jacobsoni and 1506.8 μm by 36.0 μm for V. destructor (Paraïso et al., 2011; Mondet et al., 2016).

The genus Varroa belongs to the class Arachnoidea, subclass Acari, superorder Anactinotricha, Order Gamasida and Family Varroidae (Fernandez & Coineau, 2007; Duay et al., 2003). The family has only one genus, Varroa, which includes five species: V. underwoodi described from A. cerana in Nepal, V. rinderid described by A. Koschevnikovi in Borneo, and V. jacobsoni, the natural ectoparasite of A. cerana from Java in Asia (Oudemans, 1904; Dietemann et al., 2019). The parasitic V. destructor of A. cerana is its original host and A. mellifera is its new host (Meixner, 2010). In Algeria, the Varroa mite that parasitises A. mellifera is also V. destructor (Forsgren et al., 2005). The lesions of the cuticle caused by the bite of V. destructor constitute a gateway for the invasion of other pathogens. The mite can transmit several viruses which are obligatory intracellular parasites. They use the cellular machinery of the infested host to replicate (Mondet et al., 2016), but since the infestation of Varroa mites, viral infections in honey bees have become more widespread and have higher virulence (Bakonyi et al., 2002). According to Anderson and Truemann (Pattemore et al., 2014), the main parasites affecting A. mellifera L. are the parasitic mite Acarapis woodi, which causes acariosis; the haematophagous mite Tropilaelaps clareae, which parasitises the capped brood of A. mellifera, like V. destructor; and the protozoan Malpighamoeba mellificae that develops in the Malpighian tubules, causing the amoebiasis in adult bees. This protozoan is frequently found together with Nosema spp. (Plischuk et al., 2009; Bacandritsos et al., 2010) and causes depopulation of hives without any apparent obvious signs of mortality (Bacandritsos et al., 2010; Mackowiak, 2009).

Mechanism of infection of Varroa destructor

V. destructor (formerly known as V. jacobsoni) is an obligate ectoparasite of brood and adult honey bees, which is currently considered to have the most negative impact on apiculture (Kugonza, 2021). Varroa‐infested colonies have been reported to die after 2–3 years of infestation, if not systematically treated (Rosenkranz et al., 2010). V. destructor has originally coevolved with A. cerana in Asia, but since then it has nearly reached a worldwide distribution. The exception is Australia and some isolated islands, after two host shift events to A. mellifera in Korea and Japan about 60 and 100 years ago, respectively (Rosenkranz et al., 2010).

The life cycle of this haplodiploid mite is highly adapted to the development of drone and worker brood, allowing only a narrow time window for its reproductive success (Garedew et al., 2004). Briefly, after invasion of a suitable host cell just before capping, the female mite starts feeding on the 5th‐instar larval haemolymph and initiates oogenesis within a few hours (Martin et al., 1998). Ramsey et al. (2019) have recently reported that V. destructor mite damages adult and brood bees by selectively ingesting fat bodies. Specific host signals trigger egg laying of the mite, starting with an unfertilised haploid male egg after approximately 3 days and this is followed with four or five fertilised diploid female eggs in 30‐h intervals (Rosenkranz et al., 2010). The mite offspring hatch a few hours after oviposition and pass through proto‐ and deutonymph stages until they become sexually mature, following a final moult after approximately 7 days. As soon as the first female reaches sexual maturity, the male mates with it, which is triggered by female sex pheromones, until the next female is mature (Kugonza, 2021). Fertilised females are released when the host honey bee larvae hatch and can be transmitted between individual honey bees within the same colony or spread to a new host colony through foraging and drifting of honey bees.

