Staphylococcus aureus Nasal Colonization: An Update on Mechanisms, Epidemiology, Risk Factors, and Subsequent Infections

1Staphylococcus aureus is both a human skin and mucosae commensal but also a frequent cause of serious infections with high morbidity, mortality, and healthcare-associated costs. The most frequent carriage site is the vestibulum nasi (or anterior nares), which serves as reservoir for the spread of the pathogen. This bacteria can establish solid interactions with nasal epithelial cells via various proteins and many cell surface components, thus transforming into persistent carriage. S. aureus colonizes the anterior nares of 20% to 80% of the human population. Nasal carriage has been shown to play a key role in the pathogenesis of S. aureus infections in patients undergoing surgery, dialysis, and in intensive care unit (ICU) patients, with higher infection risks in persistent carriers.

2Previously published reviews on S. aureus carriage have usually focused independently on colonization or infections, or have issued a specific underlying condition or surgery. Here, we will full review recent advances in nasal microbiota composition and interspecies interactions, epidemiology, and risk factors for S. aureus colonization as well as the link between nasal carriage and infections both in community and nosocomial context.

3The adult nasal microbiota differs between individuals, but species belonging to Corynebacterium, Propionibacterium, and Staphylococcus genera are the most abundant bacteria. In a study conducted on the nasal microbiota of 178 adults, 88.2% were Corynebacterium carriers, 83.7% Propionibacterium acnes carriers, and 90.4% Staphylococcus epidermidis carriers. Proportional abundance varied considerably between individuals.

4The health status may influence the nasal microbiota and vice versa. In a study involving healthy and hospitalized individuals, healthy adults harbored nares microbiota dominated by Actinobacteria (mainly Propionibacterium and Corynebacterium spp.) whereas patients microbiota were dominated by S. aureus and S. epidermidis. S. aureus colonization was negatively associated with the presence of other bacteria including S. epidermidis. Such counterweight effect between bacteria could be the result of interdependent activation-inhibition mechanisms as reviewed by. In fact, some bacterial species are capable of secreting anti-staphylococcal molecules modulating S. aureus abundance (Figure 1). For instance, in vitro production of H2O2 by Streptococcus pneumoniae can be bactericidal on S. aureus. Recently, an in vitro and human study demonstrated that lugdunin, a non-ribosomal synthesized bioactive compound produced by Staphylococcus lugdunensis, can prevent S. aureus nasal colonization via a bactericidal effect.

5In some cases, the bacteria-secreted molecules can modify S. aureus adhesion properties. Some types of S. epidermidis seem to be capable of synthetizing the serine protease Esp that eliminates nasal S. aureus in healthy humans, probably by degrading staphylococcal surface proteins and human receptors critical for host–pathogen interaction. As well, Propionibacterium species produce coproporphyrin III, a porphyrin metabolite that induces S. aureus aggregation which influences nasal colonization.

6Corynebacterium species are suggested to antagonize S. aureus by human cell binding competition mechanisms. In 156 healthy volunteers, observed a 71% total eradication rate of nasal S. aureus after performing up to 15 inoculations of a Corynebacterium sp. strain to the nares of S. aureus carriers.

7Intra-species competition has also been described. In a cross-sectional clinical study, it was suggested that methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) compete for colonization, MSSA being protective with regard to MRSA carriage. On the other hand, pre-existing nasal carriage with S. aureus could predispose adult patients to further staphylococcal colonization.

