Staphylococcus aureus in Agriculture: Lessons in Evolution from a Multispecies Pathogen
SUMMARY
Staphylococcus aureus is a formidable bacterial pathogen that is responsible for infections in humans and various species of wild, companion, and agricultural animals. The ability of S. aureus to move between humans and livestock is due to specific characteristics of this bacterium as well as modern agricultural practices. Pathoadaptive clonal lineages of S. aureus have emerged and caused significant economic losses in the agricultural sector. While humans appear to be a primary reservoir for S. aureus, the continued expansion of the livestock industry, globalization, and ubiquitous use of antibiotics has increased the dissemination of pathoadaptive S. aureus in this environment. This review comprehensively summarizes the available literature on the epidemiology, pathophysiology, genomics, antibiotic resistance (ABR), and clinical manifestations of S. aureus infections in domesticated livestock. The availability of S. aureus whole-genome sequence data has provided insight into the mechanisms of host adaptation and host specificity. Several lineages of S. aureus are specifically adapted to a narrow host range on a short evolutionary time scale. However, on a longer evolutionary time scale, host-specific S. aureus has jumped the species barrier between livestock and humans in both directions several times. S. aureus illustrates how close contact between humans and animals in high-density environments can drive evolution. The use of antibiotics in agriculture also drives the emergence of antibiotic-resistant strains, making the possible emergence of human-adapted ABR strains from agricultural practices concerning. Addressing the concerns of ABR S. aureus, without negatively affecting agricultural productivity, is a challenging priority.
INTRODUCTION
Staphylococcus aureus can be both a commensal bacterium and a lethal pathogen in both humans and several species of animals. The range of symptoms caused by S. aureus in each of its hosts is vast. The nature of the interactions between S. aureus and its host is the result of complex factors that include host health status, the genetic composition of the S. aureus strain, and the site of host colonization (1, 2). In addition, antibiotic use in both human medicine and agricultural production has led to the emergence of several antibiotic-resistant (ABR) and multidrug-resistant (MDR) strains. Our aim in this review is to summarize recent findings on the epidemiology, pathophysiology, genomics, clinical manifestations, and management strategies for the key S. aureus infections in livestock species in the context of antibiotic use in modern agriculture as well as implications for food production and human health.
Zoonotic and Reverse Zoonotic S. aureus Infections
More than 30% of the human population is colonized by S. aureus at any given time (3). This percentage includes the approximately 20% of the healthy adult population that are persistent carriers as well as the >30% who are intermittently colonized (4–6). S. aureus can be isolated from multiple sites on the human body, although there is substantial evidence that inside the nostrils is the most common site of colonization (7). Some demographics tend to have a higher prevalence of S. aureus carriage than others, and insulin-dependent diabetics, those on hemodialysis, intravenous drug users, and HIV-positive individuals each have a higher than average probability of colonization (7). S. aureus colonization in humans is not necessarily associated with disease; however, skin trauma, such as an injury or a surgical procedure, can result in an opportunistic skin or wound infection (7). Certain lineages of S. aureus are also responsible for a range of human infections, including bacteremia, foodborne intoxications, infective endocarditis, skin and soft tissue infection, osteoarticular infections, pleuropulmonary infections, infection of prosthetic devices, prosthetic valve endocarditis (8), epidural abscesses, meningitis, toxic shock syndrome, urinary tract infections, and septic thrombophlebitis, each of which has been previously reviewed in detail (9). The success of S. aureus as a human pathogen is in part due to genomic plasticity and the acquisition of a variety of virulence factors that are able to manipulate innate and adaptive immune responses (10).
Colonization by S. aureus is also common in a variety of animals, including nonhuman primates (11), several mammalian livestock species (12, 13), poultry (14, 15), companion animals such as dogs, cats, and horses (16), elephants (17), reptiles (18–20), and rodents (21). It is likely that the known range of species capable of carrying S. aureus will expand as studies continue to examine S. aureus colonization in wild animals (22). In addition, the few studies that have examined the prevalence of S. aureus colonization in wild animal populations have found that, as in humans, colonization is relatively common and can occur at rates of 17.7% in wild boar, 19.8% in red deer, and 21.3% in bank voles (23, 24). As in humans, S. aureus appears to be carried asymptomatically in animals but can also result in fatal infections in a number of wild and livestock species, the latter being the focus of this article.
Humans are thought to be a primary reservoir for S. aureus (25), although this dogma may be the result of uneven sampling that heavily favors the analysis of human isolates. Over the past 5,000 to 6,000 years there have been multiple cross-species transmission events that have resulted in the emergence of several successful endemic and epidemic S. aureus lineages that circulate in nonhuman species (25). Specifically, agricultural practices, which by their nature require extended close contact of humans and animals, create favorable conditions for zoonotic and reverse zoonotic transmission and eventual host adaptation of certain lineages to new host species (26). Evidence of frequent zoonotic transmission in agriculture can be found in the fact that farmers are more frequent carriers of nasal S. aureus than other healthy adults (27) and that most livestock-adapted S. aureus lineages appear to have originated from human strains (25).
The zoonotic and reverse-zoonotic transfer of S. aureus between humans and animals also has implications for the development and proliferation of ABR. Antibiotics are extensively used in agriculture and result in the emergence of MDR strains, including livestock-associated methicillin-resistant S. aureus (LA-MRSA). LA-MRSA lineages are common but vary widely based on geography, host animal, and study methodology. For example, in the United States, the prevalence of methicillin-resistant S. aureus (MRSA) in pigs varies significantly between studies, with a range of 0% to 49% between 2009 and 2015 (28). In Canada, MRSA was isolated from only 1.3% of broiler chickens in 2013 to 2014 and 0.05% (1/1,810) of dairy cows in 2007 to 2008 (29, 30). The prevalence of MRSA sequence type 398 (ST398) in pigs was 99% in 2015 in the Netherlands, 89.6% in 2018 in Spain, and 46.1% in 2018 in Italy (31–33). In China, the prevalence of MRSA was 11.2% in pigs in 2014, and 29.6% in dairy cows in 2015 (34, 35). The rate of LA-MRSA present in an area is important for local human health, since the presence of MRSA in livestock is speculated to be responsible for an increase, or at least a slower decline, in the rate of community-associated MRSA (CA-MRSA) in the human population (36). There is a link between antibiotic use in agriculture and CA-MRSA; although, whether this is due to zoonotic transmission, circulation of MRSA in the environment, remnants of antibiotics in human food, antibiotic residues circulating in the environment, or a combination of each is unknown (37, 38). The impact of MRSA in human medicine has been previously reviewed in great detail (39, 40), but in general, most communities have seen a recent plateau or decrease in the prevalence of CA-MRSA (41–43).
Clonal Complexes
S. aureus strains are highly clonal, and there is a strong correlation between the phylogenetic lineage of S. aureus isolates and host tropism (12). Multilocus sequence typing (MLST) is commonly used to define the sequence type (ST) or allelic profile based on the sequences of 7 housekeeping genes found in all strains of S. aureus. Currently, ST is almost exclusively defined by extracting the sequences of these 7 genes from the whole-genome sequence. If a group of STs shares at least 5 of 7 alleles, the group of STs can be defined as a clonal complex (CC). Five CCs are predominant in human colonization and infection: CC1 (USA400), CC5 (USA100), CC8 (USA300), CC30 (USA200), and CC45 (USA600). These CCs rarely cause disease in livestock. Other lineages, including CC97, CC121, CC133, and CC151 rarely cause disease in humans but are primarily responsible for S. aureus infections in livestock (44–46). However, when it occurs, interspecies S. aureus transmission can be of critical importance in both public health and veterinary medicine. For example, the CC398 is primarily associated with infection in pigs, but it can cause infections in pig farmers and their families (47). Conversely, transmission of certain strains of CC121 from farmer to rabbit can result in severe and highly contagious respiratory disease in farmed rabbits (48).