V. destructor infestations have a strong negative effect on the fitness of honey bees both at the individual and the colony level. Infested honey bee pupae experience severe nutritional deficiencies during development depending on the parasitisation rate, as both adult females and offspring feed on their haemolymph and fat stores (Amdam et al., 2004). This feeding activity at the early sensitive life stage, together with additional secondary infections, can alter the host physiology and may reduce its immunocompetence. The infection can also affect flight and navigation performance in adults, which will ultimately result in decreased honey bee survival (Naug, 2009; Alaux et al., 2010).

Along with the direct effects of Varroa spp., this parasitism comes with its indirect effects, as Varroa spp. can act as a reservoir and important vector of some viruses (Chen et al., 2004), like the Acute Bee Paralysis Virus, Kashmir Virus and Deformed Wing Virus (DWV) (Chen et al., 2004; de Miranda et al., 2010; Bowen et al., 1999). A few reports explore the fatal interplay between mites and DWV (Bowen et al., 1999).

3.6.2. Other pathogens affecting honey bees

Honey bees are susceptible to a wide variety of diseases, including fungal pathogens. The most common of them are presented below.

Nosemosis

Nosemosis is caused by the microsporidian parasite N. apis or N. ceranae, which are unicellular eukaryotes with a broad host‐spectrum. N. apis and N. ceranae affect insect species of economic interest like A. mellifera L. (Higes et al., 2007). The pathology related to N. apis has long been known by beekeepers (Keeling, 2009) and N. ceranae is derived from the Asian bee, which may have been imported into Europe through trade (Botías et al., 2012). They affect the digestive tract of all three bee castes (queen, worker, drone). Two species of microsporidia, N. apis and N. ceranae, are the agents of two major diseases known as Nosema A and C, respectively (Hges et al., 2010). Otti and Schmid‐Hempel (2007) reported that there is also N. bombi, which is responsible for affecting functional fitness being detected in honey bees and bumblebee as well. Both species are obligate intracellular parasites of adult bees. N. ceranae increases the energy demand of bees (Mayack & Naug, 2009) and decreases the sugar level of the haemolymph (Mayack & Naug, 2010), probably from intestinal lesions that occur when reproducing in the gut lining of the bee. In addition, the infection of N. ceranae suppresses the bee's immune response (Antúnez et al., 2009).

N. ceranae belongs to the class Microsporidia (phylum Microspora) (Wittner & Weiss, 1999) and is recently reclassified from protozoa to fungi (Adl et al., 2005). The absence of mitochondria was the basis of the hypothesis of a primitive origin (Archezoa) of microsporidia. Today we know that the absence of this organelle is part of an adaptive reduction at the molecular, biochemical and cellular level of this group of parasites due to its reliance upon host energy (Burri et al., 2006). With the presence of the mitosome, they do not have the ability to produce ATP via oxidative phosphorylation, making microsporidia highly dependent on their hosts for energy. This is the best‐known effects of N. ceranae in honey bees (Burri et al., 2006). Diagnoses of the disease can be conducted using light microscopy, GC‐MS metabolite profiling, and detecting spores harvested from the digestive tract of the bee using qPCR (Aliferis et al., 2012).

Ascosferosis

Ascosphaera apis (var. apis and var. major) (Spiltoir & Olive, 1955) is a worldwide disease caused by a sexually reproducing ascomycete fungus, known as ‘the plastered brood or the chalkbrood disease’. The spores are ingested and develop in the digestive tract and pass through the digestive mucosa after crossing the digestive wall or cuticle, the mycelium invades all tissues of the larva. Honey bee larvae can ingest the parasite at any stage; however, it is the larvae under capped brood cells that show symptoms of the disease. The infested larvae are soft and yellowish‐white, with fluffy mycelium at first, but then they firm up and turn completely yellow, as the mycelial invade their gut wall. The mycelium forms a white felting cotton‐like appearance. The infested larva dries out and mummification begins, which is why this disease is known as ‘chalkbrood disease’ (Table 2). Finally, a mosaic brood and white or black mummies will appear (Amakpe, 2010). It rarely causes mortality in honey bee colonies, but A. apis is, however, responsible for the weakening of the colony, by causing loss of larvae, resulting in a decrease in the population of foragers, honey, and pollen production (Spiltoir, 1955). No drug treatment is effective against this pathogen and management practices are needed to avoid contamination (Chiron & Hattenberger, 2008).

