Staphylococcus xylosus and Staphylococcus aureus as commensals and pathogens on murine skin
Laboratory Animal Research volume 39, Article number: 18 (2023)
Skin ulcers, skin dermatitis and skin infections are common phenomena in colonies of laboratory mice and are often found at increased prevalence in certain immunocompromised strains. While in many cases these skin conditions are mild, in other cases they can be severe and lead to animal morbidity. Furthermore, the presence of skin infections and ulcerations can complicate the interpretation of experimental protocols, including those examining immune cell activation. Bacterial species in the genus Staphylococcus are the most common pathogens recovered from skin lesions in mice. In particular, Staphylococcus aureus and Staphylococcus xylosus have both been implicated as pathogens on murine skin. Staphylococcus aureus is a well-known pathogen of human skin, but S. xylosus skin infections in humans have not been described, indicating that there is a species-specific difference in the ability of S. xylosus to serve as a skin pathogen. The aim of this review is to summarize studies that link S. aureus and S. xylosus to skin infections of mice and to describe factors involved in their adherence to tissue and their virulence. We discuss potential differences in mouse and human skin that might underlie the ability of S. xylosus to act as a pathogen on murine skin, but not human skin. Finally, we also describe mouse mutants that have shown increased susceptibility to skin infections with staphylococcal bacteria. These mutants point to pathways that are important in the control of commensal staphylococcal bacteria. The information here may be useful to researchers who are working with mouse strains that are prone to skin infections with staphylococcal bacteria.
In this review we seek to evaluate and curate the literature relevant to the staphylococcal species Staphylococcus xylosus and Staphylococcus aureus as commensals and pathogens on the skin of laboratory mice and to compare their properties to each other and to other common skin staphylococcal species such as Staphylococcus epidermidis. We also discuss potential virulence factors for these species and differences in skin structure that may contribute to the species-specificity of certain staphylococcal infections.
Staphylococcus is a genus of bacteria containing roughly 60 species and subspecies that colonize a variety of environments . Staphylococci are Gram-positive organisms in the phylum Firmicutes and they are characterized by formation of clusters of round cells (cocci). Staphylococcal bacteria are a significant component of the skin microbiome in many animals as observed in humans, mice, dogs, horses, cows, pigs, chickens and pigeons . Some species of staphylococci are frequently associated with infections of the skin and underlying tissues, while other species are rarely associated with infection. This difference in pathogenicity between species is likely influenced by the presence or absence of a variety of virulence-associated genes in the different species. One of the traits used to divide staphylococcal species is based on expression of coagulase, an enzyme which can convert fibrinogen in serum into fibrin and hence coagulate the serum. Most strains of Staphylococcus aureus are coagulase positive, while other staphylococcal species commonly encountered on the skin, such as S. xylosus and S. epidermidis, are usually coagulase negative staphylococci (CoNS) . Indeed, tests for coagulase activity are used clinically to help differentiate S. aureus from other staphylococcal species. In addition to coagulase positivity, numerous other characteristics have been used to differentiate staphylococcal species including the G + C content of the chromosome, the molecular composition of the cell wall, and patterns of antibiotic susceptibility, among other factors. This is complemented by 16S rRNA sequencing and whole genome sequencing that have allowed further refinement of the staphylococcal family tree. 16S sequencing led to the identification of 6 major staphylococcal species groupings, which can be further divided into fifteen clusters based largely on conservation and expression of factors such as coagulase, oxidase, and novobiocin resistance .
Presence of staphylococcal species on human versus murine skin
In humans, the skin is colonized by several staphylococcal species, the most prevalent and widespread of which are S. epidermidis and S. hominis [2, 4, 5]. Other staphylococcal species can also be found on human skin, including S. aureus, S. warneri, S. haemolyticus and S. capitis [2, 5, 6]. On the other hand, S. xylosus is an infrequent colonizer of human skin, though it is more often isolated from the skin of people whose work brings them into frequent contact with animals . When human skin is transplanted onto nude mice, S. xylosus can be recovered from the human skin grafts, but the percent of grafts colonized by S. xylosus is relatively low compared to the skin of host mice . This implies that inherent features of murine skin promote the colonization by S. xylosus, while features of human skin discourage S. xylosus colonization. Many of the most common staphylococcal species on human skin fall into a sub-group of the staphylococcal species known as the Epidermidis–Aureus group . On the other hand, S. xylosus, which is uncommon on human skin, falls into the Saprophyticus sub-group . Among the human colonizing staphylococcal species, S. aureus has been most intensely studied, because it is one of the primary sources of skin and soft tissue infections (SSTI) [9,10,11]. Approximately 20–30% of humans carry S. aureus as a commensal on the skin or in the nasal cavity  and higher rates of nasal carriage of S. aureus are correlated with increased rates of S. aureus SSTI infections [12,13,14]. The other staphylococcal species that are present on the skin of humans are less frequently identified as the causative agents in infections. One study has shown that roughly 10% of SSTIs are caused by staphylococcal species other than S. aureus . Staphylococcus aureus skin infections in humans can be serious and can invade into underlying tissues or enter the bloodstream, leading to life-threatening sepsis. These serious infections are complicated by the fact that some strains of S. aureus are resistant to antibiotics (e.g., the methicillin-resistant S. aureus (MRSA) strains).
A different set of staphylococcal species are common on murine skin with respect to human skin. On murine skin, the most prevalent staphylococcal species are S. xylosus and S. sciuri [2, 16, 17]. Microbiome studies of mouse ear skin from wild mice and C57BL/6 laboratory raised mice (both of the species Mus musculus) identified S. xylosus as a major colonizer , while human prevalent species such as S. epidermidis, S. hominis and S. aureus were not identified as a major species on murine skin in this study. Furthermore, S. xylosus has been repeatedly associated with infected skin wounds in mice (see Table 1), both in immunocompromised mice and in non-immunocompromised ones. Staphylococcus xylosus skin infections in mice lead to significant dermatitis often forming ulcers with serocellular crusts. When solutions containing S. aureus, S. epidermidis, S. xylosus or S. lentus were applied topically to the ear of C57BL/6 mice, S. xylosus was recovered at higher frequencies than the other Staph species when colony counts were obtained 2 days later . These data suggest that S. xylosus preferentially survives or expands on murine skin. Furthermore, it is clear that S. xylosus is a frequent pathogen in murine skin, while it is very rarely the cause of pathogenic infections in human skin.
The situation with S. aureus on murine skin is complicated. Staphylococcus aureus can be recovered from murine skin, but not all mouse colonies seem to carry S. aureus [19, 20]. Because not all mice carry S. aureus, it has sometimes been regarded as an organism transferred from human caretakers, rather than a commensal of mice. Complicating this, staphylococcal species including S. aureus and S. xylosus can spread rapidly among cohoused animals from animals  and hence transfer of S. aureus from caretakers to one or a few animals could lead to spread throughout the colony. However, in addition to potential transfer from caretakers, recent evidence shows that some colonies of mice carry mouse-adapted strains of S. aureus that differ from the strains common on human skin and these mouse-adapted strains are passed from murine parents to progeny, indicating a commensal relationship . Similar to the observances in humans, colonization by mouse-adapted S. aureus in murine models appears to show a bias towards colonization of the nares [20, 22]. Staphylococcus aureus is a causative agent of skin infections in mice [23, 24], though reports of S. aureus skin infections in mice appear to be rarer than reports of S. xylosus skin infections. However, this may reflect a publication bias and further studies are needed to understand the true prevalence of S. aureus versus S. xylosus skin infections in mice. The observations described above show that the staphylococcal bacteria on mouse and human skin have different patterns of species prevalence. The differences in staphyloccocal colonization between mice and humans are likely due to inherent properties of both the bacterial species and the host skin environment.