S. aureus has genetic barriers to interspecies adaptation through genetic transfer, such as the complex and lineage-specific restriction-modification (R-M) systems. However, S. aureus is also capable of horizontal gene transmission, which can result in rapid adaptation to new hosts through the acquisition of species-specific mobile genetic elements (MGEs).
Genomics
The first whole-genome sequences of S. aureus became available in 2001 (49), and as of July 2020, there are 11,644 complete or draft whole-genome sequences of S. aureus in the NCBI database. The majority of the available whole-genome sequences are from human isolates, followed by isolates from livestock, companion animals, and wildlife (26). Regardless of the host, the average S. aureus genome harbors approximately 2,800 genes (Table 1) (50). The most recent pangenome of S. aureus, constructed by Bosi et al. (50), revealed that S. aureus has a large open pangenome composed of 7,411 genes and a small core genome of only 1,441 genes (50). The core genes of S. aureus are dispersed throughout the genome but remarkably conserved among the different lineages, and this suggests a common ancestor with ancient evolutionary divergence (51). S. aureus carries 90 virulence factors, but only 35 are found in the core genome (50). The high variability in the presence of virulence factors between isolates contributes to explaining the range of symptoms associated with S. aureus infections (50). The S. aureus pangenome contains relatively more genes for virulence factors, including toxins, superantigens, host immune evasions elements, and adhesins than other non-aureus species of the Staphylococcus genus (52). A change in host specificity for S. aureus strains or lineages is commonly associated with the acquisition of new accessory genes, which confer traits required for survival in the new host, as well as a loss of genes required for life in the previous host (53). Movement of host-adaptive accessory genes on MGEs is common (54, 55).
TABLE 1
| Class | Virulence factors | Reference(s) |
|---|---|---|
| Adherence | Fibronectin-binding protein (FnBPA/B), clumping factor (ClfA), elastin binding protein (Ebp), extracellular intercellular adherence protein (Eap) | 307 |
| Enzyme | Coagulase, von Willebrand factor-binding protein (vWbp), staphylokinase, thermonuclease, aureolysin, serine protease, exfoliative toxin, staphopain, hyaluronate lyase, lipase | 10 |
| Immune evasion | Capsule, biofilm, chemotaxis inhibitory protein (CHIPS), staphylococcal protein A (protein A), second immunoglobulin-binding protein (Sbi) | 308 |
| Secretion system | Type VII secretion system | 309 |
| Toxin | Phenol-soluble modulins (PSMs), hemolysins (α-hemolysin, β-hemolysin, and γ-hemolysin), leukocidins (e.g., Panton-Valentine leukocidin [PVL], LukMF′), superantigens (SAgs) (e.g., staphylococcal enterotoxin and toxic shock syndrome toxin) | 10, 310 |
Mobile genetic elements facilitate host adaptation.
MGEs play a key role in pathogenicity and host adaptation in S. aureus, since they often carry host-specific survival and virulence genes. Horizontal gene transfer can be accomplished by transduction, conjugation, or transformation, the basics of which have been previously reviewed (55, 56).
Transduction has a significant impact on the ability of S. aureus to colonize new host organisms. Prophages are common in S. aureus populations, and most S. aureus isolates have between one and four different chromosomally integrated prophages (45, 57). The acquisition of a new phage, or the loss of an old one, is often associated with host-switching events. For example, β-converting prophages—named because they interrupt the chromosomal virulence gene β-hemolysin (hlb) in S. aureus and therefore block β-toxin production—are very common in human-associated lineages, with only a few exceptions, such as in ST36 (CC30/USA200) (58). A common β-converting prophage in humans is φSa3, which encodes a host-specific immune evasion cluster (IEC) (58). Excision of β-converting prophages can occur under certain conditions, including H2O2 and biofilm growth, which restore β-toxin production (59). The majority of livestock-associated lineages lack β-converting prophages (58); however, there are exceptions. For example, both poultry-adapted lineages (CC5 and CC385) carry the β-converting prophage φAvβ, which, given its independent acquisition in both poultry-associated lineages, appears to be essential to avian host adaptation (15). The reintroduction of the φSa3 prophage into livestock-associated lineages such as CC5, CC9, and CC398 has resulted in zoonotic human infections by livestock-adapted strains, which underlines the importance of prophages in host switching (60, 61). The transmission of φSa3 appears to be induced by environmental factors, such as the use of biocides (62).
The majority of S. aureus isolates also carry one or more plasmids per cell, and these plasmids vary in terms of size and gene content. Like prophages, the distribution of certain groups of plasmids is associated with lineage and host specificity (63). For example, avian lineages of S. aureus often have the pAvX plasmid which encodes several virulence factors that are important in adaptation in birds (15). Conjugation in S. aureus takes place from donor to recipient via mating pores and the type IV secretion system, since S. aureus is not known to produce sex pili (64, 65). Both transduction and conjugation have been shown to occur rapidly in vivo when cocolonization of two or more S. aureus isolates occurs (66).
S. aureus can undergo natural transformation via chromosomally encoded competence proteins (67). However, the rate at which S. aureus acquires DNA from the environment is much lower than that of other well-known bacteria such as Escherichia coli and Bacillus subtilis (68). Expression of competence genes is controlled by the sigma H factor, which is activated only under specific conditions and among only a minor fraction of the cell population (67). While transformation in S. aureus is rare, this pathway is likely responsible for the lateral movement of a large piece of DNA that has created unique S. aureus hybrid strains (69). However, the R-M systems encoded by the majority of S. aureus isolates are a major barrier to horizontal gene transfer in this species.
Restriction-modification systems decrease genetic exchange.
Despite having the ability to undergo a natural transformation, S. aureus also has highly conserved R-M systems, which have served to maintain highly clonal populations and reduce the rate of MGE transfer (70). Type I R-M systems consist of a sequence recognition protein (HsdS), a modification protein (HsdM), and a restriction endonuclease (HsdR). Since S. aureus lineages harbor two copies of lineage-specific hsdMS on genomic islands νSaα and νSaβ (71, 72), the trading of genetic elements only rarely occurs between lineages. Type II, type III-like, and type IV R-M systems have been found in S. aureus and have also been suggested as a genetic barrier to horizontal gene movement (57, 73, 74). The incompatibility of conserved R-M systems in S. aureus means that horizontal gene transfer occurs more frequently between strains of the same lineage than between strains of different lineages. S. aureus strains with defective or only one functional type I R-M gene (such as S. aureus ST398) exist, and are more receptive to incoming foreign DNA (70, 75). Therefore, as a result of its rapid acquisition of MGEs and highly plastic accessory genome, ST398 has an extremely broad host range, including humans, pigs, chickens, horses, sheep, buffalo, and rabbits (in addition to others) (47).
