**2. Overview of staphylococcal infection**

#### **2.1. The staphylococci**

Bacteria in the genus *Staphylococcus* are referred to Gram-positive spherical bacteria that widely affect man and other mammals. The bacteria are about 0.5–1.0 μm in diameter and grow in clusters, pairs, and occasionally in short chains. Staphylococci are divided into two groups based on their ability to clot blood plasma. The coagulase-positive staphylococci constitute the most pathogenic species *Staphylococcus aureus*. The coagulase-negative staphylococci (CNS) comprise over 30 other species, most of which are commensals of skin without causing infections. However, the incidence of infections of *Staphylococcus epidermidis*and other CNS has currently been rising. Among the known staphylococci, *S. aureus* is the most important human pathogen and causes a wide range of clinical infections [1]. It colonizes mainly the nasal passages, but also the other anatomical locales, such as skin, oral cavity, and gastrointestinal tract. Critically, *S. aureus* has been proved to be one of the most prevalent organisms in male and female genital tract, and its implication in the pathogenesis of reproductive diseases and infertility has attracted increasing attention [2]. In addition, the CNS stains such as *S. epider‐ midis* and *Staphylococcus haemolyticus* are also listed as the bacteria that can occupy and associated with male infertility.

#### **2.2. The pathogenesis of** *Staphylococcus aureus*

*S. aureus* is the leading cause of bacterial infections affecting an enormous population world‐ wide. By invading the bloodstream, lower respiratory tract, and skin and soft tissue, *S. aureus* can potentially cause some of the most severe hospital-associated and communityacquired illnesses. *S. aureus* produces a myriad of virulence factors that allow the organism to gain entry into tissues, attach to host cells, and secret exoproteins and toxins. The known virulence factors include lipoteichioic acid (LTA), toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin A (SEA), and staphylococcal enterotoxin B. In addition, *S. aureus* expresses a cohort of special factors that indirectly exert pathogenic effects through interfering with host defense mechanisms. This category involves capsular polysaccharide, protein A, and leukocidin. The classical Panton and Valentine (PV) leukocidin is considered as a contributing factor for necrotizing skin infections due to its leukotoxic activity [3]. Recently, a novel strategy was invented whereby *S. aureus* successfully escapes neutrophil-mediated defensive machi‐ nery and establishes its invasion and infection. In this case, *S. aureus* secretes the nuclease and adenosine synthase to convert neutrophil extracellular traps (NETs) to deoxyadenosine, which triggers the caspase-3-triggered death of immune cells [4].

#### **2.3. The host defense against staphylococcal infection**

Neutrophils represent the host's first line of defense against invasion by *S. aureus* and a critical determinant in the outcome of staphylococcal infections. Following the uptake of bacteria, neutrophils typically undergo accelerated apoptosis and are cleared by macrophages through efferocytosis. This process results in eradication of the microbe and recovery of inflammation. The pathogen recognition pattern receptor, toll-like receptor (TLR2), is proved to be the dominant receptor for *S. aureus*. TLR2 on the surface of innate immune cells recognizes the components of the bacterial cell wall such as teichoic acid, LTA, and PGN-embedded lipo‐ peptides [5]. TLR2 then dimerizes with either TLR1 or TLR6 and recruits the adaptor proteins, such as TIRAP and MyD88, and the serine/threonine kinases IRAK-1 and IRAK-4 to initiate the subsequent signaling. The signaling cascade ultimately leads to the activation of the transcription factor nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), which promotes the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-12p70 and chemokines such as (C-C motif) ligand (CCL)2, CCL3, and CCL4. Besides TLR2, C-type lecin receptors (CLRs) can also bind to surface sugars of *S. aureus* and enhance the phagocytic ability of antigen-presenting cells (APCs) [6]. The cytokines and chemokines released by the innate immune cells and/or the infected tissue cells have important roles in combating infection of *S. aureus*. They can recruit the innate immune cells to site of infection and activate the immune cells to phagocytose and kill the microbes. However, the extensive infiltration of inflammatory cells and the copious secretion of proinflammatory mediators may also cause tissue damage and immunopathology if the inflammation is unresolved.

When innate immune mechanisms are not sufficient to clear the bacterial infection, an adaptive immunity against *S. aureus*, such as T helper (Th)1 and Th17, and humoral antibody responses, might be required [7]. The production of IL-1 and IL-17A, upon activation of Th1 or Th17 cells, is presumably conductive to the abscess formation at site of infection. Abscessification is regarded as a hallmark of *S. aureus* infections and is essential for the clearance of bacteria through phagocytosis and oxidative burst. On the other hand, Th1 response during *S. aureus* infections is frequently associated with the activity of staphylococcal superantigens (SAgs). For example, TSS has been found to activate roughly 20% of T cells and trigger massive proliferation of T cells and production of cytokines [8]. A strong proinflammatory/Th1 response was also ascribed to the effect of SEA, which is another staphylococcal SAg.