8Staphylococcus aureus can be found in different body sites like the skin, rectum, vagina, gastrointestinal tract and axilla, the anterior nares appearing as the main reservoir. From a cutaneous commensal site, S. aureus can enter in contact with the nasal mucosa, then interact with epithelial cell ligands such as loricrin and cytokeratin 10 (K10) (Table 1). Once the host’s defenses are overcome, S. aureus can propagate into the anterior nares so that the host becomes an S. aureus nasal carrier. In human, nasal colonization may begin within the first days of life. This has been demonstrated in a cohort study evaluating nasal carriage of S. aureus in 100 pairs of infant–mother for a period of 6 months following delivery. The carriage rate in the first 8 weeks of life was around 40–50%, thereafter it dropped to 21% at 6 months. In addition, this study found a nasal carriage concordance in 68% of infant–mother pairs attesting the role of environmental factors in S. aureus carriage. Another study found identical strains in 80% of infant–mother pairs. In 90% of these newborns, the source of S. aureus was the maternal nasal strain (; Figure 2).

9After birth, hands are the main vector for S. aureus transmission from surfaces to the nose. The hypothesis of a link between hand and nose S. aureus carriage is supported by the double blind randomized placebo controlled trial from, who demonstrated that nasal decolonization with mupirocin applied to health-care workers resulted in a decrease of nose and hand carriage. In a cohort study including outpatients and healthy hospital employees, nasal carriage was evaluated by a single or several swabs. Participants completed a questionnaire about their nose picking behavior, a positive correlation between this habit and nasal carriage of S. aureus was found. However, it is unknown whether nose-picking patients were more frequently colonized at extra nasal sites.

10Studies realized in individuals living in the same households have revealed that these people tend to carry genetically similar strains in their nares suggesting horizontal transmission. Multisite MRSA carriage increases the risk for nasal MRSA colonization.

11In spite infrequent, airborne transmission is another possible route of S. aureus dissemination and may play a role in hospital outbreaks.

12During viral upper respiratory infections, the risk of disseminating endogenous S. aureus in the air increases and infection outbreaks may occur. In 1996, an MRSA outbreak involving 8 of 43 patients occurred in a surgical ICU of a university hospital in the United States. Investigations of the cause concluded that a single physician was the source of this outbreak; he was a nasal carrier of MRSA and suffered an upper respiratory infection. To assess airborne dispersal of S. aureus, the authors completed their findings by an experimental clinical test on this physician and showed that transmission of the bacterium increased by 40-fold when he was infected by a rhinovirus infection than when he was not. The use of a mask significantly reduced dispersal (P = 0.015).

13Healthcare workers who are asymptomatic nasal carriers can sometimes be the source of MRSA outbreaks. On the other hand, in nonoutbreak situations and in presence of control measures, healthcare workers are infrequently sources of transmission of S. aureus.

14Mobile phones of healthcare workers may be a reservoir of S. aureus. A recent study evaluated incidence of bacterial contamination of mobile phones belonging to medical staff working in the operating room. Seventy two healthcare professionals took bacterial cultures from their phones, anterior nares, and hands. The results revealed that 31 staff had S. aureus isolated from their nares, 8 from their mobile phones, and 4 from their hands. Genotyping confirmed that 7/8 of the mobile phones strains were identical to the ones isolated from the nares.

15The vestibulum nasi or anterior part of the nares is lined by a stratified, keratinized nonciliated squamous epithelium, whereas the rest of the nasal cavity, that is, its inner part is lined with a ciliated columnar epithelium.

16Both epithelia have been described as habitats for S. aureus as it will be developed in this section. Intracellular localization in nasal tissue from healthy volunteers was also described. For a successful colonization, S. aureus expresses adhesive molecules, fundamental for the establishment of interactions with human cell surface components, as it was demonstrated in vitro and in vivo (;; Figure 3). Major ligands interactions are listed in Table 1.

17The vestibulum nasi is lined by skin (; Vuyk and Watts, 2006). The uppermost layer of the epidermis is the stratum corneum or cornified layer. This layer contains keratinocytes that express proteins, such as loricrin, cytokeratin 10 (K10), involucrin, filaggrin, and other proteins.

18Clumping factor B (ClfB) and iron-regulated surface determinant A (IsdA) are staphylococcal surface proteins that can adhere to cornified envelope proteins and favor nasal colonization as it will be developed in this section.

