Millions of bacteria live on the human body. Generally these bacteria co-exist with us peacefully, but sometimes certain bacteria may enter the body and cause infections, such as gum disease or a bone infection called osteomyelitis. Many of these infections are thought to occur when the bacteria become able to form complex communities called biofilms. Bacteria living in a biofilm cooperate and make lifestyle choices as a community, so in this way, they behave like a single organism containing many cells.

A sticky glue-like material called the matrix holds the bacteria in a biofilm together. This matrix protects the bacteria in the biofilm from both the human immune system and antibiotics, allowing infections to develop and making them difficult to treat.

Previous research has shown that the supply and level of oxygen in infected tissues decreases as an infection gets worse. One bacterium that typically lives peacefully on our bodies, called Staphylococcus aureus, can sometimes cause serious biofilm-associated infections. S. aureus forms biofilms more readily when oxygen is in short supply, but it was not known how these biofilms form. Understanding how S. aureus forms biofilms could help scientists develop better treatments for bacterial infections.

Most bacterial cells have a cell wall to provide them with structural support. Mashruwala et al. found that, when oxygen levels are low, S. aureus decreases the production of a type of sugar that makes up the cell wall. At the same time, the bacteria produce more of an enzyme that breaks down cell walls. Together, these processes cause some of the bacteria cells to break open. The contents of these broken cells, including their DNA, help form the matrix that will hold together and protect the other bacterial cells in the biofilm. The experiments also identified a protein called SrrAB that switches on the process that ruptures the cells when oxygen is low.

The findings of Mashruwala et al. show how bacteria grown in the laboratory form biofilms when they are starved of oxygen. The next steps following on from this work are to find out whether the same thing happens when bacteria infect animals and whether drugs that block the rupturing of bacterial cells could be used to treat infections.

Staphylococcus aureus is a commensal bacterium that is estimated to colonize between 20–50% of the healthy human population (Naimi et al., 2003; Graham et al., 2006; Enright et al., 2002; Ohara-Nemoto et al., 2008; Zafar et al., 2007). Colonization typically occurs in the nares, throat, or on the skin (Ohara-Nemoto et al., 2008; Zafar et al., 2007; Hamdan-Partida et al., 2010). Under select conditions, S. aureus is capable of causing both invasive as well as non-invasive infections (Klevens et al., 2007; Tong et al., 2015; Williamson et al., 2013). The dominant fraction of invasive infections caused by this bacterium occur in the context of bacteremia (Klevens et al., 2007). In addition, S. aureus can infect and cause diseases of the lungs (penumonia), skin (cellulitis), skeletal tissues (ostoemyelitis), and heart tissue (endocarditis), as well as septic shock (Klevens et al., 2007; Tong et al., 2015). In the United States, pneumonia and septic shock are rapidly progressing infections and are often fatal with mortality rates in the United States (US) of 30–55% (Klevens et al., 2007). While bacteremia and endocarditis infections have a lower degree of mortality, they are associated with a higher degree of recurrence, suggestive of therapeutic recalcitrance (Klevens et al., 2007). A recent epidemiological analysis of ~8,700 cases of invasive S. aureus infections in the US found that nearly 92% cases required hospitalization (Klevens et al., 2007).

Historically, S. aureus infections in the US were largely nosocomial in origin; however, their onset or occurrence increasingly transpires in community settings (Klevens et al., 2007; Tenover et al., 2006). In the United States, pulsed-field type USA300 methicillin-resistant S. aureus (MRSA) has emerged as the dominant etiologic agent of community-associated invasive infections (Klevens et al., 2007). Treatment of S. aureus infections is often problematic due to the increasing prevalence of antibiotic resistance. S. aureus strains have been isolated that are resistant to nearly all clinically available antibiotics, including the last-line antibiotics linezolid and daptomycin (Sass et al., 2012; Sánchez García et al., 2010).