TABLE 2.

Summary of infections caused by honey bee fungal pathogens.

			Type of population
Pathogen	Disease name	Nature of the agent	Adult bees	Brood	Characteristics
Nosema apis and Nosema ceranae	Nosemosis	Microsporidia	Yes	No	Difficulty in flying, swollen abdomen, reduction or cessation of egg laying
Ascosphaera apis (Chalkbrood disease)	Ascosferosis	Ascomycete fungus	Yes	No	Mummified and desiccated larvae, covered with white mycelium, and/or black fruiting bodies, mummies deposited at the flight entrance and in front of the hive
Aspergillus flavus (Petrified brood)	Aspergillosis	Ascomycete fungus	Yes	Yes	Agitation of the bees

Aspergillosis

Aspergillus apis is a fungal disease that causes aspergillosis, which is responsible for the weakening of the colony, causing losses of larvae and adults, resulting in a decrease in the population of foragers, honey and pollen production (Table 2). Aspergillosis is a rarer mycosis than ascosferosis, commonly called ‘the disease of petrified brood’ (Foley et al., 2014) that is found in Australia, North and South America as well as Europe. Although the infection rarely causes mortality in honey bee colonies, no drug treatment is effective, making it difficult for Aspergilus spp. eradication. A. flavus, which is an ascomycete, is found in environmental moulds. A number of different species are found worldwide, that is, A. fumigatus, A. fungi, A. brasiliensis etc. A. flavus can also contaminate humans causing a severe respiratory syndrome. The common name for this when it infects honey bees is referred to as stonebrood because it turns the mummified brood into a hard pellet like substances.

Aspergillosis affects bees both at the larval stage (petrified brood) and adults with natural digestive contamination. The pathogen produces mycotoxins, called aflatoxins. Aspergillus spores are transmitted from ingested contaminated food, infected bees from other colonies, and defecation. Then, the mycelial filaments spread throughout the body of the bee or larva. The larvae die and a greyish, dark green or black ‘fuzz’ forms on the surface of the cadavers. The dead larvae are very hard, hence the name stonebrood, and adhere to the walls of the alveolus through the mycelium. They can be detected by standard methods such as PCR screening (Lee et al., 2004). With this disease, prevention is the best protection measure (i.e. removing dead larvae, burning infected combs etc.) by maintaining a healthy hive.

3.7. Mechanism of infection of Nosema apis and N. ceranae

N. apis is a long‐known intracellular microsporidian parasite of A. mellifera, whereas N. ceranae is presumed to have more recently undergone a host switch from A. cerana to A. mellifera (Fries, 2010). Today, N. ceranae has reached a global distribution (except Australia) and has progressively become more prevalent over the past decade (Klee et al., 2007; Paxton et al., 2007). N. ceranae has also been found to infect other honey bees (Fürst et al., 2014; Li et al., 2012) and bumblebee species (Li et al., 2012; Soroker et al., 2011). As N. ceranae has only recently been described and can only be reliably identified by polymerase chain reaction (PCR), a clear distinction between both Nosema species, especially in older publications, might be difficult (Budge et al., 2015).

The role and magnitude of the damage of N. ceranae infections in honey bee colonies has been controversially discussed. Major implications of N. ceranae infections in colony losses have been mainly reported in the Mediterranean region (Dainat et al., 2012; Genersch et al., 2010), but have been ruled out in countries with a more temperate climate (Gisder et al., 2010; Martin et al., 2012), suggesting that climate may influence its virulence (Genersch et al., 2010; Traver & Fell, 2015). Irrespective of this, some studies suggested a higher virulence of N. ceranae than N. apis (Williams et al., 2014; Forsgren & Fries, 2010), whereas other studies reported neither higher proliferation rates for N. ceranae or host mortality (Table 2) (Forsgren & Fries, 2010). Nevertheless, the asymmetric interspecific competition between Nosema species in sequential co‐infections may provide an alternative explanation for the global invasion success of N. ceranae (Milbrath et al., 2015).