Properties of skin staphylococcal species
As described above, S. xylosus and S. aureus belong to different sub-groups of the Staphylococcus family tree . However, they display many similarities in the mechanisms of skin colonization and their potential to become pathogenic. In terms of virulence factors, little is known about S. xylosus, since it is not a common human pathogen. However, genomic analysis of various S. xylosus isolates has identified a number of loci with significant homology to known virulence factors identified in S. aureus. Table 2 lists virulence factors described in S. aureus and indicates whether similar proteins have been identified in three other species of staphylococcal bacteria that colonize the skin of mice or humans, S. xylosus, S. epidermidis and S. sciuri. Staphylococcus xylosus possesses genes homologous to all of the S. aureus virulence factors listed in Table 2, although it should be noted that most of these genes have not been directly shown to have a pathogenic role in S. xylosus. On the other hand, S. epidermidis and S. sciuri have only been reported to contain a sub-set of these genes. This may imply that S. xylosus has more pathogenic potential than S. epidermidis or S. sciuri. These data should be interpreted with caution though, since future studies may identify additional virulence genes in one or more of these species. In addition, it is important to keep in mind that different bacterial isolates show differences in terms of the presence or absence of virulence factors, in part driven by the fact that some virulence factors are encoded on mobile genetic elements and can be transferred horizontally. Hence not all isolates of the species listed in Table 2 may contain all the virulence factors described. Despite these limitations, the current data support the idea that S. xylosus’ mechanisms of virulence may be similar to those described in S. aureus.
Some of the virulence genes shown in Table 2 include those that promote the adherence and invasion of tissue by S. aureus. These include microbial surface components recognizing adhesive matrix molecules, or MSCRAMMs for short, that bind to host extracellular matrix factors such as elastin, fibronectin, and laminin. Both S. xylosus and S. aureus can generate biofilms, which aids in their persistence following initial colonization. Production of these biofilms is largely dependent on biofilm associated protein (bap) and sas/sxs proteins [25,26,27,28]. Interestingly, S. xylosus pre-colonization of murine skin reduces the ability of S. aureus to colonize and treatments that deplete commensal staphylococcal species, including S. xylosus, increase the colonization ability of S. aureus . These data indicate that S. xylosus and S. aureus may compete for binding to similar ligands on the skin’s surface. Coculture experiments investigating biofilm formation of S. xylosus and S. aureus found that formation of S. aureus biofilms was inhibited in the presence of cell-free supernatants derived from S. xylosus, resulting in formation of S. aureus aggregates that were more susceptible to detachment . These observances suggest that S. aureus and S. xylosus may occupy similar niches in vivo. However, it is likely that the differences in the structure and function of mouse and human skin as well as differences in bacterial physiology contribute to the differential presence of these bacteria on skin in humans and mice.
Despite being most often described as a extracellular pathogen, S. aureus can internalize into epithelial cells by a mechanism in which bacterial fibronectin binding proteins (FnBPs) bind to host fibronectin, which subsequently interacts with host α5β1 integrin followed by endocytosis of the complex . Staphylococcus aureus cells can survive for some time inside mammalian cells, with survival being noted for up to 96 h in a human skin keratinocyte cell line  and up to 7 days in a human umbilical endothelial cell line . The prolonged survival of S. aureus within mammalian cells may result in a reservoir of bacteria that is hidden from certain immune responses and that can escape the activity of antibiotics [31, 34, 35]. Staphylococcus xylosus can also internalize into cells as shown by a study with NIH3T3 fibroblasts . Staphylococcus xylosus has a homolog of the FnBP proteins, but it is not yet clear if S. xylosus internalization takes place via a FnBP-fibronectin-α5β1 integrin pathway or not. These data suggest that both S. aureus and S. xylosus may have the ability to form persistent infection by hiding within cells in the skin environment.
Some S. xylosus isolates express staphylococcal enterotoxins, toxic shock syndrome toxin 1 and exfoliative toxins, which are virulence factors found in many strains of S. aureus [37, 38]. Similar to the corresponding virulence factor in S. aureus, S. xylosus phenol soluble modulins (PSMs) have been shown to be highly functional . PSMα from S. aureus has significant cytolytic activity against erythrocytes, mast cells, and neutrophils isolated from both murine and human hosts. Similarly, PSMα proteins from S. xylosus are highly pro-inflammatory with greater observed neutrophil calcium flux than S. aureus derived δ toxin and PSMα3. In addition, S. xylosus PSMα is able to induce similar mast cell degranulation as S. aureus PSMα3. Despite the pronounced in vitro results, epicutaneous application of PSM-expressing S. xylosus only resulted in minor pathogenicity in a mouse atopic dermatitis model . In SKH-1E female mice, an atopic dermatitis like condition develops upon application of δ-toxin expressing S. aureus. Infecting these mice with S. xylosus did not lead to similar atopic dermatitis like lesions and mutants of the PSM genes in  had no effect on the phenotype observed . This latter result indicate that mice may be adapted to colonization by S. xylosus and do not induce a strong inflammatory response to the bacteria, despite production of functional PSM proteins.
Iron is a rate-limiting nutrient in infection settings and S. aureus scavenges iron from the host via a number of mechanisms, including the production of hemolysins, which are proteins that lyse erythrocytes and release iron-containing hemoglobin . Staphylococcus xylosus expresses a functional delta-hemolysin protein  and hemolytic activity has observed in nearly 90% of S. xylosus isolates tested . Staphylococcus aureus also uses siderophores, such as staphyloferrin A and B [43, 44], to take up free iron from the environment via the fhu system, which mediates the uptake of the siderophores . Genomic analysis of the C2a strain S. xylosus indicates the presence of genes encoding staphyloferrin A as well the FHU system . Therefore, S. xylosus may scavenge iron from the environment using mechanisms similar to those described in S. aureus. Cumulatively, current data suggest that S. xylosus and S. aureus share expression of homologous proteins, which are known to contribute to virulence in S. aureus, though the role of most of these virulence factors in natural S. xylosus infections in mice remains to be tested.
Skin structure in mice and humans and relevance to staphylococcal colonization/infection
Skin serves as a major interface between the body interior and the exterior environment, where many microbes are found colonizing the skin’s surface. The basic cellular structure and organization of the skin of humans and mice has many similarities, but there are also key differences that distinguish the two species and that are relevant to studies using mouse models. In both mice and humans, the skin is composed of an epidermal layer, a dermal layer and a hypodermal layer. The epidermal layer is primarily composed of stratified squamous epithelial cells termed keratinocytes that undergo a differentiation program to produce a protective barrier that excludes bacteria and other contaminants, while also preventing the excess loss of fluids from underlying tissues. The dermis of both species is largely composed of fibroblasts and the extracellular matrix they secrete. The dermal compartment also contains blood vessels, immune cells, nerve endings, sweat glands, sebaceous glands and the bulbs of hair follicles. The hypodermis is composed primarily of fat cells and connective tissue and serves a cushioning function.
Despite these similarities in overall structure, there are a number of fundamental differences between the skin of mice and humans. One significant difference is in the thickness of the skin. In humans, the epidermis is composed of 5–10 layers of keratinocytes, whereas mice only have 2–3 layers of keratinocytes . In addition, mice and humans differ significantly in the number of hair follicles , with mice having a significantly higher density and a more even distribution of hair follicles than humans. The hair shafts in mice are also thicker than human body hair, which is very fine . On the other hand, humans have a significantly greater number of eccrine sweat glands that are distributed over the entire surface, while mice have sweat glands only on their paws. Human skin is attached to the underlying tissue, while murine skin is loose. Human skin contains rete ridges, projections of the epidermis that extend into the underlying dermis, while murine skin lacks rete ridges. Another key difference is the presence of the panniculus carnosus, a sub-cutaneous muscle layer underlying the entire skin in mice, but which is largely absent in human skin with the exception of a vestigial presence in specific regions .
