Introduction
Staphylococcus aureus has been a serious threat to human health throughout history and was one of the first bacterial pathogens to be identified. It was the ability of
S. aureus to cause disease that led to its first description in human pus over 130 years ago by Sir Alexander Ogston [
1,
2]. Since then,
S. aureus has proven itself well adapted for interaction with humans and is currently a leading cause of human bacterial disease worldwide [
3]. For example,
S. aureus has been reported as the leading cause of bacterial infections involving bloodstream, lower respiratory tract, and skin and soft tissue in many industrialized countries including the United States, Canada, Europe, Latin America, and the Western Pacific [
3].
S. aureus is also the most abundant cause of hospital-associated infections in the United States [
4‐
6]. Correspondingly, this large number of infections creates a significant financial burden, making detrimental impacts on public health systems around the world [
6]. With approximately half a million people acquiring staphylococcal infections in the USA per year, the cost of
S. aureus healthcare-associated infections was estimated to exceed 14 billion dollars in 2003 [
7,
8]. Interestingly, this versatile pathogen is considered a human commensal microbe, as it asymptomatically colonizes the anterior nares of ∼30% of non-institutionalized individuals [
9]. Yet given the opportunity,
S. aureus has the unique ability to cause a wide range of infections and syndromes, including skin and soft tissue infections, food borne illness, toxic shock syndrome, bacteremia, sepsis, endocarditis, osteomyelitis, necrotizing fasciitis, and pneumonia. An armament of well-studied virulence factors, ranging from secreted toxins to immune evasion molecules, lends
S. aureus effective at causing disease [
10]. In addition, the rise in occurrence and severity of infections over the last 70 years has been attributed to the evolution of highly virulent, drug-resistant strains that now challenge our ability to treat such infections. Further, there has been a recent increase in the burden of antibiotic-resistant
S. aureus within the community setting [
11,
12]. These community-associated methicillin-resistant
S. aureus (CA-MRSA) strains have an enhanced virulence potential, in that they are able to cause a wide range of disease in otherwise healthy individuals, drastically changing previous clinical epidemiology of methicillin-resistant
S. aureus (MRSA) [
13]. The enhanced virulence potential is related in part to the ability of these strains to circumvent killing by human polymorphonuclear leukocytes (PMNs or neutrophils), the most prominent cellular host defense against invading microorganisms.
This article will provide a brief history of the rise of highly-virulent, drug-resistant S. aureus strains, an overview of the role of neutrophils in host defense, and review immune evasion strategies employed by S. aureus to circumvent neutrophil function, including strategies yielding the enhanced virulence of CA-MRSA strains.
S. aureus and antibiotics: a brief history
S. aureus is notoriously adept at acquiring resistance to antibiotics, owing to much of the pathogen’s recent success [
11,
14]. Inasmuch as the development and widespread clinical use of penicillin in the early 1940s marked the beginning of the “antibiotic era,” reports of
S. aureus strains harboring resistance to penicillin by 1942 marked the beginning of our critical, ongoing battle against antibiotic resistance [
15]. Thereafter, the prevalence of penicillin-resistant
S. aureus (PRSA) increased dramatically in nosocomial settings, with the increase being attributed completely to the use of penicillin [
16‐
18]. Increases in the number of PRSA infections lead to the inefficacy of penicillin treatment within 10 years of the miracle drug’s introduction, necessitating the development of alternative treatments [
17,
19]. Likewise, the introduction of methicillin—a β-lactam antibiotic developed for treatment of PRSA infections—in 1959 quickly led to the onset of a second “epidemic wave” of antibiotic resistance, as infections caused by methicillin-resistant strains were reported 2 years later in 1961 [
17,
20,
21]. Thereafter, MRSA became endemic to hospitals and health care facilities worldwide, leading to the global MRSA pandemic in health care settings that continues today [
3,
17,
22]. A high percentage of hospital-associated
S. aureus infections in the USA are caused by MRSA [
7,
23,
24]. Notably, invasive MRSA infections are considered a major cause of human mortality in the USA—there were approximately 19,000 deaths in the USA in 2005 and the mortality rate for invasive MRSA infections was reported as 20% [
5]. In the USA, MRSA is likely the leading cause of death by any single infectious agent, with fatalities from MRSA infection estimated to surpass those caused by HIV/AIDS [
5,
25]. Antibiotic use within the nosocomial setting has created high selective pressure for development of antibiotic resistance, and
S. aureus has acquired resistance to virtually all antibiotics [
14,
26]. Multidrug-resistant MRSA strains, which combine resistance to β-lactam antibiotics with resistance to other classes of antibiotics, are becoming increasingly frequent in the healthcare setting, representing a major concern for treatment of MRSA infections [