ANTIBIOTICS IN AGRICULTURE
ABR is a serious public health concern, and the use of antibiotics in the agricultural industry has led to livestock becoming a reservoir of ABR bacteria, particularly S. aureus. Penicillin was discovered in 1928, and at that time, essentially all S. aureus isolates were susceptible to this antibiotic (76). Sulfonamides began being marketed for routine use in agriculture as early as 1938 (77). Gramicidin was successfully used to treat a mass outbreak of mastitis in dairy cows in 1940 (78). During the early 1940s in Britain, there were several trials aimed at elucidating the success of penicillin at treating bovine mastitis—to improve milk production to help the war effort (79). Just a few years later, in 1944, the first penicillin-resistant S. aureus isolates were identified (80, 81). In 1948, sulfaquinoxaline was the first antibiotic that was licensed for inclusion in poultry feeds as a prophylactic against coccidiosis (82). The use of prophylactic antibiotics in agriculture was quickly followed by a study that demonstrated that subtherapeutic doses of antibiotics had growth-promoting effects in broilers (83). Antibiotic growth promoters (AGPs) were officially licensed in the United States in 1951, in Britain in 1953, in the Netherlands in 1954, and in France in 1955, with most countries approving penicillin, oxytetracycline, and chlortetracycline for growth promotion (84–86). Between 1951 and 1970, American use of nonmedical antibiotics, mostly in agriculture, increased >30-fold (87). By 1978, the rate of penicillin resistance in S. aureus was 80% (88), and this rose to 95% by 1998 (89). As the beef industry shifted from low-density grazing to a high-intensity feedlot system in the late 1950s, prophylactic antibiotics were added to feeds to counteract increases in bacterial infections associated with higher concentrations of animals in close proximity, such as footrot (90). However, by the 1960s, several antibiotics, including chlortetracycline, oxytetracycline, and bacitracin, were fed to a part of rations to all animals regardless of infection status (77, 90). By 1975, ionophore antibiotics were licensed for use in cattle, and by 1985, 90% of cattle in the United States were being fed ionophores (90).
Antibiotics in Modern Agriculture
Globally, the use of antibiotics in agriculture exceeds that used for the treatment of human infections, and this has contributed to the growing ABR crisis (91). Concern over the growing number of ABR infections has led to certain localities placing restrictions on antibiotic use in agriculture. However, global standards governing antibiotic usage in agriculture do not exist, but instead, there is an international patchwork of different regulatory approaches to antibiotic stewardship (77). Sweden was the first country to ban AGPs in 1986 (77), and other Scandinavian countries such as Norway and Denmark also have stringent regulations. Sweden has observed an increase in penicillin-susceptible S. aureus from human infections from 0% in 2004 to 50% in 2012 (92). Germany banned the use of avoparcin as a treatment for bovine mastitis, which was followed by an EU ban in 1997 (77). The Food and Drug Administration (FDA) in the United States, while not officially banning antibiotic use except for cephalosporins and fluoroquinolones, including enrofloxacin, has issued voluntary guidelines aimed at phasing out the use of AGPs, which has resulted in a decline of antibiotic use (90, 93, 94). Middle- and low-income countries have also committed to phasing out antibiotic usage, with colistin bans in India and China (95, 96) and Vietnam introducing a ban on AGPs in 2020 (97). However, nonmedical AGPs such as bacitracin in pigs and poultry and bambermycin (flavomycin) in pigs and cattle are still available and commonly used as growth promoters in feed internationally, with the European Union being a notable exception to this generalization (93, 94, 98).
The use of medically important antibiotics remains very high in the dairy industry to treat and prevent bacterial infections. Bovine mastitis is one of the most prevalent and costly diseases in the dairy industry. In the US dairy industry, mammary gland infections cost US$2 billion annually (99). In Canada, bovine mastitis results in a loss of CAD$794 million annually from the dairy industry (100); in Britain, bovine mastitis results in losses of £168 million annually (101). Given the economic burden of this infection—as well as the negative effects it has on dairy cattle welfare—mastitis treatment and prophylaxis account for the majority of antibiotics used in adult dairy cows (102, 103). In an attempt to minimize the losses to this type of infection, approximately 90% of the dairy cattle in the United States are currently treated with long-lasting intramammary antibiotics during the dry-off period, known as dry cow therapy (DCT) (104), and this results in the use of approximately 11 tons (10,000 kg) of medically relevant antibiotics annually (105). Common antibiotics used in DCT include ceftiofur hydrochloride and penicillin combinations such as penicillin-novobiocin (105, 106). Prior to the widespread use of DCT, Streptococcus agalactiae was known to cause approximately 90% of bovine mastitis cases (107). A single dose of penicillin would resolve 90% of the cases (108). After antibiotics became readily available to treat and prevent bovine mastitis, the most common etiological agent shifted from S. agalactiae to S. aureus, and only 30% to 50% of S. aureus mastitis is effectively treated with penicillin (109–111). Initially, the lack of response to treatment from S. aureus mastitis cases was not caused by resistant strains; instead, it was due to differences in the site of infection between S. agalactiae and S. aureus. S. agalactiae causes a surficial infection in the milk ducts; however, S. aureus penetrates the duct walls of the udder and the infection can be walled off with fibrous tissue (108, 112). Numerous in vitro studies have demonstrated that S. aureus can be internalized and survive in bovine mammary epithelial cell lines (113, 114), and this ability is thought to lead to S. aureus escaping from the immune system and antibiotic treatment and contributing to recurrent S. aureus infections (115, 116). In the case of bovine mastitis, the intracellular invasion has further been demonstrated by in vivo work where viable S. aureus has been isolated from alveolar and macrophage cells from naturally infected cow milk (117). Biofilm formation of S. aureus also within mammary glands also contributes to long-term persistence and resistance to antibiotic treatment (118, 119). While speculative, the persistence of S. aureus in the bovine udder, and the frequency to which it was exposed to the antibiotics used in DCT, may have contributed to the increasing prevalence of ABR in bovine mastitis S. aureus isolates.
The differential use of certain antibiotics in agriculture and hospitals has a strong role in shaping ABR in different S. aureus lineages. This was shown by examining differences in the prevalence of resistance to tetracycline and fluoroquinolone in MRSA isolates within the same ST, where isolates were collected from human clinical specimens or livestock, specifically, pig samples (120). In LA-MRSA, 79.3% (65/82) of ST5 isolates were resistant to all tetracycline antibiotics, including chlortetracycline, oxytetracycline, and tetracycline, and fluoroquinolone resistance varied from 18.3% (15/82) for levofloxacin to 30.5% (25/82) for enrofloxacin (120). In human clinical MRSA, ST5 isolate resistance to tetracyclines was not observed, while 97.2% of isolates were resistant to all fluoroquinolones (ciprofloxacin, enrofloxacin, levofloxacin, and moxifloxacin) (61, 120). These observations are reflective of fluoroquinolone being preferred for use in human medicine, while animal feed, especially pig feed, is often supplemented with tetracycline (121–123).
Eliminating Antibiotics in Modern Agriculture
ABR is one of the biggest threats to global health and food security that exist today (124). It is projected that by 2050, ABR infections will cause 10 million human deaths annually and result in a loss of US$100 trillion from the global economy (125). The burden of ABR infections was also recently measured in the European Union in terms of disability-adjusted life-years (DALYs), and the DALY burden of ABR infections in 2018 was found to be equivalent to the combined burden of HIV, influenza, and tuberculosis in the same year (126). Given that bacteria carrying antibiotic resistance genes can be transmitted from agricultural animals to humans (127–129), several international organizations, including the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and the FDA, have recommended halting the use of nontherapeutic antibiotics in livestock (130–132). However, increased international demand for meat, along with the reliance of producers on antibiotics to meet this demand, makes agricultural producers hesitant to support a ban on nontherapeutic antibiotics.
It has been known for decades that the use of antibiotics in agriculture is contributing to the growing ABR crisis (133–136); however, the benefits of AGPs from a production perspective, including improved feed efficiency and decreases in infectious disease and animal mortality, are why the practice continues. The use of AGPs in broilers can increase body weight by up to 8% and improve feed efficiency by about 5% (137). Over the entire pig growing period, from 24 to 89 kg, AGPs improve the average growth rate by 4.2% and feed efficiency by 2.2% (138). However, similar productivity improvements can also be achieved by good management practices and strict biosecurity (139). Prophylaxis is also a common reason for antibiotic use in agriculture. In the 1940s, prior to the widespread use of antibiotics in the dairy industry, each dairy cow would have mastitis infections twice annually, and the average herd somatic cell count (SCC), a measurement of immune responses to intramammary infections, was around 750,000 cells/ml (140). Today, each year, approximately 19% of cows in dairy herds experience clinical mastitis, and the average herd-level SCC is around 184,000 cells/ml (100). This represents a 95% reduction in annual mastitis infections and an improvement in overall animal health and milk quality. Development of mastitis control programs and improvements in hygiene management, including machine milking, farm design, and the implementation of routine mastitis screening, have collectively contributed to a dramatic reduction of mastitis infections and duration; yet, DCT is still widely used in the dairy industry (141).