19Recently, demonstrated that loricrin, the most abundant protein in the cornified envelope, was the major target ligand for ClfB during S. aureus nasal colonization. Nasal colonization by a ClfB+ S. aureus strain was reduced by 80% in loricrin-deficient mice compared to wild-type mice. ClfB has also been shown to interact with cytokeratin 10, cytokeratin 8, and fibrinogen (; Table 1). The role of ClfB in the adherence of S. aureus to the nasal epithelium has been studied in vitro, in animal models, and in human studies.

20demonstrated that mutant strains of S. aureus deficient in ClfB resulted in a reduced nasal colonization in both mice and rats, as compared to the wild-type strain (ClfB+). In human, the mutant strain ClfB- of S. aureus has been reported to be cleared faster than the wild-type strain (median 3 ± 1 vs. 7 ± 4 days, p = 0.006), whereas the wild-type strain persisted for 28 days after inoculation.

21IsdA also plays a role in the adherence of S. aureus to nasal cells as demonstrated in vitro and in vivo. Mutation in IsdA gene reduced the ability of the bacteria to bind human nasal cells in vitro and to colonize the anterior nares in cotton rats. This surface protein has also been shown to bind to fibrinogen and fibronectin. The role of IsdA in nasal colonization has not been clearly demonstrated in human studies yet.

22Other S. aureus surface proteins, such as surface protein G (SasG), SasX, and the serine-aspartate repeat proteins SdrC and SdrD may also serve as ligands to the epithelial cells. Desmoglein 1 was identified as a host ligand for SdrD. Their roles in humans have not been tested yet.

23Apart from the vestibulum nasi, the inner part of the nasal cavity constitutes another ecological niche for S. aureus. The staphylococcal nonprotein adhesin, named cell wall teichoic acid (WTA) is considered as an important factor for the colonization process. In an in vivo study, WTA-deficient S. aureus mutants could not adhere to nasal cells and were unable to colonize cotton rat nares compared to wild type control strains.

24In a study combining in vitro and in vivo assessments, studied the molecular details of WTA adhesion to nasal cells. They first discovered that SREC-1 (a member of the F-type scavenger receptor) was expressed on epithelial cells in the inner nasal cavity of human and cotton rats. The authors further reported that SREC-1 interacted with WTA and confirmed these findings in infected cotton rats pretreated with antiSREC-1 antibody. A significant decrease in colonization was observed 8 h and 6 days after inoculation in the group receiving antiSREC-1 antibody, as compared to the controls. In agreement, previously demonstrated the role of WTA in the initial stages of S. aureus colonization.

25Intracellular localization of S. aureus in the nasal tissue has been described using techniques including immunohistochemical analysis, hematoxylin, and Eosin stains. Epithelial cells, endothelial cells, and inflammatory cells, especially mast cells have been described as habitats for intracellular S. aureus (ICSA). Using skin biopsies from the vestibulum nasi of randomly selected healthy participants, detected intracellular S. aureus in the stratum spinosum, one of the layers forming the epidermis. Intracellular localization of S. aureus has been reported both in patients with rhinosinusitis and healthy volunteers. In the control population from the study of, 38% had ICSA. However, in the absence of large scale population study, the true prevalence of ICSA in healthy individuals remains to determine.

26Intracellular localization of S. aureus seems to protect the bacteria from host defense mechanisms and favor antimicrobial agents’ failure, as it was demonstrated in a recent study evaluating systemic and topical antibiotics. Using a cell model of S. aureus nasal epithelium evasion, found that most of the decolonizing agents, including mupirocin, exhibited weak activity against ICSA. Elimination of ICSA was also studied in a mouse model using vancomycin. In this study, intracellular bacteria were able to establish infection even in the presence of this antibiotic, whereas planktonic bacteria were eliminated by vancomycin and did not cause infection. The intracellular residency of S. aureus could explain re-colonization and failure in decolonization observed in some healthy carriers, and the recurrence of infections observed in patients with chronic rhinosinusitis.