11]. Taken together, the high occurrence of infections caused by drug-resistant
S. aureus is problematic and demonstrates the urgent need for development of novel treatment strategies.
The majority of infections caused by MRSA have historically been hospital-associated, occurring in immunocompromised individuals or in patients with pre-disposing risk factors, such as surgery, surgical incisions, the presence of indwelling medical devices, or pre-existing infections [
6,
27‐
29]. However, MRSA epidemiology changed in the 1990s with reports of infections caused by strains of MRSA occurring outside of the healthcare setting in otherwise healthy individuals, the first reports of bona fide CA-MRSA infections [
12,
29]. CA-MRSA also spread rapidly among diverse groups of healthy individuals, demonstrating an enhanced transmissibility and/or ability to colonize, in addition to being highly virulent [
11,
18,
30‐
41]. CA-MRSA infections have been reported in regions all over the world, including Asia, Australia, Canada, Europe, South America, and the USA, rapidly reaching pandemic proportions [
42‐
51]. The epidemic spread of CA-MRSA in the USA has led to an overall increase in the burden of MRSA [
52]. Concomitant increases in staphylococcal burden have been observed worldwide since the emergence of CA-MRSA [
51,
53‐
55]. The majority of infections caused by CA-MRSA present as skin and soft tissue infections (∼90%) and most are abscesses or cellulitis with purulent drainage [
52,
53,
55‐
57]. However, the most prominent CA-MRSA strains also have a proven ability to cause severe invasive diseases such as necrotizing fasciitis and necrotizing pneumonia, rarely seen before the rise of CA-MRSA [
17,
29,
58‐
63]. Although invasive infections associated with CA-MRSA are relatively infrequent, they accounted for 14% of all invasive MRSA-associated fatalities in the USA in 2005 [
5]. Predominant CA-MRSA strains such as pulsed-field gel electrophoresis (PFGE) types USA300 and USA400 are genetically distinct from traditional HA-MRSA strains in part because they contain a unique staphylococcal cassette chromosome (SCC)
mec element (SCC
mec type IV) [
17,
64‐
68]. In contrast to larger SCC
mec elements that encode resistance to multiple antibiotics, SCC
mec type IV provides resistance to solely β-lactam antibiotics with apparently little or no fitness cost to the pathogen, likely contributing to the success of CA-MRSA strains [
17,
64‐
68]. Other genetic and molecular factors are associated with the unique ability of CA-MRSA strains to disseminate rapidly and cause disease in otherwise healthy individuals. These factors will be discussed in further detail below.
The ability of
S. aureus to cause disease has fueled much research effort aimed at understanding the intricacies of interaction between
S. aureus and host immune cells. This has resulted in the description of multiple, redundant strategies employed by
S. aureus to evade and/or combat host immune response mechanisms. Many of these strategies serve to protect/defend the microbe against primary interaction with the innate immune response, which includes interaction with neutrophils. As the major cellular component of the innate immune system, neutrophils serve as the critical, primary defense against invading organisms, providing a rapid, non-specific, and potent response to infectious challenge. Defects in neutrophil function result in serious immune deficiencies and syndromes and are associated with recurrent and often fatal
S. aureus disease [
69,
70]. Thus, there is no question that neutrophils are critical for defense against
S. aureus infections. On the other hand,
S. aureus—especially CA-MRSA—have the demonstrated ability to circumvent killing by human neutrophils, and can ultimately cause rapid destruction of these important host cells [
71,
72]. This unique ability is linked to the enhanced virulence of these strains and their capacity to cause disease [
13]. Understanding the complex interaction between
S. aureus and human neutrophils is critical to understanding the ability of
S. aureus to cause disease.
S. aureus immune evasion mechanisms
Many pathogens, including
S. aureus, have a long history of interaction with the human innate immune system. Therefore, it is not surprising that many pathogens have evolved mechanisms to evade and combat this important front line of host defense.