Biofilms are architecturally complex, multicellular communities of microorganisms of either mono- or poly-microbial compositions (Costerton, 1995; Costerton et al., 1995). It has been theorized, based upon studies using direct techniques, such as microscopy, that ~99% of bacteria establish biofilms in their natural environments (Costerton et al., 1995). A number of persistent and chronic infections in humans, such as periodontis and cystic fibrosis, are associated with the ability of the microorganisms to establish biofilms (Sedghizadeh et al., 2009; Costerton et al., 1999). In addition, biofilms of infectious agents are well characterized to form upon biomedical devices such as prosthetics, heart valves, catheters, and contact lenses (Costerton et al., 1999, 2005; Bispo and Haas, 2015). A number of staphylococcal infections, such as osteomyelitis, are also intimately connected to the ability of the bacterium to form biofilms (Joo and Otto, 2012; Otto, 2008). Reflective of their clinical significance, biofilms are considered to be the etiologic agents of recurrent staphylococcal infections (Joo and Otto, 2012; Otto, 2008).

S. aureus biofilms are typically composed of one or more extracellular polymeric molecules (DNA, proteins, or polysaccharides) that provide structural integrity and may also facilitate intercellular adhesion (Rice et al., 2007; Schwartz et al., 2012; Boles and Horswill, 2008; Cramton et al., 1999). The polymers interact to facilitate the formation an extracellular matrix. This matrix provides protection from environmental stress, innate immunity, as well as therapeutic agents (Davies, 2003). The polymer(s) utilized to facilitate biofilm formation can vary between staphylococcal isolates with some favoring DNA and/or proteins and others polysaccharides (Rice et al., 2007; Schwartz et al., 2012; Boles and Horswill, 2008; Cramton et al., 1999). The complexity of biofilm formation results in this process being highly regulated and deterministic. Biofilm formation in S. aureus is responsive to diverse signals including nutrient limitation and quorum sensing (Joo and Otto, 2012; Otto, 2008; Boles and Horswill, 2008; Majerczyk et al., 2008).

Oxygen concentrations vary greatly between healthy human tissues (between 19.7 to ~1.5%; normoxia) (Carreau et al., 2011). Oxygen concentrations also vary between healthy and infected or necrotic tissues, as well as in wounds, where concentrations are estimated to be below 1% (hypoxic) or anoxic (Carreau et al., 2011; Vogelberg and König, 1993; Arnold et al., 1987). A recent study found that S. aureus infections in skeletal tissues (osteomyelitis) cause an ~3 fold decrease in oxygen concentrations resulting in increasing hypoxia as infection proceeds (Wilde et al., 2015).

Multiple studies have focused upon the human systems that are active under hypoxia or anoxia and aid in combating bacterial infections. However, relatively little is known about how S. aureus mount a response to hypoxia or anoxia. A study by Cramton et al. found that decreased oxygen concentrations result in increased biofilm formation in S. aureus (Cramton et al., 2001). An alternate study found that S. aureus growing in biofilms are starved for oxygen and that the rate of oxygen depletion is proportional to the rate of biofilm maturation (Zhu et al., 2007). Cramton et al. also found that decreased oxygen concentrations lead to increased production of the polysaccharide intercellular adhesin (PIA), which is a polymer used by some S. aureus isolates to facilitate intercellular adhesion (Cramton et al., 2001). However, the role or requirement of PIA in low oxygen biofilms is unclear since biofilm formation in a PIA deficient strain was not examined (Cramton et al., 2001). It is also unclear how the lack of oxygen, a cell permeable molecule, translates into increased biofilm formation.

Two-component regulatory systems (TCRS) are modular signal transduction pathways that facilitate the integration of multiple stimuli into cellular signaling circuits, allowing for a rapid and robust response to environmental alterations (Stock et al., 2000; Stephenson and Hoch, 2002). In S. aureus, which encodes for classical TCRS, the systems are predicted to be composed of a histidine kinase (HK) and a DNA-binding response regulator (RR). The HK interacts with the environmental stimulus and can be either membrane associated or cytosolic. Upon stimulation, the HK alters the levels of the phosphoryl group upon the RR. In the case of most (but not all) DNA-binding RRs, altered phosphoryl levels modify the affinity of the RR for DNA resulting in altered gene transcription and a tailored physiological response (Stock et al., 2000; Stephenson and Hoch, 2002).