Economic research on the subject indicates that a ban on AGPs may actually benefit producers with good on-farm hygiene and biocontrol and be detrimental only to those producers who use antibiotics to compensate for poor management and hygiene (142). Overall, an American study that evaluated the total economic costs of halting the use of AGPs found that in 1999, a ban on AGPs would have resulted in an average increased cost of US$0.03 to 0.06 per pound of meat, which, they note, would be sustainable for the average consumer (142). In more recent years, American consumers have been willing to pay more for products raised under a no antibiotics ever (NAE) program, including a US$0.30 per pound premium for NAE boneless skinless chicken breasts in 2017 (143). The NAE system prohibits all medically important antibiotics from being used as AGPs in broilers, and while virtually no poultry was produced without antibiotics in the United States in 2009, the market has sustained a steady rise in popularity of this product. By 2018, between 45 and 55% of American broilers were being produced under the NAE system (144). However, the NAE system does present a few problems that have yet to be solved. For example, in 2018, the mortality rate in NAE birds was approximately 4.2% compared with 2.9% in conventionally raised broilers (143), and NAE birds also showed higher levels of eye burns, footpad lesions, and airsacculitis, each of which is an indicator of poor welfare (145, 146). Studies on a similar program (raised without antibiotics) in Canada found that broilers raised without antibiotics required more food and water to reach market weight and suffered from higher incidences of necrotic enteritis (147). The increased food required for NAE broilers poses environmental concerns due to the extra acres of field required for poultry production if poultry production levels are to be maintained at their current levels (148).
Some countries, including Canada, have proposed a system in which certain antibiotics are available for agricultural use and others are reserved for medical use. However, the use of nonmedical AGPs in agriculture can also contribute to the development of resistance to medically important antibiotics. For example, Synercid is a semisynthetic antibiotic that combines dalfopristin and quinupristin and is approved to treat MRSA infections in humans (149). However, there is significant evidence that virginiamycin acetyltransferases, which confer resistance to virginiamycin, also confer resistance to Synercid (150). Virginiamycin is approved for in-feed use for prophylaxis in several species, including broiler chickens and swine. MCR-1, which confers resistance to colistin, also confers resistance to bacitracin, which ensures the survival of plasmid-mediated colistin resistance in agricultural ecosystems where bacitracin is commonly used as an AGP (151). Therefore, banning AGPs based on a medical categorization system may not be effective.
Nonantibiotic alternatives.
Antibiotic use in agriculture must be reduced or stopped all together as soon as possible to decrease its contribution to the growing ABR crisis; however, solutions are required to adequately address the production, animal welfare, and environmental concerns associated with antibiotic-free agriculture. There is a huge ongoing push to develop nonantibiotic alternatives for each of these problems. Increased biosecurity and hygiene, along with decreased livestock stocking density, are likely the cheapest methods of infectious disease prevention in livestock (152). Though many farmers are able to successfully transition to NAE programs, overall, farmers need additional education, training, and support through this transition (153). Vaccination against diseases for which vaccines exist is also an important strategy to reduce antibiotic use, and ongoing vaccine development is critical to the sustainability of antibiotic-free agriculture (146). Probiotics, also referred to as direct-fed microbials (DFM), have been shown to reduce colonization by bacterial pathogens and improve growth performance (154). However, to date, none of these alternatives have been as successful as antibiotics (146), indicating the importance of this area of research moving forward.
Methicillin-Resistant S. aureus in Livestock
While penicillin was highly effective for treating S. aureus infections in 1928, today, >90% of human-associated strains are resistant to this antibiotic (155). Resistance to β-lactam antibiotics is encoded by the mecA or mecC gene located on an MGE called staphylococcal cassette chromosome mec (SCCmec) (156). Based on the International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-SCC), 13 SCCmec types (I to XIII) are currently recognized, based on combinations of the five identified mec complexes and the nine types of ccr complexes (157–160). The genetic content and the structural organization of SCCmec elements are diverse and found in several species (161). S. aureus strains contain SCCmec with mecA or mecC and are thus resistant to penicillin, methicillin, and all other β-lactam antibiotics (162). Coagulase-negative staphylococci (CoNS) have been proposed as the donor of SCCmec (mecA and mecC) to multiple clones of methicillin-susceptible S. aureus (MSSA) (163–165).
The first reported livestock MRSA infection was from a dairy cow with mastitis in 1972 (166); since then, MRSA infection and colonization have been reported in a number of animals, including pigs, chickens, and rabbits (167–169). The use of antibiotics in food animal production plays an important role in the selection of MRSA isolates. For example, S. aureus CC398 was discovered in the 2000s and has become a rapidly emerging cause of human infections associated with livestock exposure (27, 170). Phylogenetic reconstruction of the CC398 lineage suggests that CC398 was derived from human-associated MSSA CC398 and was transmitted to livestock through reverse zoonoses. This CC diversified to gain methicillin resistance by acquiring three different SCCmecs that included nine subtypes and was then reintroduced to humans (47, 171). CC398 has been found to infect a broad range of agricultural species, including pigs, cows, chickens, rabbits, sheep, buffalo, and turkey (26). The rapid radiation and broad host spectrum of this lineage are likely associated with ST398 strains having only one type I R-M system, providing a less strict genetic barrier for foreign DNA acquisition (75). The second example of the emergence of CA-MRSA being propagated through agriculture is the interhost transmission CA-MRSA from the CC97 lineage, which is common in both dairy cows and humans (172).
A rising number of MRSA isolates have been found in livestock, farm operations, farmers, and retail food products. Although there are several drugs for human MRSA infections, including vancomycin, linezolid, and daptomycin, each of these drugs is either prohibited or has restricted use in food-producing animals because they are clinically important in humans, inconvenient to administer in animals, and expensive (93, 173–175). The consequences of emerging MRSA are often overlooked in food production and veterinary medicine, although MRSA infections result in significant economic losses and a decrease in animal welfare (176).
Vancomycin-Resistant S. aureus in Livestock
Vancomycin has remained a first-line drug of choice for the treatment of MRSA infections. As the number of MRSA infections increases, a noticeable increase in the use of vancomycin has followed; thus, it is unsurprising that more than 50 vancomycin-resistant S. aureus (VRSA) isolates have been reported globally since the first case of VRSA was identified in the United States in 2002 (177, 178). Daptomycin and linezolid are commonly used for human VRSA infections, yet clinical treatments might not be effective and prolong hospitalization due to the deterioration of the primary diseases and scarcity of detailed clinical data and treatment guidelines (178). VRSA dissemination for the last decade is considerably low in humans and animals and not comparable to that of MRSA. This low incidence can be explained because of the high fitness cost of VanA-type resistance, which leads to growth reduction and growth competition (179). Increased cell thickness and modification in peptidoglycan synthesis can result in a relatively low level of vancomycin resistance in S. aureus (180). A high level of resistance to vancomycin is conferred by the vanA gene cluster that mediates and synthesis of d-Ala-d-lactase peptidoglycan precursors (181). S. aureus acquires a Tn1546-containing plasmid harboring vanA genes from enterococci and then maintains this cluster either by retaining the original plasmid or transferring the Tn1546 transposon to a resident plasmid or chromosomal DNA (182).