S. aureus has evolved an abundant repertoire of factors aimed at evasion of the innate system, including host defense strategies utilized by neutrophils. There exists significant redundancy in the numerous mechanisms employed by
S. aureus against the innate immune system, reflecting the importance of such defenses and their role in the outcome of infection.
S. aureus factors characterized to date include those that prevent recognition and binding of the pathogen by neutrophils, as well as those that provide protection against intracellular/phagosomal microbicides [
10]. In addition to passive defense mechanisms,
S. aureus secretes several cytotoxic molecules that have the ability to damage immune cells [
10].
S. aureus attempts to minimize or inhibit recognition by the host by hiding and/or modifying the bacterial surface. This is afforded by production of exopolymers such as capsular polysaccharide forming the bacterial capsule and/or polysaccharide intercellular adhesion, a unique extracellular matrix biofilm component that serves to modify the typical negative charge of the bacterial outer surface [
241‐
244]. Additionally, the well-known protein A, which binds the Fc region of IgG, lends the ability to coat the bacterial surface with non-specific antibodies (in the wrong orientation), providing immunologic disguise and potentially disrupting opsonization and phagocytic uptake [
245,
246]. Chemotaxis inhibitory protein of
S. aureus and staphylococcal complement inhibitor block receptor mediated recognition of N-formyl peptides produced by bacteria and complement-mediated uptake, respectively [
247,
248]. Curiously, despite the numerous mechanisms employed by
S. aureus to inhibit binding and phagocytosis by neutrophils, these phagocytes rapidly take up the pathogen.
Protection against host oxygen-dependent microbicidal killing mechanisms is in part provided by catalase and superoxide dismutase, which eliminate harmful ROS produced within the phagosome following ingestion [
13]. Staphyloxanthin is a golden pigment produced by
S. aureus and has also been shown to play a protective role against ROS [
249]. Mechanisms also exist for bacterial defense against oxygen-independent killing mechanisms, including those mediated by AMPs. In addition to releasing non-specific proteases [
250],
S. aureus senses the presence of AMPs via a three-component gene-regulatory system, which regulates downstream bacterial responses including the
d-alanylation of teichoic acids and incorporation of lysyl-phosphatidyl glycerol in the plasma membrane, thereby decreasing overall negative charge of the bacterial surface [
251‐
254]. These surface modifications reduce the efficiency of the binding of cationic AMPs to the bacterial surface. Furthermore, the VraFG transporter is responsible for the removal of AMPs from the cytoplasm or plasma membrane [
251,
252]. In addition to these rather passive defense mechanisms,
S. aureus produces a number of toxins that directly attack white and red blood cells. Such toxins include a family of leukocidins, α-toxin (α-hemolysin), and the recently described PSMs. These molecules have the ability to form pores in target cell membranes [
152,
255]. Lastly, several types of secreted
S. aureus toxins are also classified as superantigens, taking the strategy of overstimulating the immune response to potentiate undesired responses and cause disease [
256,
257]. Examples of superantigenic toxins include TSST and staphylococcal enterotoxins [
257].
It is evident that apoptosis plays a major role in the resolution of the acute inflammatory response, likely having an impact on the outcome of disease. That being said, some pathogens have also devised means to modulate normal turnover and apoptosis of neutrophils, leading to alterations in the desired resolution of infection [
226] (Fig.