27Our knowledge in terms of host response during S. aureus nasal colonization is still limited as compared to immune response in invasive S. aureus infection. The association between the host immune system and S. aureus nasal carriage has been recently reviewed by. The presence of S. aureus in the nares seems to induce both innate and adaptive immune system. S. aureus can otherwise overcome host defense mechanisms. The staphylococcal protein A (SpA) and the exoprotein staphylokinase could play a key role in the bacterial adaptation to the immune system and colonization process.

28Human nasal secretions have efficient natural antimicrobial activity. Indeed, they contain epithelial-cells secreted antimicrobial peptides (AMPs) contributing to the first line defense in the nose. Primary nasal epithelial cells yield AMPs such as hBD3 and RNase-7 after stimulation with cytokines (IFN-g, IL-1b, and TNF-a). Media containing S. aureus induce the expression of these AMPs less efficiently than inflammatory cytokines. Differential expression profiles of AMPs could be primary determinants for different S. aureus carriage states.

29Anti-staphylococcal responses can be induced by the involvement of Toll-like receptors (TLR). Hence, the role of TLR2 has been documented in nasal S. aureus colonization. Carrier strains of S. aureus have been shown to delay the host’s immune response compared to non-carrier strains due to the delayed TLR2 expression they stimulate in nasal epithelial cells. Different polymorphisms have been found in S. aureus nasal carriers and non-carriers; they target soluble or membrane-binding molecules such as genes encoding mannose-binding lectin, glucocorticoid receptor, C-reactive protein, beta-defensin 1, TLR-9, and interleukin-4.

30A study evaluating neutrophil depletion was performed in mice to determine the importance of neutrophil influx during carriage. Mice that received an antibody for neutrophil depletion had a significant increase in S. aureus colonization rate as compared to controls. This in vivo study highlights that neutrophil influx plays a role in clearance of S. aureus.

31As documented from serum analysis, S. aureus carriage induces an adaptive humoral immune response. Serum levels of immunoglobulin IgG and IgA specific to several staphylococcal proteins have been reported to be higher in persistent carriers than in non-carriers. But evidence that these antibodies are protective against colonization are lacking.

32In a murine model of nasal colonization, clearance of S. aureus was found to be B-cell independent but T-cell mediated. The Th17 cells, a functional T-cell lineage distinct from Th1 and Th2 are known to be involved in mucosal barriers and surface pathogen clearance. They typically produce IL-17 cytokine family., ) showed that IL-17A and IL-17F deficient mice failed to clear S. aureus experimentally inoculated through nasal route; IL-17A was required for AMP expression induced by nasal colonization. In a murine model, the IL-10 family cytokine IL-22 was secreted by Th17 cells and facilitated local expression of AMPs. IL-22 also reduced the expression of staphylococcal ligands loricrin and cytokeratin 10 and thus controlled nasal colonization.

33By contrast, in a human study evaluating nasal fluid inflammatory factors and nasal carriage with S. aureus, IL-17 was not detected. This was surprising and the authors suggested that IL-17 could be insoluble in nasal secretions. Low Th1 to Th17 cytokines ratio were found to be predictive of S. aureus carriage in volunteers after whole blood stimulation with S. aureus. Future human studies should be conducted to better understand the role of Th17 cytokines in nasal carriage.

34In order to confirm nasal carriage of S. aureus, samples are commonly collected using commercial dry or moistened sterile swabs, with no significant difference found between the two. The protocol of sampling is not really standardized but generally consists of rubbing the swab in the anterior nares of each nostril for approximately four rotary movements. Swabs are then analyzed to check presence of S. aureus. The two commonly used laboratory tests for the identification of S. aureus are the culture on chromogenic solid media – which is the less expensive test – and polymerase chain reaction, which is the gold standard and the most rapid technique for MRSA detection. It is important to note that chronic carriage of S. aureus may not only result from nasal colonization. Sampling extra-nasal sites like oropharynx, rectum, wounds, axilla increases MRSA detection rate in patients at risk for S. aureus nosocomial infection.