Resident immune cells are found in the skin in both the epidermal and dermal compartments. Innate lymphocytes (ILCs), neutrophils, macrophages, mast cells, natural killer cells, and epidermal Langerhans cells are found in the skin of both mice and humans [51, 52]. In addition, both mice and humans have αβ and γδ T cells in the skin . In human skin, T cells are primarily located in the dermis and mostly carry the αβ T cell receptor. Human skin also has a small proportion of skin resident γδ T cells . Like human skin, murine skin has dermal αβ and γδ T cells. However, one significant difference in the immune makeup of murine versus human skin is the presence of a specialized type of γδ T cells in murine skin, called dendritic epidermal T cells (DETC) . As their name suggests, they are found in the epidermal layer of the skin and have a dendritic morphology. DETC express an invariant T cell receptor composed of Vγ5 and Vδ1 chains and are involved in skin inflammatory and wound healing processes . Their functions in humans are likely carried out by multiple other cell types such as Vδ1+ and Vδ2+ γδ T cells, which share various functions including modulating wound healing and secretion of effectors such as IFNγ and IGF-1 [55, 56].
Some of the differences in structure between mouse and human skin may contribute to colonization by different staphylococcal species, although this has not been directly tested. An example of a possible structural difference that may be relevant is the differences in sweat gland distribution in mice and humans. As noted above, human skin has many more eccrine sweat glands distributed over the entire body, while murine skin has eccrine sweat glands only on the paws. The enzyme lysozyme, which breaks down bacterial cell walls, is produced by human sweat glands . Staphylococcus aureus is known to be resistant to the effects of lysozyme , while S. xylosus is not . Thus, the presence in humans of large numbers of sweat glands secreting lysozyme might lead to conditions that are unfavorable for S. xylosus colonization, while permitting S. aureus colonization. Another potentially relevant factor is that human skin has fewer hair follicles than murine skin. Studies in mice lacking EGF receptor in keratinocytes have shown overgrowth of S. xylosus and the presence of gram-positive bacteria in the hair follicles . If S. xylosus preferentially colonizes hair follicles, it may be better able to colonize animal skin where there are more hair follicles than human skin. While neither of these potential mechanisms has been experimentally validated, it is possible that these and other differences in mouse and human skin underlie the differential ability S. xylosus to colonize this tissue.
Mouse susceptibility to skin staphylococcal infections
Staphylococcus xylosus is an uncommon infectious agent in humans and for this reason it has not been studied as a pathogen using mouse models. Therefore, data concerning the immune response to S. xylosus is derived from spontaneous infections that occur in particular mouse strains. Published studies identifying S. xylosus as the causative agent in spontaneous murine skin infections are outlined in Table 1. These reports show that mouse models where there is a disruption of the skin barrier are often susceptible to S. xylosus infection. In addition, specific defects in innate and adaptive immune cell responses can also lead to susceptibility to skin infection with S. xylosus. On the other hand, spontaneous S. aureus skin infections in mice are more rarely reported and much of the data concerning pathways that regulate mouse susceptibility to S. aureus come from studies where the bacteria have been exogenously applied, epicutaneously (on the surface of the skin), intradermally (injected) or into open wounds on the skin. Infection of the deeper layers of the skin, such as the intradermal model of infection, typically leads to formation of an abscess, while infection of the superficial layers of the skin does not. Several recent reviews have described the immune response to S. aureus infection of murine skin, including important cell types and effector molecules [61,62,63]. For this reason, we focus here on the immune mechanisms that appear to be important for responses to S. xylosus. These pathways are also summarized in Fig. 1.
Skin barrier function defects
The skin forms a barrier between the external environment, where bacteria are found, and the internal tissues. Defects in this skin barrier confer susceptibility to staphylococcal infections. Mechanical disruption of the skin barrier in mice using tape stripping to remove the superficial layers that form cornified envelopes results in increased colonization and persistence by epicutaneously applied S. aureus, with a more significant effect seen in animals with increased levels of tape stripping compared to animals with mild tape stripping . Similarly, in mice lacking the cornified envelope protein filaggrin, tape-stripping and ovalbumin (OVA) sensitization resulted in significant barrier function impairment and S. aureus invasion of the dermis and underlying adipose tissue following epicutaneous application . Studies indicate that an intact skin barrier is also crucial for prevention of spontaneous S. xylosus skin infections . Treatment of murine skin with the chemical oxazolone results in an epidermal barrier defect caused by degradation of filaggrin and E-cadherin . These oxazolone-treated mice show striking increases in S. xylosus skin colonization . Spontaneous skin infections with S. xylosus have also been described in mice lacking the stearoyl-CoA desaturase (SCD1) enzyme, which is required for generation of lipids involved in establishing a water-permeability barrier in the skin . The susceptibility to staphylococcal infection in SCD1 deficient mice also extends to S. aureus, since mice with a recessive germ line mutation in SCD1 display significantly impaired clearance of intradermally injected S. aureus . The epidermal growth factor (EGF) is important for establishing the skin barrier and mice with a tamoxifen-inducible keratinocyte-specific deletion of the EGF receptor develop a barrier defect that initiates in the hair follicles . These mice also demonstrate an overgrowth of S. xylosus on the skin. Mice lacking the NFκB cofactor Nfkbiz (IκBζ) also develop spontaneous skin infections with S. xylosus . Nfkbiz can be induced in many cell types including both immune cells and epithelial cells in response to TLR signaling. In the skin, Nfkbiz is also expressed at the basal state in keratinocytes surrounding the hair follicle . Nfkbiz deficient mice have both a skin barrier defect and an overgrowth of S. xylosus on the skin . Together, these studies show that a variety of mechanical and genetic manipulations that affect the skin barrier lead to increased colonization and persistence of staphylococcal bacteria.
Defects in neutrophil functions
Bacterial infection leads first to activation and recruitment of innate immune cells, such as monocytes, macrophages and neutrophils. Neutrophils are particularly important in the control of bacterial infections, since they are the most abundant white blood cell type and they phagocytose bacteria and kill them. Neutrophils are involved in generating abscesses in response to bacterial infection and this process is dependent on the NADPH oxidase complex that generates toxic reactive oxygen species that can kill bacteria. NADPH oxidase activity is crucial for control of staphylococcal infections as shown by the fact that mice lacking components of the NADPH oxidase complex, p47phox (Ncf1) or p91phox (Cybb or Nox2), are susceptible to spontaneous skin infections by S. xylosus [71,72,73]. NADPH oxidase is also required in humans to prevent staphylococcal skin infection, since patients with chronic granulomatous disease (CGD) that have mutations in the NADPH oxidase NOX2 subunit show enhanced susceptibility to S. aureus skin infections . Production of reactive nitrogen species in neutrophils by the action of the enzyme inducible nitric oxide synthase 2 (Nos2) is also involved in bacterial killing . Mice lacking Nos2 also show a susceptibility to spontaneous skin infections with S. xylosus [76, 77]. Finally, mice lacking the integrin subunit Itgb2 (also called CD18), which is expressed on a variety of different white blood cells including neutrophils and macrophages, are susceptible to spontaneous skin infections by S. xylosus . All these studies point to the crucial role for neutrophils and the innate immune response in the control of S. xylosus skin infections.