2). Although the short life-span of neutrophils is not conducive to the long-term survival strategies employed by many intracellular pathogens,
Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, has the ability to delay neutrophil apoptosis, supporting replication and survival of the pathogen within an endosomal compartment [
189,
226,
258]. On the other hand,
S. aureus, especially CA-MRSA strains, have the remarkable ability to induce rapid lysis of neutrophils and/or accelerate PICD to the point of secondary lysis, potentiating undesired release of neutrophil contents and pathogen survival [
71,
72,
102,
226]. In either case, modulation of the normal turnover process results in pathogen survival, promotion of pathogenesis, and likely dissemination and disease (Fig.
2).
Community MRSA virulence and evasion of killing by neutrophils
The increased virulence of CA-MRSA strains was initially inferred from (a) the ability of these strains to cause disease in otherwise healthy individuals, (b) the ability of these strains to cause unusually severe disease, and (c) their ability to spread rapidly among groups of individuals. Corroborating the epidemiologic data, experimental data have demonstrated conclusively that CA-MRSA strains are more virulent than representative HA-MRSA strains in animal models of infection [
71,
72]. Increased virulence is attributed largely to an enhanced capacity of CA-MRSA strains to resist killing by neutrophils, compared to HA-MRSA strains [
72]. Survival of CA-MRSA strains in in vitro assays with human neutrophils leads to rapid lysis of these host cells, and release and ultimate growth of bacteria [
72,
259]. This follows with the idea that increased virulence lies, at least in part, in the enhanced ability to alter normal neutrophil function and turnover.
Early distinction of CA-MRSA strains from traditional HA-MRSA strains, which included differences in PFGE typing and antibiotic resistance profiles, suggested that CA-MRSA strains were not merely hospital strains that had escaped into the community. Therefore, efforts to understand the molecular basis of the enhanced virulence of CA-MRSA strains have since focused on identifying additional genotypic and phenotypic differences between CA-MRSA and traditional HA-MRSA strains. Although significant progress has been made in understanding components that contribute to the success of CA-MRSA, a complete understanding is complicated by the multi-factorial approach to virulence that is intrinsic to S. aureus. That is, no single virulence factor contributes exclusively, making it difficult to determine contributions made by individual components that have overlapping or redundant functions. Despite this obstacle, several S. aureus virulence determinants are implicated in the success of CA-MRSA.
Alpha (α)-toxin (also known as Hla or α-hemolysin) is a widely studied pore-forming toxin capable of destroying a variety of host cells, including epithelial cells, erythrocytes, fibroblasts, monocytes, macrophages, and lymphocytes (but not neutrophils), and has long been considered a major virulence determinant of
S. aureus [
260,
261]. Although it is ubiquitous among clinical isolates, recent studies have clearly demonstrated a primary role for α-toxin in experimental CA-MRSA infections. CA-MRSA strains lacking α-toxin were avirulent in a murine pneumonia model of infection compared with isogenic wild-type strains, and active and passive immunization against α-toxin provided animals protection from death in the same model [
262,
263]. Mechanistically, α-toxin elicits a host chemokine response in the murine pneumonia model, promoting an influx of neutrophils thought to be largely responsible for lung injury during infection [
264]. Importantly, the amount of α-toxin produced by CA-MRSA
in vitro correlates with the severity of lung disease observed in such animal models [
262,
265,
266]. The role of α-toxin has also been demonstrated in murine and rabbit models of CA-MRSA skin infection, providing further evidence that α-toxin plays a major role in CA-MRSA disease [
267,
268].