All 13 VRSA isolates reported in the United States belong to CC5 with only one exception, CC30, which is usually associated with community-acquired infections. Although the vanA gene cluster has been independently transferred to S. aureus on multiple occasions, why CC5 is predisposed to acquiring this gene cluster is still unknown (183). In food-producing animals, VRSA has been isolated, but the vanA gene cluster was not present despite the isolates having phenotypic vancomycin resistance (184, 185). More recently, VRSA isolates which carried vanA and vanB genes were detected in camel meat and abattoir workers (186). However, this study failed to identify the original host of VRSA isolates and demonstrate the presence of VRSA in camels, since sampling was not conducted on the animals themselves (111). Although VRSA in livestock has rarely been reported, there is a possibility of the emergence of animal-adapted VRSA clones in the future in the presence of selection pressure. This fear is supported by a study determining that ST151, which is a bovine-specific hypervirulent clone, was hypersusceptible to the acquisition of vancomycin resistance in vitro through conjugation with Enterococcus faecalis due to a lack of R-M barriers (187).
PATHOLOGY OF S. AUREUS INFECTIONS IN LIVESTOCK
The success of S. aureus as a multispecies pathogen can lead to it being regarded as a generalist pathogen; however, on a short evolutionary time span, most lineages are host specialists (26). If S. aureus was a generalist pathogen, all strains of S. aureus would have an equal ability to infect all hosts; but this is not commonly observed, and most S. aureus STs have a much better ability to infect some hosts than others. The lines of evidence for host specificity in S. aureus are reviewed elsewhere but include bacterial phylogenetic clustering based on the host, presence of host-adapted genes, and the inactivation or loss of host-associated genes from previous hosts (26). However, unlike other bacterial pathogens, spillover events—the isolated transmission of a strain to a host to which it is not well adapted—occur frequently for S. aureus in agricultural settings. In addition, host jumping—repeat spillover events leading to the acquisition of genetic changes and adaptation of a population of S. aureus to a new host—is also common in agricultural settings. Therefore, the ease, relative to that for other bacterial pathogens, with which S. aureus is able to jump between preferred hosts appears to be linked to both its propensity for horizontal gene transfer and frequent opportunities for spillover events.
Agricultural Spillover Events
The rate at which species-adapted S. aureus undergoes zoonotic transmission to humans or reverse-zoonotic transmission from humans to animals appears to be higher than that for other bacterial pathogens. Spillover events, caused by prolonged, repeated, and close contact between farm workers and livestock, can result in either permanent colonization of a new host, which gives the strain a chance to gain genetic material and broaden its host range, or a transient colonization followed by extinction from the new host (188). Close contact between farm workers and food-producing animals results in a higher prevalence of S. aureus colonization in farmers and veterinarians than in the general population. For example, during a colonization survey, Dutch swine farmers were found to be colonized with ST398 MRSA at a rate >760 times higher than in the general Dutch population (170). A separate study carried out on veterinarians in the United States revealed that the prevalence of colonization by S. aureus was 64% in veterinarians, higher than in the rest of the US population at 30% (189). Livestock-associated S. aureus nasal carriage appears to be associated with skin and soft tissue infection (SSTI), which suggests swine production work could be a risk factor for SSTI (190). The duration of animal contact is also related to the presence of LA-MRSA CC398 colonization in farm workers (191). A successful LA-MRSA CC398 colonization can last more than 1 year and pose a potential risk of human-to-human transmission (192).
S. aureus spillover events can also occur through environmental transmission or contaminated retail products. Multiple studies have shown the presence of LA-MRSA in soil, air, and water near barns (193–196). This may present an increased risk of spreading S. aureus to humans and wild animals living near the farms; although, little evidence that this is happening has been provided (197, 198). S. aureus is also commonly found in retail meat products, which is another possible route for spillover events (199–201). In addition, reverse zoonosis via spillover is also likely. A study carried out on white storks revealed that birds that inhabited human landfill sites were twice as likely to carry MRSA than storks inhabiting natural settings, with repeated exposure to human residues being blamed (202).
Host Adaptation and Specialization
Repeated spillover events can lead to a successful intrahost transmission after host adaptation and specialization occur. It is very common for S. aureus lineages that have recently jumped hosts to have several new MGEs that were not present in closely related isolates from the most recent host. This acquisition of host-associated MGEs suggests that adaptation to a new host requires the acquisition of new pathogenicity traits, including attachment proteins and immune-evading elements (26), metabolic preferences (25), different ABR abilities (47, 120), and different optimum growth temperatures (Table 1) (15). For example, CC5 is one of the most successful human-associated lineages of S. aureus globally, and several CC5 strains in both humans and livestock have now acquired methicillin resistance (120, 203). CC5 is composed of ST5 and a few closely related STs (ST1342, ST1346, and ST1350) (15). ST5 appears to have spilled from humans to poultry in the 1990s in Poland. From there, a poultry-adapted ST5 emerged and became widely distributed throughout the world in poultry. Poultry-adapted ST5 strains gained several genes required for avian infection, including two bacteriophages, two plasmids, and a pathogenicity island, and lost a number of genes involved in human pathogenesis (Fig. 1A) (15). Alternatively, the acquisition of a new MGE is not always necessary for host adaptation. As an example, CC121, which recently underwent reverse zoonotic transmission from humans to domesticated rabbits, appears to have not acquired any MGE but instead undergone nonsynonymous mutations in the dltB gene, which were sufficient to change the species range of this particular lineage (Fig. 1B) (204).
FIG 1
Since LA-MRSA CC398 is thought to have originated from human MSSA CC398 (47), this transmission is strong evidence of reverse zoonosis followed by zoonosis after acquiring mecA in an animal host and habitat. Selection pressure exerted by tetracycline and zinc, widely used in pig farms, likely facilitated the emergence and spread of MRSA CC398 (121, 122). The reemerged CC398, through multiple spillover events, has now spread into the community and other host species, followed by successful colonization via gene mutations and acquisitions of foreign DNA involved in host adaption (Fig. 1D) (205–207). This clonal complex appears to be an exception, in that it is a generalist pathogen owing to its ability to readily acquire MGEs (208).
Bovine
S. aureus diseases in cows.
S. aureus frequently causes mastitis in dairy cattle (209). Mastitis is the inflammation of the mammary gland which can be caused by intramammary infections (IMIs). Bovine IMIs can be caused by a variety of bacteria, viruses, and fungi. However, S. aureus is one of the most frequent etiological agents. Bovine IMIs caused by S. aureus can vary greatly in terms of severity, transmissibility, and persistence; thus, S. aureus mastitis is somewhat unique compared to mastitis caused by other pathogens. S. aureus can cause both acute and chronic IMIs (210). The acute form of the disease is usually severe clinical mastitis, which results in visible changes to milk (211) and is characterized by high SCCs and intense swelling of the mammary gland in severe cases. The chronic form of S. aureus mastitis is usually subclinical, which does not change the color or texture of the milk but is characterized by relatively high SCC and persistent difficult-to-treat infections (212). Chronic S. aureus IMIs are one of the most common reasons for premature culling in dairy herds (212, 213). Both chronic and acute IMIs caused by S. aureus can result in damage to the mammary epithelium due to a release of metabolites by the pathogen and the release of lysosomal enzymes and oxidative products by phagocytes in the immune response (211, 214). In chronic cases of IMIs, S. aureus is able to evade clearing by both antibiotics and by the bovine immune system by forming biofilms and surviving intracellularly in both nonprofessional and professional phagocytes (113, 117, 215).