35Epidemiological studies over periods varying from 12 weeks to 3 years have described three nasal carriage patterns for S. aureus among healthy volunteers swabbed several times. Persistent carriers which rates ranged from 10% to 30%, non-carriers which rates ranged from 10% to 47%, and the rest who were considered intermittent carriers. The definitions used for this classification varied from one study to another. In some studies, persistent carriers were the ones who had results of all of their swabs positive for S. aureus. Other studies defined cut-off values for carrier–index (number of positive swabs/number of total swabs for each person). However, there is no clear definition on the number of swabs that should be taken and what fraction should be positive before determining carriage state.

36proposed a culture rule based on the combination of qualitative and quantitative results of two consecutive nasal culture swabs taken approximately a week apart, to predict S. aureus nasal carrier state among healthy volunteers. When both cultures are positive over 103 colony forming units (cfu) a person is classified as persistent carrier. When only one of the cultures is positive, or when both cultures are positive with a low cfu, the person is considered as an intermittent carrier. performed a study in 51 volunteers with a known carriage state, who were artificially colonized with a mixture of S. aureus strains after a decolonization treatment and followed for 22 weeks. Median nasal bacterial survival was of 4 days in noncarriers, 14 days in intermittent carriers, and more than 154 days in persistent carriers (P = 0.017). The culture swabs of persistent carriers contained more bacterial loads compared to the other groups. Serum levels of anti-staphylococcal antibodies differed between persistent and nonpersistent carriers as previously stated. The authors concluded that intermittent and noncarriers share similar characteristics, and thus suggested a reclassification of S. aureus nasal carriers into persistent carriers and “other” carriers. Persistent carriers have been shown to have higher counts of S. aureus and a higher risk of infection compared to other carriers. However, bacterial loads in persistent carriers are always variable and it is hard to determine a fixed threshold for diagnosis. Persistent carriage is more common in children than in adults, but many people change their carrier state between 10 and 20 years old. Conclusions that persistent carriers harbor the same strain for many years, and intermittent carriers appear to have changing strains have been recently the subject of controversy.

37Cross-sectional studies yield a prevalence of approximately 20–30% of carriers in the general population which is a mix of persistent and intermittent carriers.

38Nasal colonization depends on host factors, such as the underlying condition or diseases (Table 2). Some studies have found that nasal carriage was more frequent in human immunodeficiency virus (HIV)-infected or obese patients, compared to healthy individuals. This higher prevalence was also found among diabetic patients undergoing dialysis compared to non-diabetic patients in the same population. Other diseases such as granulomatosiss with polyangiitis (formerly known as Wegener’s granulomatosis), rheumatoid arthritis, skin and soft tissue infections atopic dermatitis, and recurrent furunculosis have been related with an increased carriage rate.

39In healthy subjects, found similar carriage rates in men and women, while men had higher bacterial density. Reports of a higher risk of nasal carriage of S. aureus among hospital workers than the rest of the population have not been confirmed. The association between smoking and nasal carriage seems also controversial. In a study by, active smoking in healthy adults was found to be a protective factor for carriage of S. aureus, with a hypothesized bactericidal activity of cigarette smokes. Conversely, a recent study showed that smokers were more frequently colonized than non-smokers, and cessation from smoking improved clearance of nasal S. aureus in an experimental inoculation study. Many other host conditions have been punctually studied and reported as additional predisposing factor such as hormonal contraception and presence of hemoglobin in nasal secretions.

40At the genetic level, no correlation was found between genetic factors and S. aureus carriage. No significant heritability for S. aureus nasal colonization was detected in twins and family studies. Interestingly, some polymorphisms in host inflammatory response genes have been associated with S. aureus nasal carriage. The presence of the histocompatibility antigen phenotype HLA-DR3 could be a predisposition.