α-Type phenol-soluble modulins (α-PSMs) are a subset of recently reported PSMs [
152]. These molecules are surfactant-like, amphipathic, α-helical peptides (∼20–25 aa in length) with limited homology to PSMs produced in other staphylococcal species including
Staphylococcus epidermidis [
152]. The α-PSMs are ubiquitous to all sequenced
S. aureus strains, have the ability to induce neutrophil chemotaxis and cytokine release through a specific receptor-mediated process, and also have the ability to lyse neutrophils, erythrocytes, and monocytes via a receptor-independent process [
152]. Isogenic mutant CA-MRSA strains that lack α-PSMs have significantly reduced virulence in murine bacteremia and skin infection models compared to wild-type parental strains, indicating they are major determinants of CA-MRSA virulence [
152]. Notably, in vitro production of α-PSMs by CA-MRSA strains is significantly higher than that of prominent HA-MRSA strains. Additionally, overexpression of α-PSMs in a representative HA-MRSA strain increases cytotoxic capacity of culture supernatants to a level comparable to that observed with CA-MRSA culture supernatants, indicating that the difference in cytolytic capacity between CA-MRSA and HA-MRSA strains is largely due to differential production of α-PSMs [
152]. However, the contribution of α-PSMs to neutrophil lysis following phagocytosis remains to be determined. Production of α-PSMs is regulated in part by the accessory gene regulator (
agr), a well-known, global regulatory/quorum sensing system. α-Toxin and α-PSMs are both encoded in the core genome, as opposed to mobile genetic elements (MGEs), which encode many other
S. aureus virulence molecules. Recent analysis of gene expression within subclones of
S. aureus clonal complex 8 (defined by MLST), including USA300 and other closely related strains, revealed that USA300 has increased expression of core-genome encoded virulence factors such as α-toxin and α-PSMs, lending to the novel idea that enhanced virulence is based largely on differential expression of core-genome elements rather than strictly acquisition of MGEs [
269]. Differential expression of core-genome determinants is likely due to poorly understood rearrangements of gene regulatory networks in these strains.
It is likely that the extraordinary success of CA-MRSA also involves unique genetic factors that facilitate colonization and transmissibility. Although such factors may not contribute directly to virulence, they may be important for the overall burden of disease, as seen with the rapid dissemination of CA-MRSA among groups of individuals. One such factor is the type-I arginine catabolic mobile element (ACME), an MGE unique to USA300, identified by whole genome sequencing [
270]. This 31-kb MGE is physically linked to the SCC
mec type IV element and may have been acquired from
S. epidermidis [
67,
270]. ACME encodes two gene clusters, one encoding a complete arginine deiminase (
arc) pathway, and the other an oligopeptide permease operon. Arginine deiminase activity produces ammonia and ATP and might facilitate colonization by neutralizing the acidic environment found on skin as well as producing an additional source of ATP [
67]. In addition, depletion of the arginine pool may serve to prevent efficient production of nitric oxide, a key immune molecule [
271]. Oligopeptide permeases are usually involved in peptide uptake as a nutrient source, although they are also implicated in other functions such as quorum sensing, chemotaxis, cell adhesion, and resistance to AMPs [
270]. Experimental models of infection have demonstrated either no impact or a limited impact of ACME on virulence [
67,
272]. Although a function related to enhanced colonization and/or persistence on human skin, leading to increased transmissibility, has been inferred from the putative functions of genes found within ACME, the physiologic function of these gene clusters in the context of CA-MRSA pathogenesis remains to be determined. This will require experimental colonization models to directly assess any role ACME may play in the colonization, persistence, and/or transmissibility of CA-MRSA.
Panton–Valentine leukocidin (PVL) is a bi-component cytolytic toxin encoded on a prophage acquired by horizontal gene transfer [
273]. PVL has the ability to prime neutrophils, induce proinflammatory responses such as cytokine release, and has long been known, at higher concentrations, to lyse leukocytes by forming pores in target-cell membranes [
42,
274‐
279]. PVL genes are present in many strains that cause CA-MRSA infections, and the toxin is associated with
S. aureus strains that cause certain types of severe skin infections (e.g., furuncles and carbuncles) and necrotizing pneumonia [
42,
280‐
282]. It is noteworthy that PVL was also present in the pandemic phage-type 80/81 clone, which caused severe infections in hospitals and the community in the 1950s and 1960s [
283]. Therefore, elucidating the role for PVL (if any) in the success of CA-MRSA has been of great interest and remains a hotly debated topic in light of many experimental studies, some of which are conflicting. Numerous animal models of infection have been utilized to investigate PVL’s contribution during CA-MRSA infections including murine, rat, rabbit, and non-human primate models of skin infection, bacteremia, and pneumonia [
11‐
13,
17]. Generally, findings from studies to date indicate that PVL makes little or no unique contribution to the virulence of CA-MRSA, but may contribute in specific contexts resulting in severe diseases or syndromes [
12,
71,
284‐
288]. Due to that fact that PVL production is sensitive to environmental conditions (e.g., growth media) and is strain dependent, as well as the fact that the susceptibility of white blood cells to PVL differs among mammalian species, it is not surprising that conflicting findings have been reported [
289,
290]. Recently Kobayashi et al. investigated the role of PVL in a novel rabbit subcutaneous skin infection model, reporting that a USA300 wild-type and isogenic lukS/F-PV deletion strains produced similar abscesses, whereas deletion of genes encoding other well-established virulence determinants—α-toxin, α-PSMs, and Agr—decreased abscess formation [
267]. Concurrently, a rabbit intradermal skin infection model was published using similar strains, but these authors reported a role for PVL in pathogenesis of
S. aureus skin infection [
291]. These seemingly contradictory findings highlight the possibility that PVL functions in specific experimental contexts, and emphasizes the need for careful interpretation and comparison among experimental models used. Taken together, evidence to date indicates that PVL is not a major virulence determinant of CA-MRSA, but is simply one of many