The goal of this study was to examine the mechanisms by which oxygen affects S. aureus biofilm formation. Data presented show that oxygen impacts biofilm formation in its capacity as a terminal electron acceptor in cellular respiration. Consequently, growth conditions that diminish respiration elicit increased biofilm formation. Impaired respiration leads to increased cell lysis via increased expression of the AltA murein hydrolase and a concomitant decrease in the expression of wall-teichoic acids. The regulatory tuning of these two processes in a divergent manner affects cell lysis. Increased biofilm formation and cell lysis is a programmed mechanism that is governed by the SrrAB TCRS. Genetic evidence suggests that SrrAB-dependent biofilm formation occurs in response to the accumulation of reduced menaquinone.

Biofilms are the etiologic agents of recurrent staphylococcal infections. Previous work found that hypoxic growth results in increased biofilm formation of S. aureus. However, the molecular and regulatory mechanism(s) translating the lack of oxygen into biofilm formation were unknown. We report that oxygen impacts biofilm formation in its capacity as a terminal electron acceptor (TEA) for cellular respiration. Consistent with this premise, supplementing the growth medium with the alternate TEA nitrate decreased biofilm formation during anaerobic growth. Moreover, genetic or chemical inhibition of respiratory processes resulted in increased biofilm formation even in the presence of a TEA. TEA availability in the natural microenvironments of S. aureus varies, leading to the supposition that biofilm formation would be responsive to the concentration of TEA. Consistent with this logic, biofilm formation was titratable with respect to the concentration of a TEA or a molecule that inhibits respiration.

Fermenting biofilms were dependent upon the presence of high-molecular weight DNA. High-molecular weight DNA in S. aureus biofilm matrixes (eDNA) has been shown to originate from genomic DNA, and thus, its presence suggested that fermenting cells undergo increased autolysis (Rice et al., 2007). Lending support to this concept, fermentative biofilm formation was attenuated upon chemical inhibition of autolysis or genetic inactivation of the AtlA murein hydrolase. Fermenting cells underwent increased autolysis in a AtlA-dependent manner and the matrix from the atlA::Tn strain had nearly undetectable levels of eDNA. S. aureus biofilms incorporate cytosolic proteins into their matrixes and AtlA has been implicated in the release of cytosolic proteins via a process that is not completely understood (Foulston et al., 2014; Pasztor et al., 2010). We found that fermenting cells had increased activity for a cytosolic protein in the extracellular mileu and an atlA::Tn strain was deficient in the release of this protein. Fermenting biofilms were also readily disrupted upon supplementing media with proteinase K suggesting that, in addition to eDNA, proteins are integral components of the fermentative biofilm matrix.

The increased role of AtlA in fermenting biofilms was due to a combination of two divergent cellular responses. First, fermenting cells increased the transcription of atlA and autolysis and murein hydrolase assays confirmed that this was translated into increased AtlA activity. Second, fermenting WT cells that had been heat-killed displayed an increased amenability to AtlA-dependent cleavage when used as substrates in murein hydrolase assays. These findings suggested that the cell surface was being altered to facilitate cell lysis. Wall-teichoic acids (WTA) are cell surface glycopolymers that are covalently attached to peptidoglycan and negatively impact AtlA activity (Biswas et al., 2012; Schlag et al., 2010). The transcription of WTA biosynthesis genes was decreased during fermentative growth. Autolysis and murein hydrolase assays, as well as the WTA synthesis inhibitor tunicamycin, confirmed that WTA expression was decreased during fermentative growth. Since two cellular processes are divergently modulated at the transcriptional level in response to an environmental stimulus (TEA availability) to affect autolysis, we propose that this process be termed as programmed cell lysis (PCL), which is illustrated in our working model shown in Figure 7.