S. aureus can also cause contagious mastitis, where a single lineage quickly spreads throughout a dairy herd, as well as sporadic noncontagious mastitis, which usually does not spread beyond a single cow (216). In addition to ST typing, S. aureus can also be grouped at the subspecies level by genotyping. Studies conducted in European countries have found that genotype B (GTB) is highly contagious, while other genotypes cause sporadic noncontagious mastitis (216–219). In dairy herds, a few dominant clones of contagious S. aureus tend to dominate, indicating transmissibility within the herd as well as the preference for particular phenotypic traits (220–222).
S. aureus can also cause skin infections, including folliculitis or, more commonly, impetigo in cattle (223). Impetigo in cattle is usually associated with udder skin but can also be found on other skin, especially areas of folding, and the resultant lesions may be very painful (224).
Bovine S. aureus infections have the ability to cause foodborne intoxications in humans through the consumption of contaminated bovine milk, taken from an animal with mastitis. S. aureus has the capability to produce a variety of enterotoxins that cause abdominal pain, violent vomiting, and severe diarrhea in humans (225). Outbreaks associated with raw milk cheese have also been reported. S. aureus appears to grow and produce toxins during the cheese-making process (226, 227).
Host adaptation and virulence factors.
Molecular dating has estimated that human-to-bovine transmission of S. aureus happened postdomestication, as early as 5,500 years before the present (BP), and has occurred on at least five independent occasions (228–230). Globally dispersed bovine-adapted S. aureus lineages predominately belong to CC8, CC97, CC133, and CC151 (26, 228, 231, 232). A notable trend in ruminant-adapted lineages is the loss of genes specifically involved in human infections, which likely increases their fitness in ruminants. For example, RF122 (CC151) is known as a highly virulent mastitis strain that lost the functions of major human-associated surface proteins such as protein A and clumping factor A due to premature stop codons (233). Bovine-specific MGEs are also found in RF122 (233). Cattle are also an important reservoir for S. aureus, although this could be due to sampling bias (26). Bovine-associated S. aureus has been studied the most among livestock-associated S. aureus strains (234).
Biofilm-producing S. aureus strains tend to be more successful in colonization and long-term persistence in the mammary gland (235, 236). Bacterial biofilms are more resistant to both antibiotic treatment and host immune defense mechanisms than their sessile counterparts (237), and the ability to form intramammary biofilms may contribute to the persistence of S. aureus infections (Fig. 2A). In persistent S. aureus colonization in the mammary gland, intrahost selection of SigB-deficient pathotypes, which have an increased ability to form biofilms, appears to occur (238); although, there are exceptions, including S. aureus NCTC8325 strains, which are SigB deficient yet still form very poor biofilms (239).
FIG 2
Intracellular survival of S. aureus in nonprofessional and professional phagocytes plays an important role in host adaptation in terms of persistence in the intramammary gland. S. aureus can act as an intercellular pathogen in a variety of eukaryotic cells, including bovine mammary epithelial cells (113). Viable intracellular S. aureus cells have also been isolated from alveolar cells and macrophages derived from the milk of chronically mastitic cows (117). The ability of chronic S. aureus to act as an intracellular pathogen also explains how this pathogen can persist for long periods of time without causing apparent inflammation in both humans and animals (240). The ability of S. aureus to express capsular polysaccharide (CP) appears to be inversely related to its ability to invade host cells, since the absence of capsule appears to assist with the adherence and invasion of eukaryotic cells (210, 241–243). Capsule-negative S. aureus strains are more prone to inducing chronic infection than capsule-positive strains (243). The expression of CP is regulated in a density-dependent manner via quorum sensing, indicating it has an important role in the progress of infections (244).
Panton-Valentine leukotoxin (PVL) is a bicomponent toxin that has specific activity in leukocytes and is expressed by certain S. aureus strains (245, 246). Functional leukotoxins require two components: an S subunit to bind a specific receptor on the host cell surface and an F component, which can undergo oligomerization resulting in the formation of pores in the host cell, eventually leading to cellular death (247). One member of the leukotoxin family known as LukM and LukF-PV subunits (LukMF′) is exclusively harbored by S. aureus of ruminant origin and associated with severe inflammation during bovine mastitis (Table 2) (248, 249). Severe inflammation is a result of LukMF′ having cytotoxicity against neutrophils, resulting in a strong inflammatory reaction and therefore clinical mastitis (250). LukM exhibits high specificity toward the specific chemokine receptor CCR1 on bovine neutrophils (248, 251, 252). The genes encoding LukM and LukF-PV (lukM-lukF-PV) are encoded on a temperate phage φPV83 and can be transmitted to other S. aureus strains horizontally (245). The level of production of LukMF′ by S. aureus in vivo directly correlates with the severity of clinical mastitis (253). Strains of S. aureus that express high levels of the LukMF′ complex have a point mutation in the start codon of a repressor protein (rot), which is responsible for repressing the transcription of various toxins (253). Strains that overexpress LukMF′ are associated with the same genetic lineage (ST479) (253).
TABLE 2
| Host | Host-specific determinant(s) | Related disease | Virulent factorsa |
|---|---|---|---|
| Bovine | MGEs (SaPIbov1, SaPIbov3, SaPIbov4, φSaBov, and φPV83) | Mastitis, skin infection | LukMF′, vWbpSbo4, vWbpSbo5 |
| Small ruminants | MGEs (SaPlov1, SaPlov2, φSaov1, φSaov2, and φSaov3) | Mastitis, skin infection | LukMF′, vWbpSov2, ETE |
| Swine | No known swine-specific determinants | Neonatal septicemia, skin infection | ETB, ETD, ETE |
| Rabbit | Mutations in dltB gene | Mastitis, skin infection, respiratory disease | α-Hemolysin, γ-hemolysin, PVL |
| Poultry | MGEs (φAv1, φAvβ, pAvY, pAv1, and SaPIAv) | Podomermatitis, BCOb | α-Hemolysin, staphopain A (ScpA) |
a
Virulence factors known to be highly active or specific to the host.
b
Bacterial chondronecrosis with osteomyelitis.
Staphylococcal superantigens (SAgs) represent a family of immunostimulatory exotoxins secreted by staphylococcal species, including S. aureus, potentially leading to an uncontrollable cytokine storm (254). SAgs appear to play an important role in bovine mastitis, and most bovine S. aureus isolates contain five or more genes encoding SAgs, although the exact role of SAgs in the pathogenesis of mastitis is still unclear (255). SAgs interfere with host immune response and thus may be important in persistent infections (256). SAgs induce the proliferation of T cells and the massive release of proinflammatory cytokines, this uncontrolled stimulation can impede the effectiveness of the immune response by disrupting the recruitment of effector cells (Fig. 2A) (254). The bovine pathogenicity island SaPIbov is found in bovine-associated lineages such as CC151 and CC133 (255). SaPIbov contains several toxin proteins, including toxic shock syndrome toxin 1 (TSST-1), staphylococcal enterotoxin-like protein, and a bovine variant of staphylococcal enterotoxin C (SEC) (257) (Fig. 1C).
Small Ruminants
S. aureus diseases in sheep and goats.
Domesticated sheep and goats are sources of meat, wool, and dairy products. Goat milk production has continued to increase worldwide due to the high consumption and flavor that is preferred over bovine milk by certain consumers (258). Mastitis is the primary disease caused by S. aureus in both sheep and goats. S. aureus causes acute gangrenous mastitis before and after parturition and is highly persistent during lactation in goats (259, 260). Kids that nurse on milk or colostrum from a doe with acute mastitis can develop staphylococcal dermatitis (259).