Nosema spp. undergo analogous life cycles and are typically horizontally transmitted via the faecal–oral route by ingestion of spores from the environment (Fries, 2010; Fürst et al., 2014; Natsopoulou et al., 2015; Graystock et al., 2015). The pathogen might also be sexually transmitted (Roberts et al., 2015). Ingested Nosema spores germinate in the midgut lumen and penetrate the membrane of epithelial cells with their polar tube to inject their sporoplasm. The spherical sporoplasm develops into a spindle‐shaped meront, which replicates several times until first oval sporonts and the new generation of spores are formed after 4 days postinfection (Gisder et al., 2011). Ultimately, they are released into the lumen via cell lysis, where they can infect neighbouring cells or may be defecated.

Although Nosema species are known to have lost sexual reproduction (Ironside, 2007), recent reports of recombination of N. ceranae raise new questions about its life cycle (Gómez‐Moracho et al., 2015; Sagastume et al., 2011; Le Conte et al., 2015). Despite the controversies mentioned above, N. ceranae infections have been shown to negatively affect honey bee health at the individual level, which may also lead to reduced colony fitness under certain conditions. Depending on the intensity of the Nosema infection, honey bees may also experience nutritional and energetic stress (Aufauvre et al., 2014; Chaimanee et al., 2012) and/or immunosuppression (Holt et al., 2013), which possibly makes them more vulnerable to other pathogens such as black the Queen Cell Virus (BQCV) (Francis et al., 2014). Additionally, N. ceranae appears to inhibit apoptosis in its host cell, which might be a mechanism of self‐protection, thus enhancing its reproductive success (Doublet et al., 2017). Recent transcriptome and proteome data suggested modifications in epithelium renewal and apoptosis‐related pathways were associated with N. ceranae infections (Holt et al., 2013; Dussaubat et al., 2012; Vidau et al., 2014).

3.8. Current therapy and potential alternative treatments

Few methods have been suggested for the preventive and curative treatment of the pathogens described above for individual bees or entire colonies. Therefore, there is a great potential to discover other possible alternatives to reduce pathogen loads or infestation levels, either using synthetic treatments or sustainable organic biocontrol medications.

3.9. Synthetic pesticides: fumigation against Varroa mites

Based on the obtained literature, there is use of a small range of effective acaricides (i.e. pyrethroids, organophosphate and formamidine) to minimise the impact of Varroa mites. A pesticide that eliminates 99% of the Varroa population can effectively contain the development of Varroa in the colony, but rarely eliminates the infestation completely long‐term. In 2011, the most effective control against Varroa mites offered by the pharmaceutical industries were treatments based on three synthetic acaricide molecules: Tau Fluvalinate (Apistan 10.3%, Vita, Hampshire, UK), Coumaphos (CheckMite, Bayer AG, GER), and amitraz (Apivar, Geraldine, NZ). However, the continuous use of these products can have major drawbacks. Excessive use can lead to toxicity to bees, contaminate hive products (beeswax), and affect other nontarget insects and other essential organisms for proper ecosystem functioning. The artificial selection for drug resistance of mite populations with the constant use of these treatments occurs quite rapidly as well. Under such circumstances, the overuse of these products unfortunately resulted in a decreased efficiency (< 50%) or the total lack of efficacy against Varroa infestations all together (Hernandez et al., 2021; Richard et al., 2012).