Figure 7

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The cell walls of gram-positive bacteria have been long recognized to serve as proton reservoirs (Koch, 1986; Calamita et al., 2001). The walls of respiring cells have a low pH and calculations estimate that the local pH can decrease by 3–4 units (Koch, 1986; Calamita et al., 2001). Further, energy-limiting conditions, such as fermentative growth, or proton trapping, influence bacterial autolysis (Kemper et al., 1993; Jolliffe et al., 1981). Thus, it has been clear that cell wall composition, the localized pH of the cell wall, and cellular autolysis are interconnected. However, the mechanisms underlying these interconnections have remained elusive. A recent study by Biswas et al. shed light on these processes in S. aureus (Biswas et al., 2012). Biswas et al. found that WTA traps protons at the cell surface and they proposed that this results in decreased pH of the microenvironment, and thereby, inhibits AtlA activity (Biswas et al., 2012). We found that the influence of pH upon AtlA activity, in both murein hydrolase, as well as autolysis assays, was almost entirely as a result of alterations in WTA expression. These findings both confirm and extend the model put forth by Biswas et al. (2012). An alternate study by Schlag et al. proposed that WTA negatively affects AtlA activity by interfering with its binding to the cell surface (Schlag et al., 2010). We found that at a pH of 5, tunicamycin treated cells bound a majority of the bacteriolytic activity corresponding to AtlA. In contrast, binding was absent in cells not treated with tunicamycin, regardless of whether they were cultured aerobically or fermentatively. Thus, our findings also confirmed and extended the findings of Schlag et al. However, the complete absence of WTA synthesis is unlikely to be a phenomenon that would be physiologically encountered. Therefore, in fermenting S. aureus, where the final pH of the culture medium is ~5, we propose that the model of Biswas et al. would dominate with respect to autolysis and biofilm formation.

Acidic pH has long been recognized to elicit biofilm formation in S. aureus (Regassa et al., 1992); however, the mechanisms underlying this phenotype have been unclear. Foulston et al. found that cytoplasmic proteins released into the extracellular mileu associate with the exterior of cells, in a pH-dependent and reversible manner, facilitating matrix formation (Foulston et al., 2014). The association of the proteins with the cells increases with decreasing pH (Foulston et al., 2014). Foulston et al. conducted their study in a medium that leads to a decrease in pH over growth (Foulston et al., 2014). Thus, it was unclear whether low pH was necessary for the release of the cytoplasmic proteins. Data presented herein suggest that low pH optimizes AtlA function and thereby effects the release of the cytoplasmic proteins, extending the findings of Foulston et al. Further, the physiological condition(s) under which this mechanism would be relevant was not entirely clear. In the present study we demonstrate that this mechanism is pertinent in the context of an environmental signal (oxygen) that is crucial in infection progression. Finally, we note that the pH of the skin and nares, which are sites colonized by S. aureus, is lower than the homeostatic 7.4 (Weinrick et al., 2004). However, to our knowledge, it is unknown if low pH contributes to S. aureus biofilm formation in vivo.

Respiration is a process mediated predominantly by membrane associated cellular factors. A strain lacking the SrrAB TCRS, consisting of a transmembrane histidine kinase (SrrB) (Pragman et al., 2004), was attenuated in biofilm formation. A strain lacking SrrAB had decreased transcription of atlA, increased transcription of WTA biosynthesis genes, and displayed multiple phenotypes consistent with the transcriptional data. Further, the biofilm deficient phenotype of the ΔsrrAB strain was partially suppressed by the introduction of atlA in multicopy. These data suggest that SrrAB influences PCL and biofilm formation by divergently influencing AtlA and WTA expression.

