MicrobiologyBytes

Staphylococcus aureus is responsible for the vast majority of bacterial skin infections in humans. The propensity for S. aureus to infect skin involves a balance between cutaneous immune defense mechanisms and virulence factors of the pathogen. The tissue architecture of the skin is different from other epithelia especially since it possesses a corneal layer, which is an important barrier that protects against the pathogenic microorganisms in the environment. The skin surface, epidermis, and dermis all contribute to host defense against S. aureus. Conversely, S. aureus utilizes various mechanisms to evade these host defenses to promote colonization and infection of the skin.

This review focuses on host-pathogen interactions at the skin interface during the pathogenesis of S. aureus colonization and infection.

Host-pathogen interactions between the skin and Staphylococcus aureus. Curr Opin Microbiol. 01 Dec 2011

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Gathering and sharing of information is extremely important in human society. Especially in times of war, the difference between victory and defeat can depend on the ability to obtain, encrypt, and share information, and sophisticated systems have been developed for exactly this purpose. Similarly, in their constant battles with competitors and the host immune system, (opportunistic) microbial pathogens have developed sophisticated cell–cell communication systems termed quorum sensing (QS) that allow exchange of critical information. In return, competing microbes, as well as the host immune system, have developed means to intercept and decode these messages. The information obtained by this molecular espionage is used for their benefit, either to win the war (microbe against microbe), or to prepare for an upcoming battle (microbe against immune system).

QS is a system that enables microbes to monitor population cell density through the production, secretion, and sensing of small diffusible molecules. When such molecules reach a threshold concentration, microbial cells in the vicinity detect the signal and coordinately respond by modifying their gene expression; often these genes are associated with virulence and pathogenesis. Several different types of QS molecules have been described for a wide variety of microbial species.

To illustrate the clinical importance of this microbial spy game, this short review focuses on the biological activity of a single bacterial QS molecule on surrounding microbes and the host immune system and its diverse “meaning” to different receivers. Infections related to burn wounds, cystic fibrosis, and periodontal diseases consist most commonly of the bacteria Pseudomonas aeruginosa and Staphylococcus aureus and the fungus Candida albicans, and represent niches with an active host response. This short review provides five facts about how the P. aeruginosa QS molecule plays a pivotal role in this triangle of interspecies interactions and how microbial behavior elicited by this small signalling molecule has consequences for the host response.

Microbial Spy Games and Host Response: Roles of a Pseudomonas aeruginosa Small Molecule in Communication with Other Species. (2011) PLoS Pathog 7(11): e1002312. doi:10.1371/journal.ppat.1002312

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Methicillin-resistant Staphylococcus aureus (MRSA), first identified in the 1960s, was initially considered to be a nosocomial pathogen (hospital acquired infection). Beginning in the late 20th century, a specific clone of MRSA known as USA300 emerged as a leading cause of community-acquired infection, but doubts remain as to where many cases of MRSA infection originate, and how to break the transmission of this dangerous strain.

A new study finds that 8% of hospital outpatients carrying methicillin-resistant MRSA lived with an MRSA-positive pet. When faced with chronic and or recurrent MRSA cases, physicians should consider the possibility of household pets as MRSA source. Patients should be informed of this possibility. Unnecessary close contact should be avoided and heightened hygiene practices should be instituted. Sampling/swabbing of all the human and animals in a household seems appropriate to identify unrecognized sources and break potential cycles of reinfection especially in cases involving immunocompromised patients.

Transmission of MRSA between Companion Animals and Infected Human Patients Presenting to Outpatient Medical Care Facilities. PLoS ONE 6(11): e26978. doi:10.1371/journal.pone.0026978
Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen in both human and veterinary medicine. The importance of companion animals as reservoirs of human infections is currently unknown. The companion animals of 49 MRSA-infected outpatients (cases) were screened for MRSA carriage, and their bacterial isolates were compared with those of the infected patients using Pulsed-Field Gel Electrophoresis (PFGE). Rates of MRSA among the companion animals of MRSA-infected patients were compared to rates of MRSA among companion animals of pet guardians attending a “veterinary wellness clinic” (controls). MRSA was isolated from at least one companion animal in 4/49 (8.2%) households of MRSA-infected outpatients vs. none of the pets of the 50 uninfected human controls. Using PFGE, patient-pets MRSA isolates were identical for three pairs and discordant for one pair (suggested MRSA inter-specie transmission p-value = 0.1175). These results suggest that companion animals of MRSA-infected patients can be culture-positive for MRSA, representing a potential source of infection or re-infection for humans. Further studies are required to better understand the epidemiology of MRSA human-animal inter-specie transmission.