Recently it has been determined that efficacies that are below 70% mortality for Varroa mites results in sustainable growth of the population and they continue to grow to the point that produces irreversible damage to honey bee colonies. According to some studies conducted around the world, the life of a synthetic pesticide in beekeeping is a few years, if it is being used continuously. After this period, the proportion of Varroa mites resistant to the miticide is sufficient to neutralise the effect of the treatment, which is the case for amitraz in Turkey (Girisgin et al., 2019), and Coumaphos and Pyrethroids in Spain (Le Conte et al., 2020).

3.10. Biotechnological methods

The removal of male brood and the selection of bee lines that are more tolerant to parasites are considered good biotechnological alternative control methods to reduce the use of chemicals and the resistance to synthetic acaricides in the EU and other countries (Le Conte et al., 2020). Unfortunately, due to the rapid reproduction rate of the Varroa mite and the long selection process for resilience in bees, these methods may take a while to show promising results. Furthermore, the artificial insemination of queens and the use of drug combinations may be more promising strategies than regular mating programs, depending on the beekeeping operation. Moreover, new RNAi treatments have been developed to control Varroa mites (Garbian et al., 2012) and DWV. New vaccine candidates have been recently tested (Giese et al., 2013). Giese et al. (2013) developed an oral DNA vaccine application for honey bees that is biologically safe. The mechanism of action of this vaccine restores the immune system of bees, as the V. destructor suppresses the honey bee's humoral and cellular immune response.

3.11. Organic acids and essential oils from medicinal plants

Rademacher and Harz (2006) reported that organic oxalic and formic acids as well the isolated compound thymol from thyme's essential oil (EO) are commonly used for Varroosis control worldwide. This can be applied by trickling, fumigation or spraying. There is a large body of research on the use of EO products and their components in honey bee colonies with excellent literature reviews (Qadir et al., 2021). Research over the last 20 years has been conducted to determine the optimal concentrations, timing of application, with respect to the beekeeping season, the amount of residue build up in hive products, toxicity to the colony, methods of application, specifics of application with respect to varying climate, hive type and beekeeping methods, to optimise the effectiveness of these alternative treatment methods (Jack et al., 2021).

Overall, research on the use of organic acids and other alternatives to acaricides against varroosis can be summarised with the following general conclusions: (1) they are sufficiently effective against varroosis; (2) the volatile products from formic acid and thymol are some of the most effective treatments; (3) formic acid is the only acaricide that has been shown to be toxic on phoretic Varroa mites and Varroa mites in capped brood cells; and (4) oxalic acid is effective on phoretic mites only. For maximum effectiveness, the application should be made during a period when there is no brood. Therefore, the use of oxalic acid is favoured in areas where there is a cessation of egg laying during the year. This is the case in temperate regions during autumn and winter. Thymol is fat‐soluble and accumulates in the bee's wax. However, it degrades between treatment periods. Problematic accumulation of thymol residues in wax does not occur under a normal use program (Doublet et al., 2017). There is little risk of residues and accumulation of organic acids in hive products. In addition, these acids are water soluble (not found in wax) and occur naturally in honey. To date, there are no reports of increased resistance to these three products.

There are a number of studies on alternative EO, their isolated components, and other natural treatments for varroosis and other important diseases. Conti et al. (2020) used the EO from Artemisia annua, A. verlotiorum, Cinnamomum verum and Citrus reticulata against the honey bee mite V. destructor. Most of the EO showed high repellent activity after 24 h exposure. C. verum was the most effective in vitro (EC₅₀ of 1.30 μL/L) and was tested to control varroosis in field trials, confirming that its efficacy is greater than 65%. It is encouraging that C. verum and other EO biofriendly products may be used to control varroosis with no known side effects on the bee colonies.