T cells are crucial for control of skin S. aureus infections in mice and γδ T cells that produce IL-17 have been particularly implicated in this process using mouse models. However, different mouse models have yielded somewhat disparate and sometimes contradictory results based on the strain of mice and the infection model used. For many studies of S. aureus pathogenesis, mice of the C57BL/6 genetic background have been used. In studies using C57BL/6 mice, loss of γδ T cells, but not αβ T cells, led to impaired clearance of primary intradermal S. aureus infections . In the skin, γδ T cells are the primary source of the cytokine IL-17 , and IL-17 and IL-17 receptor are both also required for optimal clearance of murine skin infections by S. aureus [79,80,81]. Loss of IL-17 receptor signalling in humans also leads to susceptibility to skin Staphylococcal infections . Supporting an important role for γδ T cells in anti-Staphylococcal responses, RNA-sequencing of draining lymph nodes at 28 days post-infection showed expansion of a particular TCR Vγ6 and TCR Vδ4 sequences, while there was not strong enrichment for specific αβ TCR sequences . Some studies in C57BL/6 wild-type mice show a minimal protection afforded by a primary S. aureus skin infection and secondary infection results in similar lesion sizes and bacterial burdens [83, 84]. However, in another study, C57BL/6 mice did show protection in a secondary infection, though this was due to an innate immune response since a similar protective effect was observed in Rag1−/− mice . The reasons for the discrepancy in secondary responses of C57BL/6 mice in these studies are not apparent, but may be due to differences in experimental protocols such as the dose, timing and site of infection. C57BL/6 mice with a deletion of IL-1β were shown to have a worse primary response with increased bacterial burden, but a normal secondary response suggesting that there was development of immunological memory . The protective response in IL-1β-deficient mice was shown to be mediated by γδ T cells producing TNF and IFNγ and to not require specific antibodies .
C57BL/6 mice are known to have a bias towards developing Th1 cells , leading to increased IFNγ secretion. On the other hand, Balb/c strain mice have a Th2 bias and develop more T cells secreting IL-4 . When studying Balb/c mice with S. aureus skin infections, differences were found in comparison to studies using C57BL/6 mice. In Balb/c mice, the protective responses to secondary infection were found to be significantly stronger than in C57BL/6 mice [84, 85]. This memory response in Balb/c mice was dependent on CD4 T cells, which drive production of protective antibody responses [84, 85]. On the other hand, C57BL/6 mice don’t develop protective antibody under the same conditions. IL-17 is required for the secondary responses to repeat infections by S. aureus in Balb/c mice, while IFNγ in C57BL/6 mice blocks a protective effect . The differing results obtained in different conditions indicate that careful attention should be paid to experimental variables such as mouse strain and infection protocols in order to best determine the roles of adaptive immunity in Staphylococcal infection.
Few studies have exogenously infected mice with S. xylosus and hence most of the data concerning immune responses relevant to S. xylosus clearance are derived from spontaneous infections. Rag1-/- mice, which completely lack B cells and T cells, have been shown to be susceptible to spontaneous S. xylosus skin infection . Similarly, nude mice, which lack T cells due to a thymic defect caused by mutation of Foxn1, are also susceptible to spontaneous skin infections by S. xylosus [88, 89]. However, the latter observation should be interpreted cautiously because the Foxn1 protein also regulates keratinocyte growth and differentiation in the skin and hair follicles . Hence, nude mice may show susceptibility to S. xylosus either because they lack T cells or because they have aberrant skin differentiation or both. Topical infection of skin with S. xylosus in wild-type mice elicits significant recruitment CD8+ T cells, whose recruitment accelerates wound healing . B cells may also have a role in controlling S. xylosus infections. Mice lacking the Rif1 gene, which is involved in B cell class-switch recombination, develop skin infections with S. xylosus . This may indicate that specific Ig classes are more effective in controlling S. xylosus infection and that class switching is required for bacterial clearance.
Human patients with diabetes are susceptible to development of diabetic foot ulcers on the skin of the feet  and these are often colonized by S. aureus . Staphylococcus aureus infection of diabetic foot ulcers is associated with delayed wound healing. Patients with diabetes also tend to show higher rates of nasal carriage of S. aureus . Together these observations suggest that diabetes may either promote the growth and attachment of staphylococcal bacteria and/or impair the immune response to the bacteria.
Interestingly, studies of the wound microbiome in diabetes prone db/db mice, which lack the leptin receptor, found that S. xylosus was often one of the first and most prevalent colonizers in a skin wounding model and that its colonization was strongly associated with development of a chronic wound . Similarly, wild-type C57BL/6 mice where diabetes was induced by injection of streptozotocin had deficiencies in clearing skin infections with S. aureus, which could be reversed by treating with prostaglandin E2 that induces dendritic cell dependent induction of Th17 cells [97, 98]. Streptozotocin-induced diabetes also impairs healing of S. aureus infected skin wounds in rats .
A model of human diabetic foot ulcers has been developed which involves the injection of S. aureus bacteria into the hind footpad of mice, with or without diabetes. db/db mice injected in the hindpaw with S. aureus show defects in bacterial killing accompanied by reduced neutrophil respiratory burst leading to chronic infections . Similarly, non-obese diabetic (NOD) mice with diabetes and wild-type C57BL/6 mice where diabetes was induced with a high fat diet also show impaired clearance of S. aureus in the hindpaw injection model [101, 102]. The susceptibility observed in high fat diet induced diabetic mice was attributed to significantly reduced expression of Aicda, which induces somatic hypermutation and class switch recombination in B cells, likely contributing to significantly decreased IgG and IgE responses in diabetic mice versus controls . Cumulatively, these findings indicate that diabetes contributes to susceptibility to staphylococcal infections, including infections of the skin.
In this review, we’ve summarized reports of the bacterial species Staphylococcus xylosus as a cause of skin infections in mice, including laboratory mice used in research. Staphylococcus xylosus is a commensal of murine skin, but can become pathogenic when there are disruptions to the skin barrier and/or when the host immune response is compromised. The presence of diabetes is also a risk factor for S. xylosus infections. Staphylococcus aureus can also serve as both a commensal and pathogen of murine skin, but not all strains of mice carry S. aureus and there are fewer published reports describing skin infections with S. aureus than with S. xylosus. Unlike in mice, S. xylosus rarely causes infections of the skin or other tissues in humans, while S. aureus is a well-known and important pathogen in humans.
Staphylococcus xylosus strains express many genes with significant similarity to known virulence factors of S. aureus, but for the most part, the roles of these genes in S. xylosus infection have not been studied. In addition to its roles in mice, S. xylosus is also a common pathogen of food animals, including cattle , goats  and trout . Staphylococcus xylosus can also be recovered from pet animals, such as dogs and cats [2, 106,107,108,109] and at least one instance of human infection with S. xylosus caused by dog bite has been reported . Given the potential of S. xylosus to cause infections in research animals, food animals and pets and the possibility that such infections may be transmitted to humans, it would be of benefit to better understand the pathological mechanisms employed by S. xylosus that allow it to colonize tissues and persist in the presence of immune responses.
Availability of data and materials
No experimental datasets were collected for this study.
Skin and soft-tissue infection
Methicillin-resistant Staphylococcus aureus
Microbial surface components recognizing adhesive matrix molecules
Innate lymphoid cell
Dendritic epidermal T cell
Epidermal growth factor
Nicotinamide adenine dinucleotide phosphate
Chronic granulomatous disease
Götz F, Bannerman T, Schleifer K-H. The genera staphylococcus and macrococcus. In: Dworkin M, Falkow S, Rosenberg E, Schleifer K-H, Stackebrandt E, editors. The prokaryotes. New York: Springer; 2006. p. 5–75.
Nagase N, Sasaki A, Yamashita K, Shimizu A, Wakita Y, Kitai S, et al. Isolation and species distribution of staphylococci from animal and human skin. J Vet Med Sci. 2002;64(3):245–50.