41As previously said, at the immune system level, polymorphisms in genes encoding some proteins and differential expression profiles of AMPs could be the determinants of the various carriage states.

42In a study involving 93 type 1 diabetes patients, vitamin D receptor polymorphisms were determined in Deoxyribonucleic acid (DNA) extracted from peripheral blood leukocytes. Analysis showed that presence of specific alleles coding for vitamin D receptors were associated with an increased rate of S. aureus colonization.

43Staphylococcus aureus nasal colonization has been identified as a major risk factor for the development of patent staphylococcal infections, weather community acquired, or nosocomial which increases the risk by 2 to 10 times. The risk of infection in nasal carriers has been mainly studied in surgical patients (general, orthopedic, cardiac, and neurosurgeries), patients on hemodialysis, patients on chronic ambulatory peritoneal dialysis (CAPD), HIV-infected patients, and intensive care unit patients. It has also been shown to be the primary risk factor for recurrent furunculosis, nasal colonization being present in almost 60% of individuals with furuncles and impetigo (Figure 2 and Table 3).

44Developing a post-operative infection is a multifactorial process usually combining preoperative, intraoperative, and post-operative factors. Nasal colonization can actually be considered as a preoperative risk factor for MRSA and MSSA infections. S. aureus can spread from the anterior nares to other areas on the skin surface and thus contaminate the surgical wound during the operative procedure. It has been shown that around 80% of strains causing a staphylococcal infection at the site of surgery have molecular identity with S. aureus isolates in the nares of concerned patients.

45Surgical site infections (SSI) are one of the most common post-operative complications and represent 20 to 30% of healthcare associated infections (HCAI). While enterobacteria and other uro-digestive bacteria are dominant in infections after gastrointestinal, urological and gynecological surgeries, S. aureus predominates in orthopedic and cardiac surgery settings. In orthopedic patients, biofilms can form on the implants leading to therapeutic challenges. According to the French Institute for Public Health Surveillance in 2014, S. aureus composed 19.4% of isolated germs in SSIs after coronary surgeries, 51.9% of organisms causing SSIs in orthopedic surgeries, and 29.3% of organisms causing infections in gynecologic obstetric surgery in 2014. Similar implications have been also found in other countries.

46Several studies including case–control and multivariate analysis have identified nasal carriage of S. aureus an independent risk factor for SSIs. In the case–control study from, cardiac surgery patients were screened for their nasal carriage status the day before surgery and followed for the development of an SSI. S. aureus wound infections occurred in 40 patients as opposed to 120 controls who did not develop infection. Nasal carriage, identified in 52% of cases as compared to 12% of controls, was found to be a significant risk factor for the development of these post-operative infections with an OR = 9.6, 95% CI (3.9–23.7). In a study involving 357 patients undergoing major heart surgery, nasal carriers had a higher incidence of SSI than non-carriers (12.5% vs. 5%, P = 0.01). Similar conclusions were obtained for orthopedic patients with an incidence increasing from 3- to 11-fold.

47Surgical site infections have an important impact on the patient and the healthcare system. These infections increase hospital stay, mortality and healthcare costs and decrease health-related quality of life. A retrospective database analysis in France concluded that staphylococcal infections led to approximately 1.0 and 1.4 additional hospitalizations per patient, 22.1 and 22.4 additional hospital days, and an excess cost of €15,475 and €13,389 after cardiothoracic and orthopedic surgeries respectively. The rate of in-hospital mortality was 2.6 times and six times higher among infected patients than non-infected patients in cardiothoracic and orthopedic procedures.