S. aureus secreted molecules that can contribute to infection.
A recent surface proteome study of USA300 identified an abundant, novel two-component leukotoxin, LukGH, related to other two-component toxins of
S. aureus such as PVL [
292]. LukGH is localized to the cell surface and is secreted into culture medium. Importantly, LukGH has potent cytolytic activity toward neutrophils, acts synergistically with PVL to cause neutrophil lysis in vitro, and is highly expressed during phagocytosis. These results suggest LukGH contributes to USA300 virulence [
292]. Further investigation is required to demonstrate a physiologic role for LukGH in the ability to cause disease.
Neutrophil defects and S. aureus infections
Acquired and congenital defects of the immune system are associated with an increased susceptibility to infectious disease. Description of numerous primary immunodeficiency diseases (PIDs), defined here as a genetically determined disorder resulting in an enhanced susceptibility to infectious disease, has served to bolster the importance of many human immune functions, including the role of neutrophils in defense against bacterial pathogens such as
S. aureus [
209,
293‐
295]. PIDs are broadly classified based on their underlying molecular defect and include deficiencies in humoral immunity (B lymphocytes, antibodies), cell-mediated immunity (T cell-mediated), combined humoral and cell-mediated immunity, and non-specific host defense (phagocytes, natural killer cells, complement pathway). PIDs characteristically present in childhood with persistent, recurrent, and difficult to treat infections. Importantly, pathogen susceptibility patterns, sites of infection, and complications of infection are known to vary according to immune deficit, and are major considerations made during diagnosis [
293,
295]. Each class of primary immunodeficiency has a characteristic set of infectious predispositions that are often employed to guide initial diagnostic testing [
293]. Defects in T cell function are generally associated with infections caused by viruses and
Candida species, whereas patients with primary phagocyte defects yield an increased susceptibility to specific bacterial and fungal infections [
209]. In some cases, pathogen susceptibility points to the specific disorder; susceptibility to intracellular pathogens such as mycobacteria,
Salmonella, and
Listeria is suggestive of a defect in the interferon-γ−interleukin-12 signaling axis [
209], while infections caused by
S. aureus and
Aspergillus species predominate among patients with CGD [
293].