Lamers RP, Muthukrishnan G, Castoe TA, Tafur S, Cole AM, Parkinson CL. Phylogenetic relationships among Staphylococcus species and refinement of cluster groups based on multilocus data. BMC Evol Biol. 2012;12:171.
Findley K, Oh J, Yang J, Conlan S, Deming C, Meyer JA, et al. Topographic diversity of fungal and bacterial communities in human skin. Nature. 2013;498(7454):367–70.
Kloos WE, Musselwhite MS. Distribution and persistence of Staphylococcus and Micrococcus species and other aerobic bacteria on human skin. Appl Microbiol. 1975;30(3):381–5.
Kloos WE, Schleifer KH. Simplified scheme for routine identification of human Staphylococcus species. J Clin Microbiol. 1975;1(1):82–8.
Mardh PA, Hovelius B, Hovelius K, Nilsson PO. Coagulase-negative, novobiocin-resistant staphylococci on the skin of animals and man, on meat and in milk. Acta Vet Scand. 1978;19(2):243–53.
Kearney JN, Gowland G, Holland KT, Cunliffe WJ. Maintenance of the normal flora of human skin grafts transplanted to mice. J Gen Microbiol. 1982;128(10):2431–7.
Bouvet C, Gjoni S, Zenelaj B, Lipsky BA, Hakko E, Uckay I. Staphylococcus aureus soft tissue infection may increase the risk of subsequent staphylococcal soft tissue infections. Int J Infect Dis. 2017;60:44–8.
Ray GT, Suaya JA, Baxter R. Incidence, microbiology, and patient characteristics of skin and soft-tissue infections in a U.S. population: a retrospective population-based study. BMC Infect Dis. 2013;13:252.
Vella V, Galgani I, Polito L, Arora AK, Creech CB, David MZ, et al. Staphylococcus aureus skin and soft tissue infection recurrence rates in outpatients: a retrospective database study at 3 US medical centers. Clin Infect Dis. 2021;73(5):e1045–53.
Kalmeijer MD, van Nieuwland-Bollen E, Bogaers-Hofman D, de Baere GA. Nasal carriage of Staphylococcus aureus is a major risk factor for surgical-site infections in orthopedic surgery. Infect Control Hosp Epidemiol. 2000;21(5):319–23.
Munoz P, Hortal J, Giannella M, Barrio JM, Rodriguez-Creixems M, Perez MJ, et al. Nasal carriage of S. aureus increases the risk of surgical site infection after major heart surgery. J Hosp Infect. 2008;68(1):25–31.
Toshkova K, Annemuller C, Akineden O, Lammler C. The significance of nasal carriage of Staphylococcus aureus as risk factor for human skin infections. FEMS Microbiol Lett. 2001;202(1):17–24.
Cardona AF, Wilson SE. Skin and soft-tissue infections: a critical review and the role of telavancin in their treatment. Clin Infect Dis. 2015;61(Suppl 2):S69-78.
Belheouane M, Vallier M, Cepic A, Chung CJ, Ibrahim S, Baines JF. Assessing similarities and disparities in the skin microbiota between wild and laboratory populations of house mice. ISME J. 2020;14(10):2367–80.
Tavakkol Z, Samuelson D, deLancey Pulcini E, Underwood RA, Usui ML, Costerton JW, et al. Resident bacterial flora in the skin of C57BL/6 mice housed under SPF conditions. J Am Assoc Lab Anim Sci. 2010;49(5):588–91.
Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, et al. Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature. 2015;520(7545):104–8.
Schulz D, Grumann D, Trube P, Pritchett-Corning K, Johnson S, Reppschlager K, et al. Laboratory mice are frequently colonized with Staphylococcus aureus and mount a systemic immune response-note of caution for in vivo infection experiments. Front Cell Infect Microbiol. 2017;7:152.
Holtfreter S, Radcliff FJ, Grumann D, Read H, Johnson S, Monecke S, et al. Characterization of a mouse-adapted Staphylococcus aureus strain. PLoS ONE. 2013;8(9):e71142.
Gimblet C, Meisel JS, Loesche MA, Cole SD, Horwinski J, Novais FO, et al. Cutaneous leishmaniasis induces a transmissible dysbiotic skin microbiota that promotes skin inflammation. Cell Host Microbe. 2017;22(1):13–24.
Sun Y, Emolo C, Holtfreter S, Wiles S, Kreiswirth B, Missiakas D, et al. Staphylococcal protein A contributes to persistent colonization of mice with Staphylococcus aureus. J Bacteriol. 2018. https://doi.org/10.1128/JB.00735-17.
Wullenweber-Schmidt M, Lenz W, Bronnemann K. Can the association of athymic mice (Han:NMRI-nu) with Staphylococcus sciuri prevent infection with Staphylococcus aureus? Experiences from a field study. Z Versuchstierkd. 1989;32(1):49–56.
Hikita I, Yoshioka T, Mizoguchi T, Tsukahara K, Tsuru K, Nagai H, et al. Characterization of dermatitis arising spontaneously in DS-Nh mice maintained under conventional conditions: another possible model for atopic dermatitis. J Dermatol Sci. 2002;30(2):142–53.
Rosenstein R, Gotz F. What distinguishes highly pathogenic staphylococci from medium- and non-pathogenic? Curr Top Microbiol Immunol. 2013;358:33–89.
Schiffer C, Hilgarth M, Ehrmann M, Vogel RF. Bap and cell surface hydrophobicity are important factors in Staphylococcus xylosus biofilm formation. Front Microbiol. 2019;10:1387.
Schiffer CJ, Schaudinn C, Ehrmann MA, Vogel RF. SxsA, a novel surface protein mediating cell aggregation and adhesive biofilm formation of Staphylococcus xylosus. Mol Microbiol. 2022;117(5):986–1001.
Tristan A, Lina G, Etienne J, Vandenesch F. Biology and pathogenicity of staphylococci other than Staphylococcus aureus and Staphylococcus epidermidis. In: Fischetti VA, Novick RP, Ferretti JJ, Portnoy DA, Rood JI, editors. Gram-positive pathogens. 2nd ed. Hoboken: Wiley; 2006. p. 572–86.
SanMiguel AJ, Meisel JS, Horwinski J, Zheng Q, Grice EA. Topical antimicrobial treatments can elicit shifts to resident skin bacterial communities and reduce colonization by Staphylococcus aureus competitors. Antimicrob Agents Chemother. 2017;61(9):e00774-e817.
Leroy S, Lebert I, Andant C, Talon R. Interaction in dual species biofilms between Staphylococcus xylosus and Staphylococcus aureus. Int J Food Microbiol. 2020;326:108653.
Sinha B, Francois P, Que YA, Hussain M, Heilmann C, Moreillon P, et al. Heterologously expressed Staphylococcus aureus fibronectin-binding proteins are sufficient for invasion of host cells. Infect Immun. 2000;68(12):6871–8.
Gunaratnam G, Tuchscherr L, Elhawy MI, Bertram R, Eisenbeis J, Spengler C, et al. ClpC affects the intracellular survival capacity of Staphylococcus aureus in non-professional phagocytic cells. Sci Rep. 2019;9(1):16267.
Siegmund A, Afzal MA, Tetzlaff F, Keinhorster D, Gratani F, Paprotka K, et al. Intracellular persistence of Staphylococcus aureus in endothelial cells is promoted by the absence of phenol-soluble modulins. Virulence. 2021;12(1):1186–98.
Bravo-Santano N, Behrends V, Letek M. Host-targeted therapeutics against multidrug resistant intracellular Staphylococcus aureus. Antibiotics (Basel). 2019;8(4):241.
Watkins KE, Unnikrishnan M. Evasion of host defenses by intracellular Staphylococcus aureus. Adv Appl Microbiol. 2020;112:105–41.