48Methicillin-resistant S. aureus carriage could increase the risk for the development of SSIs. In a systematic review, patients colonized with MRSA were four times more likely to develop invasive infection than patients colonized with MSSA. MRSA infections are reported to cause up to 40% of HCAI worldwide with particularly high incidence in the United States and many European countries and have been shown to have increased morbi-mortality as compared to MSSA. In a study carried out by, patients with SSI due to MRSA had a 2.6 higher risk of dying within 3 months, the duration of hospital stay was 6 days longer, and the related cost was increased of $23,000 compared to patients with SSI due to MSSA. On the other hand, a meta-analysis of 31 cohort studies on S. aureus bacteremia, showed significantly higher mortality with MRSA than with MSSA. However, the reasons for increased fatality rate with MRSA infections are unclear. Some authors suggest that MRSA and MSSA bacteria are equally virulent but MRSA infections usually develop in patients previously treated with antibiotics. Thus, as previously suggested, the differences in patients’ fatality rate may rather reflect the severity of underlying conditions than a higher bacteria-related increased virulence.

49Nasal carriage of S. aureus has also been found to be a risk factor for subsequent infections in nonsurgical patients. screened 14,008 adults who had nasal swab on admission in a nonsurgical department, 3420 (24%) were positive for S. aureus. The follow-up identified 81 patients who developed S. aureus bacteremia between 2 and 120 days after swabbing, which was three times more frequent in carriers than in non-carriers. Interestingly, the death rate from S. aureus bacteremia was higher in non-carriers than carriers. This could be due to the protective immunity of anti-staphylococcal antibodies. Approximately, 80% of S. aureus blood isolates causing bacteremia were of endogenous origins and identical to those isolated from the anterior nares of corresponding patients, thus confirming previous report.

50A prospective cohort study evaluated the occurrence of S. aureus infections in 5161 patients who were screened for nasal carriage when admitted to the ICU. ICU-associated S. aureus infections were defined by the development of infection >48 h after their admission to the unit. These infections occurred in 113 patients and nasal colonization was associated with a 2.5 to 4.7-fold increased risk.

51In HIV-positive patients, a prospective cohort study evaluating 231 subjects every 3 months for a minimum of two years, has reported a 6% incidence of S. aureus infections, nasal carriers being more at risk [p = 0.04, OR = 3.6 (0.9–15.4)].

52In hemodialysis and chronic peritoneal dialysis patients, most of infectious complications come from endogenous origin. S. aureus is the most common isolated agent from central venous catheter-related bacteremia, or exit-site infections of peritoneal dialysis catheters. Nasal carriers are at increased risk of contracting these infections.

53Staphylococcus aureus is the most frequently isolated pathogen from diabetic foot infections. A study compared the genotypic profiles of S. aureus strains isolated from the nares and diabetic foot ulcer infections of 276 patients. The bacterium was isolated from both sites in 36% of the population, and identical strains were found in 65% of cases. Further investigations should be performed in order to confirm the benefit of screening and treating nasal carriers in this population.

54Nasal carriage of S. aureus constitutes a risk factor for the development of skin and soft tissue infections caused by this germ in non-hospitalized and non-diseased subjects. It has been shown to be the primary risk factor for recurrent furunculosis. Nasal carriage is also a risk factor for secondary bacterial pneumonia in patients having influenza A virus infection. The viral infection causes host physiologic changes that generates the dissemination of S. aureus from nasal tissue to the lungs as demonstrated in a mouse model.

55Nasal carriage of S. aureus is multifactorial and can predispose carriers to subsequent infections. Nasal decolonization of carriers is therefore recommended in patients undergoing cardiothoracic and orthopedic surgeries.

56A full understanding of host-pathogen interactions can help find new decolonization strategies. New fields on colonization mechanisms should be investigated. For example, the role of mycobiota starts to be described in the pathophysiology of chronic respiratory diseases. Interaction of nasal S. aureus with the nasal fungal communities would be an interesting perspective to develop. On the other hand, some reports suggest that S. aureus can regulate host inflammatory gene expression. Epigenetics mechanisms could be interesting to investigate in order to better understand tolerance mechanisms in S. aureus colonization processes.

57AS wrote the review paper. FB, J-LM, OB, and J-MR corrected the manuscript. All authors approved and revised the final version of the manuscript.

58The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.