Propolis' chemical composition is variable, rich in balsam, flavones, flavanones and chalcones. A study was set up to determine if the chemical composition of propolis would affect honey bee colony health. Tolerant and susceptible bee colonies to V. destructor were compared. Susceptible colonies had higher balsam (72.0% more resin) levels than tolerant ones (58.0%). Caffeic acid and pentenyl caffeates (15.0% had also higher levels in propolis in tolerant colonies, compared to susceptible colonies (11.4%). Therefore, propolis can enhance individual and social immunity of the honey bee against V. destructor (Popova et al., 2014). Propolis extracts have also shown to be effective against Nosema spp. (Naree et al 2021a; Naree et al, 2021b; Yemor et al, 2015; Suwannapong et al, 2018)

Some very interesting observations were made by Hsu et al. (2021) when looking for the activity of the fungal Aureobasidium melanogenum (strain CK‐CsC) effects in honey bees. The authors measured the survival, nutrient gene expression, gut microbiota and toxicity of newly emerged bees cultured in vitro. Although the product was nontoxic to honey bees, it caused an increase in nutrient gene expression, and increased mortality of the pathogen. The bees that were fed with the A. melanogenum strain had higher concentration of Bacteriodetes and Actinobacteria in their gut flora, showing a promising probiotic potential. Care must be taken when interpreting these data as the supernatant from the treatment caused a high rate of bee mortality as well.

3.12. Complementary discussion on disease pathology

The present study allowed us to present an overview of the most common pathologies from which A. mellifera bees suffer worldwide. Most of the reported pathologies are predominantly related to acarid parasites and fungal infections. These pathogens seem to have overshadowed European and American Foulbrood, which are known to be bacterial infections that impact honey bee health as well. According to the literature, V. destructor is increasing in its prevalence and is likely to be a major global problem for the beekeeping industry. The success of Varroa population growth is closely related to the different developmental phases of the bee, which go through egg, larvae and pupal stages before reaching the adult phase (Cherifi, 2015).

We have established through our research that the evolution of the Varroa spp. population depends on the different castes, and we have confirmed that the Varroa spp. has a preference for the drone brood over the worker brood. This could be explained by the size of the drone larvae, and the longer duration of their development. The drone brood also allows better feeding of the founding mother and her offspring. Several researchers have noted the importance of these two parameters (size and development time of the drones) in the development of this pathogenic ectoparasite.

It is important to note that some parasitised honey bee specimens are hairless, even though data from the literature have highlighted this characteristic as a typical symptom of a viral infection. For honey bees, when the disease occurs, the first symptom observed is not the difficulty in flying, but a significant hair loss as soon as the bees emerge from their honeycomb cell. The acute depilation gives a black and shiny aspect to their body and consequently these bees seem smaller than healthy bees. Moreover, viral infections can enter the nervous system of A. mellifera. Therefore, some infections are manifested by certain symptoms such as the incapacity to fly, disorientation, ataxia (trembling) and paralysis.

The present data collection showed that parasites and other pathogens attack certain lobes of the brain and especially the mushroom bodies, which plays a central role in bee behaviour, and the regulation of circadian rhythm as well as locomotion. The pedunculated body, made up of a thick and short peduncle, contains two calyces, one median, and the other lateral (olfactory); these play a role in memory and locomotion functions (Chevin, 2012). Kenyon cells play a role in learning (olfactory), memory and locomotion. These cells, present in the intrinsic neurons, process and convey the information received along the stalk to the vertical and medial lobes and make contact with the extrinsic efferent neurons.

In addition, it has been shown that the viral particles of chronic bee paralysis are present in the brain, in the abdominal and thoracic nerve ganglia, and in the hypopharyngeal glands. Some authors have also reported that cultures isolated and identified from larval mummies, obtained from colonies infected with mycoses, presented similarities across the different life stages. The most typical kinds of growth from these cultures were Ascosphaera spp. and Aspergillus spp.