Krugner-Higby L, Brown R, Rassette M, Behr M, Okwumabua O, Cook M, et al. Ulcerative dermatitis in C57BL/6 mice lacking stearoyl CoA desaturase 1. Comp Med. 2012;62(4):257–63.
Banaszkiewicz S, Walecka-Zacharska E, Schubert J, Tabis A, Krol J, Stefaniak T, et al. Staphylococcal enterotoxin genes in coagulase-negative staphylococci-stability, expression, and genomic context. Int J Mol Sci. 2022;23(5):2560.
Fijalkowski K, Struk M, Karakulska J, Paszkowska A, Giedrys-Kalemba S, Masiuk H, et al. Comparative analysis of superantigen genes in Staphylococcus xylosus and Staphylococcus aureus isolates collected from a single mammary quarter of cows with mastitis. J Microbiol. 2014;52(5):366–72.
Reshamwala K, Cheung GYC, Hsieh RC, Liu R, Joo HS, Zheng Y, et al. Identification and characterization of the pathogenic potential of phenol-soluble modulin toxins in the mouse commensal Staphylococcus xylosus. Front Immunol. 2022;13:999201.
Hammer ND, Skaar EP. Molecular mechanisms of Staphylococcus aureus iron acquisition. Annu Rev Microbiol. 2011;65:129–47.
Hebert GA, Hancock GA. Synergistic hemolysis exhibited by species of staphylococci. J Clin Microbiol. 1985;22(3):409–15.
Vela J, Hildebrandt K, Metcalfe A, Rempel H, Bittman S, Topp E, et al. Characterization of Staphylococcus xylosus isolated from broiler chicken barn bioaerosol. Poult Sci. 2012;91(12):3003–12.
Cheung J, Beasley FC, Liu S, Lajoie GA, Heinrichs DE. Molecular characterization of staphyloferrin B biosynthesis in Staphylococcus aureus. Mol Microbiol. 2009;74(3):594–608.
Cotton JL, Tao J, Balibar CJ. Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A. Biochemistry. 2009;48(5):1025–35.
Cabrera G, Xiong A, Uebel M, Singh VK, Jayaswal RK. Molecular characterization of the iron-hydroxamate uptake system in Staphylococcus aureus. Appl Environ Microbiol. 2001;67(2):1001–3.
Vermassen A, de la Foye A, Loux V, Talon R, Leroy S. Transcriptomic analysis of Staphylococcus xylosus in the presence of nitrate and nitrite in meat reveals its response to nitrosative stress. Front Microbiol. 2014;5:691.
Gerber PA, Buhren BA, Schrumpf H, Homey B, Zlotnik A, Hevezi P. The top skin-associated genes: a comparative analysis of human and mouse skin transcriptomes. Biol Chem. 2014;395(6):577–91.
Zomer HD, Trentin AG. Skin wound healing in humans and mice: challenges in translational research. J Dermatol Sci. 2018;90(1):3–12.
Kamberov YG, Karlsson EK, Kamberova GL, Lieberman DE, Sabeti PC, Morgan BA, et al. A genetic basis of variation in eccrine sweat gland and hair follicle density. Proc Natl Acad Sci USA. 2015;112(32):9932–7.
Naldaiz-Gastesi N, Bahri OA, Lopez de Munain A, McCullagh KJA, Izeta A. The panniculus carnosus muscle: an evolutionary enigma at the intersection of distinct research fields. J Anat. 2018;233(3):275–88.
Liu Y, Cook C, Sedgewick AJ, Zhang S, Fassett MS, Ricardo-Gonzalez RR, et al. Single-cell profiling reveals divergent, globally patterned immune responses in murine skin inflammation. iScience. 2020;23(10):101582.
Quaresma JAS. Organization of the skin immune system and compartmentalized immune responses in infectious diseases. Clin Microbiol Rev. 2019;32(4):e00034-e118.
Cruz MS, Diamond A, Russell A, Jameson JM. Human alphabeta and gammadelta T cells in skin immunity and disease. Front Immunol. 2018;9:1304.
Sutoh Y, Mohamed RH, Kasahara M. Origin and evolution of dendritic epidermal T cells. Front Immunol. 2018;9:1059.
Toulon A, Breton L, Taylor KR, Tenenhaus M, Bhavsar D, Lanigan C, et al. A role for human skin-resident T cells in wound healing. J Exp Med. 2009;206(4):743–50.
Wang L, Kamath A, Das H, Li L, Bukowski JF. Antibacterial effect of human V gamma 2V delta 2 T cells in vivo. J Clin Investig. 2001;108(9):1349–57.
Na CH, Sharma N, Madugundu AK, Chen R, Aksit MA, Rosson GD, et al. Integrated transcriptomic and proteomic analysis of human eccrine sweat glands identifies missing and novel proteins. Mol Cell Proteom. 2019;18(7):1382–95.
Bera A, Herbert S, Jakob A, Vollmer W, Gotz F. Why are pathogenic staphylococci so lysozyme resistant? The peptidoglycan O-acetyltransferase OatA is the major determinant for lysozyme resistance of Staphylococcus aureus. Mol Microbiol. 2005;55(3):778–87.
Bera A, Biswas R, Herbert S, Gotz F. The presence of peptidoglycan O-acetyltransferase in various staphylococcal species correlates with lysozyme resistance and pathogenicity. Infect Immun. 2006;74(8):4598–604.
Klufa J, Bauer T, Hanson B, Herbold C, Starkl P, Lichtenberger B, et al. Hair eruption initiates and commensal skin microbiota aggravate adverse events of anti-EGFR therapy. Sci Transl Med. 2019;11(522):eaax2693.
Brandt SL, Putnam NE, Cassat JE, Serezani CH. Innate immunity to Staphylococcus aureus: evolving paradigms in soft tissue and invasive infections. J Immunol. 2018;200(12):3871–80.
Liu Q, Mazhar M, Miller LS. Immune and inflammatory reponses to Staphylococcus aureus skin infections. Curr Dermatol Rep. 2018;7(4):338–49.
Miller LS, Cho JS. Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol. 2011;11(8):505–18.
Wanke I, Skabytska Y, Kraft B, Peschel A, Biedermann T, Schittek B. Staphylococcus aureus skin colonization is promoted by barrier disruption and leads to local inflammation. Exp Dermatol. 2013;22(2):153–5.
Nakatsuji T, Chen TH, Two AM, Chun KA, Narala S, Geha RS, et al. Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression. J Investig Dermatol. 2016;136(11):2192–200.
Turner CT, Zeglinski MR, Richardson KC, Santacruz S, Hiroyasu S, Wang C, et al. Granzyme B contributes to barrier dysfunction in oxazolone-induced skin inflammation through E-cadherin and FLG cleavage. J Investig Dermatol. 2021;141(1):36–47.
Amar Y, Schneider E, Koberle M, Seeholzer T, Musiol S, Holge IM, et al. Microbial dysbiosis in a mouse model of atopic dermatitis mimics shifts in human microbiome and correlates with the key pro-inflammatory cytokines IL-4, IL-33 and TSLP. J Eur Acad Dermatol Venereol. 2022;36(5):705–16.
Georgel P, Crozat K, Lauth X, Makrantonaki E, Seltmann H, Sovath S, et al. A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria. Infect Immun. 2005;73(8):4512–21.
Kim Y, Lee YS, Yang JY, Lee SH, Park YY, Kweon MN. The resident pathobiont Staphylococcus xylosus in Nfkbiz-deficient skin accelerates spontaneous skin inflammation. Sci Rep. 2017;7(1):6348.
Shiina T, Konno A, Oonuma T, Kitamura H, Imaoka K, Takeda N, et al. Targeted disruption of MAIL, a nuclear IkappaB protein, leads to severe atopic dermatitis-like disease. J Biol Chem. 2004;279(53):55493–8.