Ovine facial staphylococcal dermatitis is mainly localized around the ocular area of adult sheep and tends to be seasonal (261). Sucking flies seem to be a potential seasonal factor of facial staphylococcal dermatitis, expanding the lesions and spreading diseases within a flock. A molecular epidemiology study revealed that more than 50% of flies were S. aureus positive during the summer season on ovine dairy farms (262). S. aureus can cause ovine necrotic dermatitis, also known as staphylococcal dermatitis, that often occurs on the legs and above the lips (263). Another skin disease called contagious ovine digital dermatitis (CODD) has been reported more often since the late 1990s (264). Although Dichelobacter nodosus is considered the primary causal etiological agent of CODD, a microbiome study revealed that Staphylococcus species were also associated with virulent ovine footrot (265).
Host adaptation and virulence factors.
Relatively few lineages appear to have adapted to small ruminants compared to those that have adapted to cattle (228). A global study revealed that CC133 is the most prevalent ovine-associated clonal complex, although CC522 and CC700 are also commonly found in sheep (231). S. aureus isolates adapted to caprine hosts appear to be closely related to ovine-associated S. aureus isolates (228, 266). The virulence factors of S. aureus strains isolated from ovine and caprine are similar. Specifically, two staphylococcal pathogenicity islands, SaPlov1 and SaPlov2, and three prophages, φSaov1, φSaov2, and φSaov3, are found in S. aureus ED133 (CC133) isolated from sheep and goats (267, 268). SaPlov1 encodes unique ovine-specific TSST-1, SEC, and staphylococcal enterotoxin L (SEL) variants (268) that have been previously shown to have ovine-specific activity (269). SaPlov2 encodes a von Willebrand-binding protein (vWbpSov2) which stimulates the coagulation of ruminant plasma (267), a staphylococcal complement inhibitor (SCIN) which inhibits phagocytosis through interaction with complement convertases (270), and two proteins that are homologous to regulatory proteins that confer fusidic acid resistance (271). vWbpSov2 proteins also appear to be important in abscess formation and persistence in host tissues (272), which may represent an intermediate step in ruminant colonization (12). φSaov2 encodes a staphylococcal enterotoxin A (SEA), and φSaov3 encodes the LukM/LukF-PV components (268). Additionally, a recent study has identified a new exfoliative protein E (ETE) that is able to degrade the extracellular segments of desmoglein 1 in ovine and caprine epidermis, which may contribute to colonization in small ruminants (273).
Swine
S. aureus diseases in pigs.
S. aureus is not a common swine pathogen and is not associated with herd-level outbreaks in pigs (274). Skin infections such as porcine skin exfoliation and exudative epidermis in pigs are much more commonly caused by Staphylococcus hyicus that produces swine-specific exfoliative toxins (ExhA, ExhB, ExhC, and ExhD) (275). However, S. aureus can be associated with porcine skin infections, septicemia, mastitis, vaginitis, metritis, osteomyelitis, and endocarditis (274). S. aureus is problematic in neonatal pigs, where neonatal septicemia can be fatal in piglets under 10 days of age. In adult pigs, osteomyelitis and other deep-tissue infections are usually experienced as an extension of chronic skin infections (274).
Host adaptation and virulence factors.
CC9 and CC398 are commonly found in pigs and have arisen independently (12, 26, 276). Although species-adapted S. aureus is frequently found colonizing pigs, it rarely causes infections (277). This nonpathogenic characteristic is somehow related to the species-specific manner of virulence factors produced by S. aureus. For example, exfoliative toxins produced by S. aureus, which are homologous to those in S. hyicus, are specifically more active to the extracellular domains of mouse and human than swine desmoglein 1, although S. aureus exfoliative toxin B (ETB), exfoliative toxin D (ETD), and ETE appear to be able to cleave swine desmoglein 1 in vitro (273, 275). CC398 is considered a broad host range lineage, having now been found in pigs, humans, ruminants, poultry, horses, and companion animals (276). CC398 was transmitted from pigs to humans in the Netherlands in 2004 and has rapidly spread worldwide (27, 207). Most S. aureus strains have type I R-M systems on both genomic islands νSaα and νSaβ, which limits the acquisition of foreign DNA. Some ST398 strains appear to miss one type I R-M system, and this deficiency may enhance its ability to acquire new MGEs (75, 208). Furthermore, the sequences of the type I R-M system in CC398 are highly conserved and significantly different from those in other lineages, suggesting restricted MGE circulations within this lineage (278).
Rabbit
S. aureus diseases in rabbits.
Typical manifestations of S. aureus infections in rabbits are subcutaneous abscesses, mastitis, pododermatitis, and septicemia (279). Occasionally, S. aureus can result in abscess formation in the lungs, livers, and uteri of adult rabbits, resulting in poor production, infertility, and death (13). In one notable but localized outbreak, S. aureus caused severe respiratory disease and pneumonia in rabbits at the flock level (48). Rabbit-pathogenic S. aureus strains have often been sorted into high- and low-virulence strains (280). At the level of the individual rabbit, symptoms and prognosis of S. aureus infection are consistent between low-virulence and high-virulence strains. However, low-virulence S. aureus strains usually stay limited to individual rabbits, whereas high-virulence strains lead to uncontrollable deadly infections at the flock level (13, 281). S. aureus skin infections in rabbits can arise as small dermal lesions and invasive subcutaneous abscesses. In the hairless young, S. aureus infections cause exudative dermatitis with high mortality (280). Internal organs can be affected by abscess formation resulting from septicemia.
S. aureus mastitis in rabbits has been reported to be the most common cause of culling in farms (281). There are two types of S. aureus mastitis in rabbits: (i) acute or gangrenous and (ii) chronic or purulent mastitis (280). The former type can spread rapidly through a rabbitry; litters of affected does can die of starvation and does can die within hours of first exhibiting symptoms. The latter type can cause chronic lesions and result in autosterilization (280).
Host adaptation and virulence factors.
The vast majority of rabbit-pathogenic S. aureus strains have been classified as being part of either the ST121 or ST398 lineages (282). While ST398 is a broad-range lineage, ST121 appears to be a human lineage which has made a recent host jump into the domesticated rabbit population. The human-to-rabbit host jump of S. aureus ST121 is estimated to have occurred approximately 40 years ago and resulted from a single nucleotide mutation of dltB in the core genome (Fig. 1B) (204). The S. aureus dlt operon consists of four genes, dltABCD, that are involved in increasing positive charge of the cell surface, and the dltB gene encodes a membrane-embedded enzyme required for d-alanylation of teichoic acids (Fig. 1B) (283, 284). Similar mutations in the dltB gene are also found in several rabbit S. aureus isolates from several distinct nonrelated lineages, including ST1, ST8, ST9, ST45, ST96, ST133, and ST398 (204). These similar mutations in the dltB gene in STs from different clonal lineages indicate that human-to-rabbit host-switching events likely occurred independently on multiple occasions, but each event was dependent on an adaptive mutation within the same gene. Among three identified mutations within the dltB gene, the first single nonsynonymous mutation is sufficient to cause rabbit skin infection, whereas two additional mutations can enhance the persistence of S. aureus in infected lesions (204). S. aureus isolates have not acquired a single MGE that is unique to rabbit isolates. Instead, the loss of human-specific MGEs such as SaPI and β-converting phage appears to be responsible for the reduced fitness costs in the rabbit niche.
In pathogenic strains of S. aureus ST121 and ST96, which cause chronic mastitis in rabbits, the presence of a variety of cytotoxins and adhesins has been noted (285). All strains isolated from dead rabbits in Fujian, China, were identified as either ST121 or ST398, and all isolates were positive for nuc, hla, hlb, clfA, clfB, and fnbA genes (282). Of note, all ST121 isolates contained the lukSF-PV gene encoding PVL, while most of ST398 isolates carried the fnbB gene (282). These various virulence factors in different STs likely decide pathogenic behaviors in the host. The presence of PVL in certain strains is correlated with the development of necrotizing pneumonia in humans (286, 287), but the role of PVL in this disease, if there is one, is not fully understood. Fibronectin-binding protein B increases adhesive capacity (288). Both PVL and fibronectin-binding protein B appear to play a similar role in rabbits. Most importantly, rabbit erythrocytes are much more sensitive to α-hemolysin and γ-hemolysin produced by S. aureus than human cells (Fig. 2B) (289).