Honey bees’ hygienic behaviour is one major factor associated with resistance to V. destructor and other diseases that can be used in combination with the other control (i.e. acaricides, phytotherapy, propolis) methods mentioned above. To improve this phenotypic and genotypic characteristic, breeding must be incentivised to increase the genetic stock of managed honey bees. Moreover, hygienic and honey production can also be further selected in the future (Le Conte et al., 2015; Le Conte et al., 2020; Büchler et al., 2010). There is consistent data that demonstrates the great resilience potential of honey bee colonies from reproduction programs that select for enhancing disease resistance.

4. CONCLUSION

In the light of the data obtained from the present research, the honey bee is affected by several pathogens that particularly affect the wings, the pilosity, the nervous system and the digestive tract. The pathologies are related to the presence of parasites (Varroa), viruses and fungi (Nosema spp., Aspergillus spp. and Ascospheara spp.). These diseases have more literature reported on them in comparison to European and American Foulbrood. Recently, the first honey bee vaccine has been developed for the treatment of American Foulbrood that has around a 50% efficacy rate (Dickel et al, 2022). Therefore, Beekeepers are faced with similar challenges when faced with these bacterial infections, which translates to very few treatment options, and the increased risk of antibiotic resistance. Varroa is evidently the most reported disease in relation to honey bee health worldwide. The present literature review took a census of the parasites and other pathogens that affect bees worldwide, which also included a few promising treatment alternatives from the rise of synthetic drug resistance. However, it would be interesting to undertake a more in‐depth study of bee pathologies by obtaining papers from a larger spatiotemporal scale and from different languages to be able to amplify our understanding, which would include the awareness of different possible therapeutic alternatives that are used in different cultures and from different scientific perspectives.

Honey bees are important for maintaining our biome diversity and mass production of food. However, the constant use of chemicals to suppress infectious diseases to maintain the health of bees may not be sustainable in the long run. our literature review supports the notion that in order to reverse the current honey bee declines a one health approach is needed, which emphasises the need for the integration of hive‐specific solutions, a reappraisal of engagement with the many stakeholders whose actions affect bee health, and recontextualising both of these within landscape scale efforts (Donkersley et al, 2020). Along these lines, we are recently recognising the impact of air pollution on honey bee health (Thimmegowda et al, 2020) and other environmental exposures that have yet to be fully recognised which coincide with the previously known stressors (Mayack et al, 2022). To address the problem of drug resistant pathogens, present recommendations are to increase dose concentrations or to use a combination of treatments, which may look appealing at first, but would have a damaging effect after a short period of time, thereby reducing the options for an effective therapy. Moreover, here we show the arrival of some attractive biofriendly treatment methods that could reduce selection pressure of bee pathogens when used prudently.

In conclusion, there is a need for further developments of treatment options to beekeepers, either more synthetic options, gene editing, vaccines, or alternative treatments, so that we can address the prevalent diseases distributed worldwide and that have existed for a long time in order to improve the health of an organism that is already heavily managed and is unable to develop its own naturally selected defence mechanisms. We understand that the preservation of the honey bee is not only a local necessity for beekeepers, but it is also a call for ensuring human survival under the Global Health initiative.

AUTHOR CONTRIBUTIONS

Shahin Nekoei: validation; visualisation; writing – review & editing. Mahsa Rezvan: methodology; writing – review & editing. Faham Khamesipour: conceptualisation; investigation; supervision; writing – original draft. Christopher Mayack: investigation; methodology; writing – original draft. Marcelo Beltrão Molento: investigation; methodology; writing review & editing. Pablo Damián Revainera: formal analysis; methodology; writing – original draft.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

FUNDING INFORMATION

The authors received no financial support for the research , authorship and/or publication of this article.

ETHICS STATEMENT

None.

Nekoei, S. , Rezvan, M. , Khamesipour, F. , Mayack, C. , Molento, M. B. , & Revainera, P. D. (2023). A systematic review of honey bee (Apis mellifera, Linnaeus, 1758) infections and available treatment options. Veterinary Medicine and Science, 9, 1848–1860. 10.1002/vms3.1194

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analysed in this study.