Gozalo AS, Hoffmann VJ, Brinster LR, Elkins WR, Ding L, Holland SM. Spontaneous Staphylococcus xylosus infection in mice deficient in NADPH oxidase and comparison with other laboratory mouse strains. J Am Assoc Lab Anim Sci. 2010;49(4):480–6.
Jackson SH, Gallin JI, Holland SM. The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med. 1995;182(3):751–8.
Pizzolla A, Hultqvist M, Nilson B, Grimm MJ, Eneljung T, Jonsson IM, et al. Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections. J Immunol. 2012;188(10):5003–11.
Buvelot H, Posfay-Barbe KM, Linder P, Schrenzel J, Krause KH. Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease. FEMS Microbiol Rev. 2017;41(2):139–57.
Fang FC, Vazquez-Torres A. Reactive nitrogen species in host–bacterial interactions. Curr Opin Immunol. 2019;60:96–102.
Kastenmayer RJ, Fain MA, Perdue KA. A retrospective study of idiopathic ulcerative dermatitis in mice with a C57BL/6 background. J Am Assoc Lab Anim Sci. 2006;45(6):8–12.
Won YS, Kwon HJ, Oh GT, Kim BH, Lee CH, Park YH, et al. Identification of Staphylococcus xylosus isolated from C57BL/6J-Nos2(tm1Lau) mice with dermatitis. Microbiol Immunol. 2002;46(9):629–32.
Scharffetter-Kochanek K, Lu H, Norman K, van Nood N, Munoz F, Grabbe S, et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med. 1998;188(1):119–31.
Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Investig. 2010;120(5):1762–73.
Marchitto MC, Dillen CA, Liu H, Miller RJ, Archer NK, Ortines RV, et al. Clonal Vgamma6(+)Vdelta4(+) T cells promote IL-17-mediated immunity against Staphylococcus aureus skin infection. Proc Natl Acad Sci USA. 2019;116(22):10917–26.
Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30(1):108–19.
Levy R, Okada S, Beziat V, Moriya K, Liu C, Chai LY, et al. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc Natl Acad Sci USA. 2016;113(51):E8277–85.
Dillen CA, Pinsker BL, Marusina AI, Merleev AA, Farber ON, Liu H, et al. Clonally expanded gammadelta T cells protect against Staphylococcus aureus skin reinfection. J Clin Investig. 2018;128(3):1026–42.
Montgomery CP, Daniels M, Zhao F, Alegre ML, Chong AS, Daum RS. Protective immunity against recurrent Staphylococcus aureus skin infection requires antibody and interleukin-17A. Infect Immun. 2014;82(5):2125–34.
Chan LC, Chaili S, Filler SG, Miller LS, Solis NV, Wang H, et al. Innate immune memory contributes to host defense against recurrent skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus. Infect Immun. 2017;85(2):e00876-e916.
Locksley RM, Heinzel FP, Sadick MD, Holaday BJ, Gardner KD Jr. Murine cutaneous leishmaniasis: susceptibility correlates with differential expansion of helper T-cell subsets. Ann Inst Pasteur Immunol. 1987;138(5):744–9.
Acuff NV, LaGatta M, Nagy T, Watford WT. Severe dermatitis associated with spontaneous Staphylococcus xylosus infection in Rag(-/-)Tpl2(-/-) mice. Comp Med. 2017;67(4):344–9.
Bradfield JF, Wagner JE, Boivin GP, Steffen EK, Russell RJ. Epizootic fatal dermatitis in athymic nude mice due to Staphylococcus xylosus. Lab Anim Sci. 1993;43(1):111–3.
Russo M, Invernizzi A, Gobbi A, Radaelli E. Diffuse scaling dermatitis in an athymic nude mouse. Vet Pathol. 2013;50(4):722–6.
Brissette JL, Li J, Kamimura J, Lee D, Dotto GP. The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes Dev. 1996;10(17):2212–21.
Linehan JL, Harrison OJ, Han SJ, Byrd AL, Vujkovic-Cvijin I, Villarino AV, et al. Non-classical immunity controls microbiota impact on skin immunity and tissue repair. Cell. 2018;172(4):784–96.
Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell. 2013;49(5):858–71.
Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367–75.
Dunyach-Remy C, Ngba Essebe C, Sotto A, Lavigne JP. Staphylococcus aureus toxins and diabetic foot ulcers: role in pathogenesis and interest in diagnosis. Toxins (Basel). 2016;8(7):209.
Lin SY, Lin NY, Huang YY, Hsieh CC, Huang YC. Methicillin-resistant Staphylococcus aureus nasal carriage and infection among patients with diabetic foot ulcer. J Microbiol Immunol Infect. 2020;53(2):292–9.
Kim JH, Ruegger PR, Lebig EG, VanSchalkwyk S, Jeske DR, Hsiao A, et al. High levels of oxidative stress create a microenvironment that significantly decreases the diversity of the microbiota in diabetic chronic wounds and promotes biofilm formation. Front Cell Infect Microbiol. 2020;10:259.
Dejani NN, Brandt SL, Pineros A, Glosson-Byers NL, Wang S, Son YM, et al. Topical prostaglandin E analog restores defective dendritic cell-mediated Th17 host defense against methicillin-resistant Staphylococcus aureus in the skin of diabetic mice. Diabetes. 2016;65(12):3718–29.
Jacquet R, LaBauve AE, Akoolo L, Patel S, Alqarzaee AA, Wong Fok Lung T, et al. Dual gene expression analysis identifies factors associated with Staphylococcus aureus virulence in diabetic mice. Infect Immun. 2019;87(5):e00163.
Xie X, Zhong R, Luo L, Lin X, Huang L, Huang S, et al. The infection characteristics and autophagy defect of dermal macrophages in STZ-induced diabetic rats skin wound Staphylococcus aureus infection model. Immun Inflamm Dis. 2021;9(4):1428–38.
Park S, Rich J, Hanses F, Lee JC. Defects in innate immunity predispose C57BL/6J-Leprdb/Leprdb mice to infection by Staphylococcus aureus. Infect Immun. 2009;77(3):1008–14.
Farnsworth CW, Schott EM, Benvie A, Kates SL, Schwarz EM, Gill SR, et al. Exacerbated Staphylococcus aureus foot infections in obese/diabetic mice are associated with impaired germinal center reactions, Ig class switching, and humoral immunity. J Immunol. 2018;201(2):560–72.
Rich J, Lee JC. The pathogenesis of Staphylococcus aureus infection in the diabetic NOD mouse. Diabetes. 2005;54(10):2904–10.
Kot B, Piechota M, Antos-Bielska M, Zdunek E, Wolska KM, Binek T, et al. Antimicrobial resistance and genotypes of staphylococci from bovine milk and the cowshed environment. Pol J Vet Sci. 2012;15(4):741–9.
Bernier Gosselin V, Dufour S, Middleton JR. Association between species-specific staphylococcal intramammary infections and milk somatic cell score over time in dairy goats. Prev Vet Med. 2020;174:104815.
Oh WT, Jun JW, Giri SS, Yun S, Kim HJ, Kim SG, et al. Staphylococcus xylosus infection in rainbow trout (Oncorhynchus mykiss) as a primary pathogenic cause of eye protrusion and mortality. Microorganisms. 2019;7(9):330.
Cox HU, Hoskins JD, Newman SS, Foil CS, Turnwald GH, Roy AF. Temporal study of staphylococcal species on healthy dogs. Am J Vet Res. 1988;49(6):747–51.
Hariharan H, Matthew V, Fountain J, Snell A, Doherty D, King B, et al. Aerobic bacteria from mucous membranes, ear canals, and skin wounds of feral cats in Grenada, and the antimicrobial drug susceptibility of major isolates. Comp Immunol Microbiol Infect Dis. 2011;34(2):129–34.