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Researchers have discovered a toxin – SElX – released by methicillin-resistant Staphylococcus aureus (MRSA) which leads the body’s immune system to go into overdrive and damage healthy cells. SElX is made by 95 per cent of S. aureus strains, making it a potential drug target to fight this hospital superbug. SElX belongs to a family of toxins known as superantigens that can invoke an extreme immune response. When it is released it triggers an over multiplication of immune cells, which can lead to high fever, toxic shock and potentially fatal lung infections looked at a strain of MRSA known as USA300 that can cause severe infections in otherwise healthy individuals. If we can find ways to target this toxin, we may be able to stop it from triggering an over-reaction of the body’s immune system and prevent severe infections.

A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia. (2011) PLoS Pathog 7(10): e1002271. doi:10.1371/journal.ppat.1002271

Other research has linked a naturally occurring mutation in the bacterium Clostridium difficile to severe and debilitating diarrhoea in hospital patients undergoing antibiotic therapy. These antibiotics destroy the “good” bacteria in the gut, which allows this “bad” bacterium to colonise the colon, where it causes bowel infections that are difficult to treat. The mutation wipes out an inbuilt disease regulator, called anti-sigma factor TcdC, producing hypervirulent strains of C. difficile that are resistant to antibiotics and which have been found to circulate in Canada, the US, UK, Europe and Australia. The results suggest that bacterial strains carrying this mutation have the potential to produce more of the harmful toxins that cause disease in susceptible individuals – commonly patients aged 65 years or over. As we now have a better understanding of these strains, we can design new strategies to prevent, control and treat these infections.

The Anti-Sigma Factor TcdC Modulates Hypervirulence in an Epidemic BI/NAP1/027 Clinical Isolate of Clostridium difficile. (2011) PLoS Pathog 7(10): e1002317. doi:10.1371/journal.ppat.1002317

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The emergence of resistance against most current drugs emphasizes the need to develop new approaches to control bacterial pathogens, particularly Staphylococcus aureus. Bacterial fatty acid synthesis is one such target that is being actively pursued by several research groups to develop anti-Staphylococcal agents. Recently, the wisdom of this approach has been challenged based on the ability of a Gram-positive bacterium to incorporate extracellular fatty acids and thus circumvent the inhibition of de novo fatty acid synthesis. The generality of this conclusion has been challenged, and there is enough diversity in the enzymes and regulation of fatty acid synthesis in bacteria to conclude that there is not a single organism that can be considered typical and representative of bacteria as a whole. We are left without a clear resolution to this ongoing debate and await new basic research to define the pathways for fatty acid uptake and that determine the biochemical and genetic mechanisms for the regulation of fatty acid synthesis in Gram-positive bacteria. These crucial experiments will determine whether diversity in the control of this important pathway accounts for the apparently different responses of Gram-positive bacteria to the inhibition of de novo fatty acid synthesis in presence of extracellular fatty acid supplements.

Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery? Curr Opin Microbiol. Aug 20 2011

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Staphylococcus aureus is an important human pathogen that is found in the nasal passages of approximately 1/3 of the population. The nose serves as a reservoir for spread of this pathogen and predisposes the host to potential infection. Factors contributing to S. aureus nasal colonization are only beginning to be understood. The collection and analysis of human nasal secretions provided evidence that the presence of haemoglobin in nasal secretions can promote S. aureus nasal colonization. Hemoglobin reduced expression of the S. aureus agr quorum sensing regulatory system known to be involved in surface colonization, and it was found that induction of the agr system reduced nasal colonization. These findings suggest that individuals experiencing frequent nosebleeds would be prone to S. aureus colonization and epidemiological data supports these findings. By understanding host factors and bacterial molecular mechanisms involved in nasal colonization we may one day be able to design novel decolonization strategies.