SrrAB output was previously shown to be altered under conditions of hypoxia and nitric oxide stress (Kinkel et al., 2013). However, the cellular molecule(s) that influence SrrAB activity are unidentified. We found that SrrAB-dependent biofilms increased as a function of decreased respiratory activity. SrrAB-dependent biofilms were formed upon accumulation of reduced, but not oxidized menaquinone, and SrrAB output was abrogated in the absence of menaquinone. These findings suggest that (1) menaquinone is necessary for stimulus transmission to SrrAB, and (2) the oxidation state of the cellular menaquinone pool influences SrrAB output. We also considered the possibility of two alternate signals that could affect SrrAB output: culture pH and decreased proton motive force. Fermentative growth of S. aureus upon TSB results in the release of acidic by-products, which decrease the pH of the extracellular mileu (Somerville et al., 2003). Diminished respiration also decreases the proton-motive force. However, heme and menaquinone auxotrophs are both deficient in respiration and the concentration of fermentative by-products and the pH in the spent media is similar in these strains ((Hammer et al., 2013) and data not shown). These strains also display a similar decrease in membrane potential (Hammer et al., 2013). Yet, only a heme auxotroph forms SrrAB-dependent biofilms. Thus, we deem it unlikely that pH or alterations in proton motive force alter SrrAB activity with respect to biofilm formation.

It is worth noting the similarities that exist between the Escherichia coli ArcAB TCRS and SrrAB. Although these TCRS do not display significant homology, the stimuli influencing their activity are similar. ArcB is proposed to donate electrons from conserved cysteine residues to oxidized quinones resulting in silencing of kinase activity (Malpica et al., 2004). Similar to ArcB, SrrB contains three conserved cysteine residues, which may facilitate redox interactions with the menaquinone pool. While this leads to the supposition that the molecular mechanism of SrrB signaling may be similar to ArcB, further biochemical analyses are required to make this conclusion. The Bacillus subtilis TCRS ResDE displays similarities to SrrAB and it also responds to changes in the respiratory status. However, unlike SrrB, ResE does not contain cysteine residues and studies have deemed it unlikely that the menaquinone pool influences ResDE activity (Geng et al., 2007).

Similar to S. aureus, B. subtilis increases biofilm formation under hypoxic growth and this phenotype is reversed upon supplementation with the alternate TEA nitrate (Kolodkin-Gal et al., 2013). Biofilm formation in B. subtilis coincided with increased transcription of genes required for matrix production, which was mediated via the membrane-associated kinases KinA and KinB (Kolodkin-Gal et al., 2013). B. subtilis ResD binds to the promoter regions or within the coding regions of lytF and cwlO, which encode for two major bacillus autolysins, suggesting it modulates the transcription of these genes (Henares et al., 2014; Ohnishi et al., 1999; Ishikawa et al., 1998; Yamaguchi et al., 2004). Further, the binding of ResD to these DNA regions was limited to fermentative growth (Henares et al., 2014). However, to our knowledge, it is currently unknown whether ResDE has a role in respiration dependent biofilm formation. The gram-negative bacterium Pseudomonas aeruginosa also increases biofilm formation under hypoxic growth and this phenotype is also reversed upon supplementation with the alternate TEA nitrate (Dietrich et al., 2008, 2013). However, the regulatory mechanisms driving respiration dependent biofilm formation in P. aeruginosa are unknown. Thus, it seems likely that increased biofilm formation in response to TEA limitation is conserved among diverse bacteria. However, the genetic and regulatory bases underlying biofilm formation may differ.

Clinical isolates of S. aureus that are incapable of respiration, termed as small colony variants (SCV), display increased resistance towards antibiotics and cause persistent infections (Proctor et al., 2006; Melter and Radojevič, 2010). The SCV phenotype often, but not always, arises as a result of mutations in genes necessary for heme biosynthesis resulting in non-functional terminal oxidases (Hammer et al., 2013; Proctor et al., 2006). Our finding that a heme auxotroph forms SrrAB-dependent biofilms lends considerable insight into the mechanisms that may predominate within clinical SCV strains.