Kloos WE, Zimmerman RJ, Smith RF. Preliminary studies on the characterization and distribution of Staphylococcus and Micrococcus species on animal skin. Appl Environ Microbiol. 1976;31(1):53–9.
Muniz IM, Penna B, Lilenbaum W. Treating animal bites: susceptibility of Staphylococci from oral mucosa of cats. Zoonoses Public Health. 2013;60(7):504–9.
Singh A, Jain R. Staphylococcus xylosus meningitis following dog bite. Indian Pediatr. 2016;53(10):931.
Thornton VB, Davis JA, St Clair MB, Cole MN. Inoculation of Staphylococcus xylosus in SJL/J mice to determine pathogenicity. Contemp Top Lab Anim Sci. 2003;42(4):49–52.
Heilmann C, Hussain M, Peters G, Gotz F. Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface. Mol Microbiol. 1997;24(5):1013–24.
Dordet-Frisoni E, Dorchies G, De Araujo C, Talon R, Leroy S. Genomic diversity in Staphylococcus xylosus. Appl Environ Microbiol. 2007;73(22):7199–209.
Tormo MA, Knecht E, Gotz F, Lasa I, Penades JR. Bap-dependent biofilm formation by pathogenic species of Staphylococcus: Evidence of horizontal gene transfer? Microbiology (Reading). 2005;151(Pt 7):2465–75.
Nemeghaire S, Vanderhaeghen W, Argudin MA, Haesebrouck F, Butaye P. Characterization of methicillin-resistant Staphylococcus sciuri isolates from industrially raised pigs, cattle and broiler chickens. J Antimicrob Chemother. 2014;69(11):2928–34.
Xu J, Tan X, Zhang X, Xia X, Sun H. The diversities of staphylococcal species, virulence and antibiotic resistance genes in the subclinical mastitis milk from a single Chinese cow herd. Microb Pathog. 2015;88:29–38.
Tesch W, Strassle A, Berger-Bachi B, O’Hara D, Reynolds P, Kayser FH. Cloning and expression of methicillin resistance from Staphylococcus epidermidis in Staphylococcus carnosus. Antimicrob Agents Chemother. 1988;32(10):1494–9.
Chanayat Y, Akatvipat A, Bender JB, Punyapornwithaya V, Meeyam T, Anukool U, et al. The SCCmec types and antimicrobial resistance among methicillin-resistant Staphylococcus species isolated from dogs with superficial pyoderma. Vet Sci. 2021;8(5):85.
Harrison EM, Paterson GK, Holden MT, Morgan FJ, Larsen AR, Petersen A, et al. A Staphylococcus xylosus isolate with a new mecC allotype. Antimicrob Agents Chemother. 2013;57(3):1524–8.
Couto I, Sanches IS, Sa-Leao R, de Lencastre H. Molecular characterization of Staphylococcus sciuri strains isolated from humans. J Clin Microbiol. 2000;38(3):1136–43.
Becker K, Ballhausen B, Kock R, Kriegeskorte A. Methicillin resistance in Staphylococcus isolates: the “mec alphabet” with specific consideration of mecC, a mec homolog associated with zoonotic S. aureus lineages. Int J Med Microbiol. 2014;304(7):794–804.
Ruiz-Ripa L, Gomez P, Alonso CA, Camacho MC, Ramiro Y, de la Puente J, et al. Frequency and characterization of antimicrobial resistance and virulence genes of coagulase-negative Staphylococci from wild birds in Spain. Detection of tst-carrying S. sciuri isolates. Microorganisms. 2020;8(9):1317.
Pinheiro L, Brito CI, de Oliveira A, Martins PY, Pereira VC, da Cunha ML. Staphylococcus epidermidis and Staphylococcus haemolyticus: molecular detection of cytotoxin and enterotoxin genes. Toxins (Basel). 2015;7(9):3688–99.
Park JY, Fox LK, Seo KS, McGuire MA, Park YH, Rurangirwa FR, et al. Detection of classical and newly described staphylococcal superantigen genes in coagulase-negative staphylococci isolated from bovine intramammary infections. Vet Microbiol. 2011;147(1–2):149–54.
Podkowik M, Park JY, Seo KS, Bystron J, Bania J. Enterotoxigenic potential of coagulase-negative staphylococci. Int J Food Microbiol. 2013;163(1):34–40.
Moraveji Z, Tabatabaei M, Shirzad Aski H, Khoshbakht R. Characterization of hemolysins of Staphylococcus strains isolated from human and bovine, southern Iran. Iran J Vet Res. 2014;15(4):326–30.
Stepanovic S, Vukovicc D, Trajkovic V, Samardzic T, Cupic M, Svabic-Vlahovic M. Possible virulence factors of Staphylococcus sciuri. FEMS Microbiol Lett. 2001;199(1):47–53.
Şeker E, Özenç E, Baki Acar D, Yılmaz M. Prevalence of methicillin resistance and panton-valentine leukocidin genes in Staphylococci isolated from pirlak sheep with subclinical mastitis in Turkey. Kocatepe Vet J. 2019;12(4):424–9.
Fijalkowski K, Peitler D, Karakulska J. Staphylococci isolated from ready-to-eat meat—identification, antibiotic resistance and toxin gene profile. Int J Food Microbiol. 2016;238:113–20.
Li H, Li X, Lu Y, Wang X, Zheng SJ. Staphylococcus sciuri exfoliative toxin C is a dimer that modulates macrophage functions. Can J Microbiol. 2011;57(9):722–9.
Valderas MW, Gatson JW, Wreyford N, Hart ME. The superoxide dismutase gene sodM is unique to Staphylococcus aureus: absence of sodM in coagulase-negative staphylococci. J Bacteriol. 2002;184(9):2465–72.
Barriere C, Bruckner R, Talon R. Characterization of the single superoxide dismutase of Staphylococcus xylosus. Appl Environ Microbiol. 2001;67(9):4096–104.
Schaeffer CR, Woods KM, Longo GM, Kiedrowski MR, Paharik AE, Buttner H, et al. Accumulation-associated protein enhances Staphylococcus epidermidis biofilm formation under dynamic conditions and is required for infection in a rat catheter model. Infect Immun. 2015;83(1):214–26.
Mehlin C, Headley CM, Klebanoff SJ. An inflammatory polypeptide complex from Staphylococcus epidermidis: isolation and characterization. J Exp Med. 1999;189(6):907–18.
Vuong C, Durr M, Carmody AB, Peschel A, Klebanoff SJ, Otto M. Regulated expression of pathogen-associated molecular pattern molecules in Staphylococcus epidermidis: quorum-sensing determines pro-inflammatory capacity and production of phenol-soluble modulins. Cell Microbiol. 2004;6(8):753–9.
Yao Y, Sturdevant DE, Otto M. Genomewide analysis of gene expression in Staphylococcus epidermidis biofilms: insights into the pathophysiology of S. epidermidis biofilms and the role of phenol-soluble modulins in formation of biofilms. J Infect Dis. 2005;191(2):289–98.
Fergestad ME, Touzain F, De Vliegher S, De Visscher A, Thiry D, Ngassam Tchamba C, et al. Whole genome sequencing of Staphylococci isolated from bovine milk samples. Front Microbiol. 2021;12:715851.
This work was supported by a Grant from the National Institute of Allergy and Infectious Disease (NIAID R01 AI122720).
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Battaglia, M., Garrett-Sinha, L.A. Staphylococcus xylosus and Staphylococcus aureus as commensals and pathogens on murine skin. Lab Anim Res 39, 18 (2023). https://doi.org/10.1186/s42826-023-00169-0