Hemoglobin Promotes Staphylococcus aureus Nasal Colonization. (2011) PLoS Pathog 7(7): e1002104. doi:10.1371/journal.ppat.1002104
Staphylococcus aureus nasal colonization is an important risk factor for community and nosocomial infection. Despite the importance of S. aureus to human health, molecular mechanisms and host factors influencing nasal colonization are not well understood. To identify host factors contributing to nasal colonization, we collected human nasal secretions and analyzed their ability to promote S. aureus surface colonization. Some individuals produced secretions possessing the ability to significantly promote S. aureus surface colonization. Nasal secretions pretreated with protease no longer promoted S. aureus surface colonization, suggesting the involvement of protein factors. The major protein components of secretions were identified and subsequent analysis revealed that hemoglobin possessed the ability to promote S. aureus surface colonization. Immunoprecipitation of hemoglobin from nasal secretions resulted in reduced S. aureus surface colonization. Furthermore, exogenously added hemoglobin significantly decreased the inoculum necessary for nasal colonization in a rodent model. Finally, we found that hemoglobin prevented expression of the agr quorum sensing system and that aberrant constitutive expression of the agr effector molecule, RNAIII, resulted in reduced nasal colonization of S. aureus. Collectively our results suggest that the presence of hemoglobin in nasal secretions contributes to S. aureus nasal colonization.

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Iron is required for Staphylococcus aureus growth and persistence and hence must be acquired during infection. Most vertebrate iron is utilized as a cofactor in biochemical reactions that occur intracellularly. This intracellular pool of iron is generally not available to extracellular pathogens such as S. aureus. Moreover, the amount of free iron found within the serum is negligible, as it is usually complexed to high-affinity iron-binding proteins. This process of iron sequestration by the host, also referred to as nutritional immunity, inhibits the growth of invading microorganisms. In response to this severe iron limitation, S. aureus has evolved sophisticated strategies to obtain iron required to proliferate within vertebrates. This review provides a comprehensive analysis of the pathways S. aureus utilizes to obtain iron during infection.

Molecular Mechanisms of Staphylococcus aureus Iron Acquisition. Annual Review of Microbiology June 2, 2011 doi: 10.1146/annurev-micro-090110-102851
The unique redox potential of iron is an ideal cofactor in diverse biochemical reactions. Iron is therefore vital for the growth and proliferation of nearly all organisms, including pathogenic bacteria. Vertebrates sequester excess iron within proteins in order to alleviate toxicity and restrict the amount of free iron available for invading pathogens. Restricting the growth of infectious microorganisms by sequestering essential nutrients is referred to as nutritional immunity. In order to circumvent nutritional immunity, bacterial pathogens have evolved elegant systems that allow for the acquisition of iron during infection. The gram-positive extracellular pathogen Staphylococcus aureus is a commensal organism that can cause severe disease when it gains access to underlying tissues. Iron acquisition is required for S. aureus colonization and subsequent pathogenesis. Herein we review the strategies S. aureus employs to obtain iron through the production of siderophores and the consumption of host heme.

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It is eye-opening to search the internet for the term MRSA (methicillin-resistant Staphylococcus aureus) these days. Instead of epidemiological treatises from Morbidity and Mortality Weekly Report, or reports of decreasing surgical site infections attributed to the advent of active surveillance followed by decolonization and contact isolation procedures, one finds that the first items that are highlighted link to Michael Jackson’s nose infection following another of his minor rhinoplastic touch-ups; a web page devoted to the new best-seller wannabe, Maryn McKenna’s book Superbug, The Fatal Menace of MRSA; and recently World MRSA Day (October 2nd, in case your laboratory wishes to have an event) sponsored by the MRSA Survivors’ Network. Yes, MRSA has celebrity spokespersons, in the shape of actors Tanner Richie and Alicia Cole. How did this microbe, only a few years older than HIV, become so infamous? Actually, we have ourselves partly to blame…

MRSA: a case of pathogens, politics and penalties. Trends Microbiol. 23 Feb 2011
In the current era of public scientific ‘debate’ such as the scientific merit of climate change, it should come as no surprise that a bacterium would have its 15 minutes of political limelight. Furthermore, a few dedicated citizens can truly influence the lives of many by changing the law of the land. For microbiologists, who often complain that our contributions go unnoticed and that we have no political power, this story serves to prove otherwise.