While we suggest the usage of the term PCL in the context of the mechanisms outlined herein, we note that this should not be confused with the process of programmed cell death (PCD) in bacteria or in eukaryotes (Rice and Bayles, 2008; Kerr et al., 1972; Kroemer et al., 2009). Mechanistically, these are distinctly unique processes. Moreover, the morphological and biochemical markers determined in our study do not satisfy the criteria set forth by the committee on cell death (Kroemer et al., 2009). However, in the holistic view there are intriguing parallels between S. aureus PCL and eukaryotic PCD. PCD occurs as a homeostatic measure in multicellular organisms, whereby a genetically programmed mechanism of cellular catabolism eliminates select quantities and types of cells (Kerr et al., 1972; Kroemer et al., 2009). PCD is crucial for a variety of processes ranging from proper cell turnover and embryonic development to the functioning of the immune system (Kerr et al., 1972; Kroemer et al., 2009). While PCD occurs at the cellular level, and typically in a localized environment, it provides benefits at the organismal level (Kerr et al., 1972). Similar to PCD, the findings presented herein suggest that PCL may provide bacteria with a population-level advantage by facilitating biofilm establishment, thereby imparting protection from the immune system and therapeutic agents.

Respiration in eukaryotic cells relies upon using oxygen as a substrate. Similar to PCL, hypoxia or anoxia trigger PCD in eukaryotes (Shimizu et al., 1996; Weinmann et al., 2004). PCD occurs as one of two distinct biochemical modalities: apoptosis or necrosis. Hypoxia triggered PCD manifests as a mixture of apoptosis and necrosis (Shimizu et al., 1996). Anoxia triggered PCD is largely an apoptotic process (Weinmann et al., 2004). Interestingly, anoxia-triggered PCD is dependent upon mitochondrial membrane permeabilization by the pro-apoptotic Bcl-2 family proteins Bax and Bak (Weinmann et al., 2004; Kuwana et al., 2002). Recent evidence suggests that Bax and Bak function as holin-like proteins and facilitate the formation of oligomeric membrane pores (Kuwana et al., 2002; Pang et al., 2011). S. aureus also encodes for two holin-like proteins termed CidA and LrgA (Ranjit et al., 2011). The cid operon genes, cidA and cidB have been implicated in programmed cell death in aerobically cultured cells (Chaudhari et al., 2016). CidA was previously proposed to have role in cell lysis (Rice et al., 2007). This role was predicated upon the phenotype of a cidA mutant; however, recent studies suggest that this was likely an outcome of a secondary mutation (Rice et al., 2007; Chaudhari et al., 2016). CidB, is predicted to be a membrane-associated protein, however its precise function and biochemical activity(s) are yet to be defined (Rice et al., 2003; Windham et al., 2016; Chaudhari et al., 2016). In our hands, cidA::Tn, cidB::Tn, and lrgA::Tn strains were not attenuated in fermentative biofilm formation suggesting a functional separation of the S. aureus PCD and PCL pathways, with respect to biofilm formation.

In summary, we report that oxygen impacts S. aureus biofilm formation in its capacity as a terminal electron acceptor. Decreased respiration results in programmed cell lysis via increased expression of AtlA and decreased expression of wall-teichoic acids. These processes are governed by the SrrAB TCRS and evidence suggests this occurs in response to the accumulation of reduced menaquinone. The AtlA-dependent release of cytosolic components facilitates biofilm formation.

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Author details

1. Ameya A Mashruwala

   Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, United States

   Contribution

   AAM, Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-5583-4174

2. Adriana van de Guchte

   Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, United States

   Contribution

   AvdG, Validation, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-0771-3842

3. Jeffrey M Boyd

   Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, United States

   Contribution

   JMB, Conceptualization, Resources, Supervision, Funding acquisition, Project administration, Writing—review and editing

   For correspondence

   jmboyd@SEBS.rutgers.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-7721-3926

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