Poultry
S. aureus diseases in chickens.
S. aureus in poultry is a normal part of the flora but is also the most common pathogen isolated from lesions involved with skin, bone, and joint infections (290). S. aureus is also prevalent in poultry hatcheries (291). After S. aureus enters the systemic circulation via lesions or by translocation through compromised respiratory or gastrointestinal barriers, it can develop into septicemia and potentially induce inflammation in any body site of chickens (292). Pododermatitis, or “bumble foot,” is characterized by inflammation and necrotic lesions of the plantar surface of the footpads in chickens (293). S. aureus is known as one of the most frequently isolated pathogens from cases of footpad dermatitis. In a recent study, bacterial pathogens in egg-laying hens with pododermatitis were examined, and the most prevalent bacterial species was S. aureus at 68% (75/111) followed by Enterococcus faecalis at 14% (15/111) (294).
Bacterial chondronecrosis with osteomyelitis (BCO) emerged in the 1970s and is now recognized as the leading cause of lameness and significant economic loss in the poultry industry (295, 296). Although S. aureus has been isolated from BCO lesions, other recent studies have shown that S. aureus might not be the primary etiological agent responsible for BCO (297, 298).
Host adaptation and virulence factors.
Domesticated poultry-adapted S. aureus includes the CC5 lineage, which is also widely distributed in several host species, including humans, but a subgroup of CC5 has become specialized to poultry and is now found globally (15). The CC385 lineage is highly adapted to and is only found in avian species but is widely distributed among wild birds such as pheasants and grouse (25, 299). In both of these lineages, the φAvβ prophage and the pAvX plasmid are common (15) (Fig. 1A). The β-converting prophage φAvβ encodes an ornithine cyclodeaminase whose enzymatic function is still unclear (300). Several other avian-adapted S. aureus lineages also have φAvβ, implying multiple independent lateral transfers of φAvβ between S. aureus avian species (15, 301). Most CC5 avian-adapted isolates also contain the φAv1 phage, the pathogenicity island SaPIAv, and the pAvY plasmid, while human and bovine CC5 isolates consistently do not contain these MGEs (15).
Avian-adapted S. aureus isolates have an extended optimal growth temperature of 42°C, which is the average avian body temperature, while human-adapted strains grow optimally at 37°C (299). The cysteine protease (ScpA) encoded on the pAvX plasmid is correlated with a highly proteolytic phenotype found in a diseased chicken (15, 302). ScpA appears to be associated with enhanced pathogenicity of S. aureus by inhibiting CXCR-2-dependent neutrophil activation and chemotaxis, yet the high production of cysteine protease seems not to be essential for S. aureus infections in poultry (303). From a chicken embryo model, S. aureus isolates from broiler chickens were categorized into virulent, avirulent, and intermediate groups (301). This model study was then followed by a proteomic study that revealed the similar expression levels of the cysteine protease in both virulent and avirulent strains and significantly upregulated expression of α-hemolysin and bifunctional autolysin only in virulent strains (Fig. 2C) (304). Although the hemolytic activity of major hemolysins toward chicken cells was negligible in a study with a human-origin S. aureus strain (289), poultry S. aureus isolates were demonstrated to be able to lyse chicken erythrocytes (299), which suggests increased host-specific pathogenicity. The bifunctional autolysin appears to play an important role in cell division and facilitates bacterial attachment to host cells (305, 306).
FUTURE OUTLOOK
S. aureus has been transmitted between humans and livestock through zoonosis and reverse-zoonosis for the past 6,000 years and, given expansion of human populations and increases in demand for animal products, interspecies transmission will likely continue into the future. Whole-genome sequencing along with detailed phylogenetic analyses has led to the construction of likely interspecies transmission pathways, all of which indicate that humans are an important reservoir for this pathogen. However, even in primarily livestock-associated S. aureus lineages, the availability of genomic data for human isolates routinely outnumbers the availability of whole-genome sequences for animal isolates, and this sampling bias may play a role in humans being identified as a primary reservoir. It is clear that there is interspecies transmission between wild animals and humans as well as between wild animals and livestock; although, little work has been done to understand the circulation or pathology of S. aureus in wild populations. Further understanding the prevalence, genomic diversity, and pathogenesis in understudied host species, including wild animals, is likely to provide new insights into this pathogen. Wildlife populations also likely harbor novel MGEs that pose an unknown level of risk to humans and livestock.
Bovine mastitis is likely the most well-studied disease in livestock today. However, other livestock-associated S. aureus infections are surprisingly understudied and, given the high animal welfare and economic costs of these infections, building a better understanding of the range of animal infections and the mechanisms of pathogenesis of each should be a focus of future work. This work should also focus on the development of treatment options and management practices that prevent S. aureus transmission in agricultural settings without the use of antibiotics. There are now several options for treating drug-resistant S. aureus infections in humans, but few are available in agricultural settings—with good reason. However, this means that routine surveillance of MDR S. aureus in livestock is critical to decreasing the transmission of this important pathogen.
The overall literature on S. aureus is also suggestive of a large disconnect between medical research, agricultural research, and wildlife biology, in spite of this pathogen being important in each field. Although human S. aureus infections are better understood than livestock S. aureus infections, there are still several aspects of human infection that are poorly understood, which contributes to the prevalence of this infection in human medicine. Perhaps a collaborative approach between medical doctors, veterinarians, and wildlife biologists toward understanding S. aureus would help to produce a holistic picture of transmission and evolution. A sustained OneHealth approach to understanding S. aureus would likely be highly beneficial.
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Author Bios
Soyoun Park
Faculty of Agricultural and Environmental Sciences, McGill University, Sainte-Anne-de-Bellevue, Quebec, Canada
Soyoun Park is now completing her PhD in food science at McGill University, where she investigates foodborne pathogens. Her background in biotechnology originated from her Master’s degree at Chonnam National University, South Korea, where she studied molecular microbiology. Her PhD project took advantage of her knowledge in biotechnology and metagenomics to study microbial dynamics in bovine mastitis. She is investigating the bacterial interactions between Staphylococcus aureus and bovine commensal bacteria to develop early diagnostic and therapeutic strategies to control S. aureus mastitis. Her research interest is understanding bacterial interactions and studying useful biomolecules capable of treating bacterial infections in humans and animals.
Faculty of Agricultural and Environmental Sciences, McGill University, Sainte-Anne-de-Bellevue, Quebec, Canada
Jennifer Ronholm is an Assistant Professor in the Faculty of Agricultural and Environmental Science at McGill University. Her research interests are focused on identifying and characterizing antagonistic interactions that occur between bacterial pathogens and the commensal microorganisms that comprise the gastrointestinal microbiome of agricultural animals. If commensal microorganisms are found which have strong antagonistic interactions with enteric bacterial pathogens, then these could be developed into probiotic alternatives to prophylactic antibiotics. In 2020, Dr. Ronholm was named to World Economic Forum’s Young Scientists Community, which recognizes an elite group of 25 international researchers under the age of 40 annually. She holds a PhD degree from the University of Ottawa in Microbiology and Immunology.
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Published In
Clinical Microbiology Reviews
Volume 34 • Number 2 • 17 March 2021
eLocator: 10.1128/cmr.00182-20
PubMed: 33568553
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© 2021 American Society for Microbiology. All Rights Reserved.
History
Published online: 10 February 2021
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2021.
Staphylococcus aureus in Agriculture: Lessons in Evolution from a Multispecies Pathogen. Clin Microbiol Rev
34:10.1128/cmr.00182-20.
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