Related:

• MRSA: Methicillin-resistant Staphylococcus aureus
• Clustering of MRSA strains across Europe
• Staphylococcus aureus: superbug

Antibiotics can have ecological effects that impact the efficacy of other antimicrobial agents or facilitate the development of secondary infections. When antibiotics are administered, particularly when they are overused or misused, they change the environment and the biome, which in turn can lead to the selection or development of bacterial strains resistant to a wide range of antibiotic agents, extending beyond the particular antibiotic or antibiotic class initially administered. Certain antibiotic agents also change the normal bacterial flora or environment within the gastrointestinal tract, which in turn can promote the colonization and overgrowth of particular bacteria (e.g. Clostridium difficile), and increase the risk of gastrointestinal infections associated with these bacteria. Antibiotic usage can also have an impact on skin and mucosa colonization (such as for methicillin-resistant Staphylococcus aureus) with significantly increased risk of subsequent infections. These forms of ‘collateral damage’ associated with antibiotic use are important considerations when deciding how best to use antibiotics to prevent or treat infections in the hospital (and community) setting. This review looks at some of the ecological effects of antibiotics used in the hospital and their potential for collateral damage of the nosocomial environment. Collateral damage is becoming an increasing problem due to the increasing severity of illness in hospitalized patients and the increasing use of broad-spectrum antibiotics. The ultimate goal is to understand how to better use antibiotics to optimize their beneficial effects, while minimizing risk of collateral damage, in other words, to improve antibiotic stewardship within hospitals and other institutions.

Beyond the target pathogen: ecological effects of the hospital formulary. (2011) Curr Opin Infect Dis. 24 Suppl 1: S21-31
Antibiotic therapy has the potential for intended as well as unintended consequences due to ecological effects that extend beyond the target pathogen. This review examines some of the collateral damage and collateral benefit that may occur when using antibiotic therapy. Antibiotics excreted in the gastrointestinal tract cause alterations of the indigenous flora. Such disruptions may increase the risk of colonization and overgrowth of pathogenic bacteria, including resistant species, with the potential for serious infection for an individual patient as well as possible hospital-wide dissemination resulting in local outbreaks of infection. For example, Clostridium difficile infection (CDI), and particularly associated diarrhea and colitis, is a potentially serious and growing problem in hospitals worldwide, and is associated with disruption of gut flora through use of broad-spectrum antibiotics, especially those with antianaerobic activity. Infection control measures and improved antibiotic stewardship are key measures for CDI prevention. Another example is the risk of intestinal colonization and overgrowth with resistant bacteria, which is heightened in surgical patients requiring antimicrobial therapy for intraabdominal infections. Results from two Optimizing Intra-Abdominal Surgery with Invanz studies (OASIS-I and OASIS-II) suggested emergence of resistant Enterobacteriaceae was less likely in these patients treated with ertapenem than in those treated with ceftriaxone/metronidazole or piperacillin/tazobactam. Finally, recent studies have reported that increased use of a nonpseudomonal carbapenem such as ertapenem does not reduce the susceptibility of Pseudomonas aeruginosa to pseudomonal carbapenems, for example, imipenem or meropenem. In fact, data from one study showed increased ertapenem/decreased imipenem use was associated with improved susceptibility of P. aeruginosa to imipenem, probably due to decreased selective pressure for resistant species. Improper antibiotic use can be associated with detrimental effects related to the ecological impacts of these drugs. Improved antibiotic stewardship and appropriate infection control measures are key to minimization of the collateral damage associated with antibiotic therapy and may even have collateral benefits.