Several PIDs have been described for a range of underlying primary neutrophil defects, including functional defects in neutrophil adhesion, chemotaxis, phagocytosis, vesicle trafficking, NADPH oxidase assembly/function, MPO deficiency, glucose/glycogen metabolism, signal transduction, and granular defects [
70]. Many of these defects are closely associated with increased susceptibility to
S. aureus infections, and often result in life-threatening and/or fatal complications. Severe congenital neutropenia (SCN) is associated with mutations from two different genes; mutation in HAX1, a mitochondrial protein thought to have an anti-apoptotic role, is associated with an autosomal dominant form of SCN, while mutation of ELA2, the gene encoding elastase 2, is associated with an autosomal recessive SCD resulting from endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and apoptosis [
70]. Infectious complications arising in SCN patients include cellulitis, perirectal abscesses, peritonitis, stomatitis, and meningitis commonly resulting from infections caused by
S. aureus and
Pseudomonas aeruginosa [
209,
296]. Leukocyte adhesion deficiency types 1 and 2 (LAD1 and 2) are caused by defects in adhesion molecules such as CD18 (β
2 integrin; LAD1) or an inability to fucosylate glycoproteins acting as ligands for E-selectins (LAD2), respectively [
209,
293,
295]. As a result of their inability to make initial attachment, or adhere tightly to endothelial cells, neutrophils are unable to egress from the vasculature to sites of infection [
209,
293]. Clinical manifestations include delayed separation of the umbilical cord, poor wound healing, recurrent skin and soft-tissue infections, genital mucosa infections, intestinal and respiratory tract infections, and severe periodontitis. Infecting pathogens include
S. aureus, Gram-negative enteric bacteria,
Candida species, and
Aspergillus species [
209]. Chédiak–Higashi syndrome is a disorder caused by mutations that affect the lysosomal transport protein LYST, and thus prevents normal phagolysosome formation and granule fusion [
209,
293,
295]. This syndrome is partly characterized by recurrent, severe
S. aureus infections. Other neutrophil disorders associated with
S. aureus infections include neutrophil-specific granule deficiency and hyper-IgE syndrome (Job’s syndrome) [
209,
293]. Importantly, some of these neutrophil disorders may involve defects in regulation of neutrophil apoptosis and/or turnover. Taken together, neutrophil function plays a major role in clearance of invading bacterial pathogens such as
S. aureus
.
Summary and outlook
S. aureus remains a major cause of human infections, and the rise of highly virulent, drug-resistant strains has made treatment increasingly difficult. As a result, the overall burden of disease has increased within both the hospital and community settings, emphasizing the need for alternative therapeutic approaches. Although progress has been made toward understanding mechanisms used by S. aureus to evade innate host defenses, especially those involving neutrophils, our knowledge in this area is incomplete. The ability of S. aureus to evade primary host defenses plays a major role in the outcome of infection, as evidenced by the enhanced ability of CA-MRSA to evade and combat innate immunity and ultimately destroy neutrophils. This process likely contributes to the enhanced virulence of prominent CA-MRSA strains and their capacity to cause severe disease in otherwise healthy individuals. Therefore, a comprehensive understanding of the interface between innate host defense and S. aureus is needed to identify alternative therapeutic approaches. Underlying host genetic factors are likely important determinants of susceptibility to severe disease and must also be considered for development of alternative treatments.
Renewed efforts—fueled by the rise of antibiotic-resistant strains—to develop vaccines that promote opsonophagocytosis of
S. aureus have not been successful. The problem is twofold. First,
S. aureus opsonized in normal human serum is readily phagocytosed by human neutrophils and there is no need to improve efficiency of uptake, which is the primary purpose of opsonophagocytic vaccines. Second,
S. aureus, especially CA-MRSA, causes lysis of neutrophils following phagocytosis [
297,
298]. This is a significant problem because, as stated above, neutrophils are the most prominent cellular defense against
S. aureus infections. Ideally, a therapeutic maneuver would enhance the killing capacity of neutrophils after uptake of the pathogen or render
S. aureus incapable of defending itself against microbicides produced by neutrophils. Novel approaches to target virulence as a means of attenuating disease are underway and include strategies such as passive immunization with antibodies against main virulence determinants of
S. aureus [
299]. Some potential targets have been provided by identification of virulence determinants of CA-MRSA, including α-toxin and α-PSMs. For example, passive immunization with anti-α-toxin antibodies provides protection against lethal pneumonia in a murine model of infection, demonstrating the potential utility of such therapy as an adjunct to antibiotic administration [
263]. However, much functional redundancy exists among the numerous
S. aureus virulence determinants, requiring a combinatorial therapeutic approach that includes targeting the most important virulence determinants. Therefore, elucidation of the contribution of host factors, as well as the major bacterial virulence determinants, to the development of severe disease is of major interest to future research.