#### **2.4. Clinical manifestations of staphylococcal infection**

**2. Overview of staphylococcal infection**

Bacteria in the genus *Staphylococcus* are referred to Gram-positive spherical bacteria that widely affect man and other mammals. The bacteria are about 0.5–1.0 μm in diameter and grow in clusters, pairs, and occasionally in short chains. Staphylococci are divided into two groups based on their ability to clot blood plasma. The coagulase-positive staphylococci constitute the most pathogenic species *Staphylococcus aureus*. The coagulase-negative staphylococci (CNS) comprise over 30 other species, most of which are commensals of skin without causing infections. However, the incidence of infections of *Staphylococcus epidermidis*and other CNS has currently been rising. Among the known staphylococci, *S. aureus* is the most important human pathogen and causes a wide range of clinical infections [1]. It colonizes mainly the nasal passages, but also the other anatomical locales, such as skin, oral cavity, and gastrointestinal tract. Critically, *S. aureus* has been proved to be one of the most prevalent organisms in male and female genital tract, and its implication in the pathogenesis of reproductive diseases and infertility has attracted increasing attention [2]. In addition, the CNS stains such as *S. epider‐ midis* and *Staphylococcus haemolyticus* are also listed as the bacteria that can occupy and

*S. aureus* is the leading cause of bacterial infections affecting an enormous population world‐ wide. By invading the bloodstream, lower respiratory tract, and skin and soft tissue, *S. aureus* can potentially cause some of the most severe hospital-associated and communityacquired illnesses. *S. aureus* produces a myriad of virulence factors that allow the organism to gain entry into tissues, attach to host cells, and secret exoproteins and toxins. The known virulence factors include lipoteichioic acid (LTA), toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin A (SEA), and staphylococcal enterotoxin B. In addition, *S. aureus* expresses a cohort of special factors that indirectly exert pathogenic effects through interfering with host defense mechanisms. This category involves capsular polysaccharide, protein A, and leukocidin. The classical Panton and Valentine (PV) leukocidin is considered as a contributing factor for necrotizing skin infections due to its leukotoxic activity [3]. Recently, a novel strategy was invented whereby *S. aureus* successfully escapes neutrophil-mediated defensive machi‐ nery and establishes its invasion and infection. In this case, *S. aureus* secretes the nuclease and adenosine synthase to convert neutrophil extracellular traps (NETs) to deoxyadenosine, which

Neutrophils represent the host's first line of defense against invasion by *S. aureus* and a critical determinant in the outcome of staphylococcal infections. Following the uptake of bacteria, neutrophils typically undergo accelerated apoptosis and are cleared by macrophages through efferocytosis. This process results in eradication of the microbe and recovery of inflammation.

**2.1. The staphylococci**

160 Genital Infections and Infertility

associated with male infertility.

**2.2. The pathogenesis of** *Staphylococcus aureus*

triggers the caspase-3-triggered death of immune cells [4].

**2.3. The host defense against staphylococcal infection**

Manifestations of staphylococcal infections usually depend on the type of infection, the site, the route, and the microbial dose. Common types of infections include skin infections (e.g. folliculitis, furuncles, impetigo, wound infections, and scalded skin syndrome), soft-tissue infections (e.g. pyomyositis, septic bursitis, and septic arthritis), toxic shock syndrome, purpura fulminans, endocarditis, osteomyelitis, pneumonia, food poisoning, and urinary tract infection [1, 9]. Despite associated with such a wide spectrum of clinical manifestations, *S. aureus* is still a commensal bacterium. Approximately 30% of the human population is colonized with this microbe [10]. However, with a growing number of health care–associated and antibiotic-resistant strain–driven infections, the pathogenic staphylococcal infection has significantly increased during the past two decades. In particular, the dramatic rising of antibiotic-resistant strains has become a serious threat to public health. The term MRSA refers to methicillin-resistant *S. aureus* with the potential to resist all β-lactam antibiotics such as penicillins and cephalosporins. Resistance is usually conferred by the acquisition of a nonnative gene encoding a penicillin-binding protein (PBP2a) that has significantly lower affinity for β-lactams [11]. In addition to MRSA, the vancomycin-intermediate/resistant *S. aureus* (VISA/VRSA) strain has also been reported in staphylococcal infection, particularly in some cases of enterococcal infection.
