Fig. 1: Haemolysis caused by S.aureus.
Staphylococcus aureus is one of a peculiar bacteria. S. aureus, also known as a golden staph, i.e. Latin aureus, forms golden-yellow colonies on agar plates. Sometimes, it also causes haemolysis, the breakdown of red blood cells, when grown on agar plates containing blood (Fig. 1). S. aureus is frequently found on the skin and in the nostrils, and an estimated 20% of the human population carry S. aureus without any symptoms. On the other hand, S. aureus is also an important pathogen causing a wide range of diseases.
Staphylococcus aureus is a spherical bacterium, i.e. Latin coccus (Fig. 2A), and belongs to a group of Gram-positive bacteria. Unlike Gram-negative bacteria, the Gram-positive bacteria have a thick bacterial cell wall that is made of peptidoglycan. This additional layer has structural and functional roles, for example, it counteracts the osmotic pressure of the cytoplasm. Thanks to the presence of peptidoglycan, the bacteria retain crystal violet stain that is used during the Gram test. This makes the bacteria look purple under the microscope, therefore, S. aureus is positive for Gram stain (Fig. 2B). On the other hand, Gram-negative bacteria, such as Escherichia coli, have much thinner peptidoglycan layer. Consequently, they cannot retain the violet stain but they take up a red counterstain instead and thus appear reddish or pinkish under the microscope (Fig. 2B).
Fig. 2: A. Scanning electron micrograph of S.aureus. B Gram staining, named after histologist Hans Christian Gram, who developed the staining procedure in order to identify bacteria in infected tissues.
The distinction of bacteria between Gram-positive and Gram-negative is important for the correct diagnosis and consequently for the right antibiotic treatment. While some antibiotics kill Gram-positive bacteria, they are harmless to Gram-negative bacteria. Interestingly, despite their thicker peptidoglycan layer, the Gram-positive bacteria are generally more vulnerable to antibiotics than gram-negative bacteria. However, both types of bacteria have developed antibiotic resistance, mostly due to the improper and excessive use of antibiotics.
In healthy people, S. aureus does not cause any complications, on the contrary, it is an active part of a microflora. Microflora is a group of all the microorganisms which reside on or within a human body, for example on the skin (Fig. 3), in the respiratory or gastrointestinal tract. The presence and maintenance of beneficial commensal bacteria confers several health benefits for us. Firstly, microflora helps us to prevent infections by competing with pathogenic bacteria for nutrients and space and thus reducing the chance of acquiring infections. Secondly, commensal bacteria produces metabolites that break down certain nutrients in the gut thus influencing our digestion and metabolism. Last but not least, microflora most likely shape our immune responses and alterations or imbalance of the microflora composition for instance during an antibiotic treatment, might contribute to diseases such as Crohn’s disease or ulcerative colitis. However, the overall role and effect of microflora on our health is still not well understood and requires many more studies.
S. aureus, on the other hand, can also be a significant human pathogen that causes a wide range of illnesses. S. aureus is responsible for minor skin infections such as pimples, impetigo, folliculitis, carbuncles, and abscesses, as well as for life-threatening diseases including pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, bacteraemia, and sepsis. The primary site of infection is usually a scratch on the skin followed by an extensive tissue destruction and necrosis. In addition, S. aureus is one of the most common causes of hospital-acquired (also called nosocomial) infections and is often the cause of postsurgical wound infections. S. aureus has an incredible ability to persist and form biofilms on medical devices and thus constitute a further source of infections. Therefore, S. aureus infections are especially dangerous for patients who are immuno-compromised or convalescing from surgeries.
Even though S. aureus can be present on the skin, the majority of people carries it in the anterior nares of the nasal passages and in the ears. The ability to harbour S. aureus results from a combination of an altered host immunity and the bacterium's ability to escape host innate immunity. The carriage of S. aureus is an important source of nosocomial and community-acquired infections, especially in the context of the increasing prevalence of methicillin-resistant S. aureus strains (MRSA) within the community. MRSA is clinically the most dangerous strain since only a single plasmid (a genetic element that carries genes for an antibiotic resistance) is responsible for bacterial resistance to the most frequently prescribed β-lactam antibiotics such as penicillins, cephalosporins and carbapenems. Surprisingly, MRSA was reported only shortly after the first use of methicillin in 1960 (Fig. 4). Nowadays, due to the overuse of antibiotics, MRSA has become the most frequently isolated antibiotic-resistant pathogen in the hospitals worldwide. This is especially worrying since hospital-acquired MRSA infections were shown to increase morbidity, the risk of mortality and the costs of treatment for both the patients and the hospitals.
Furthermore, distinct bacterial strains and species can exchange their genetic information via a process called horizontal gene transfer. This helps bacteria to survive during unfavourable conditions and thus significantly speeds up the spread of resistance genes within bacterial populations. Consequently, in 2002, S. aureus strain resistant to vancomycin (VRSA), an antibiotic that is used to treat MRSA infections, was isolated from patient who was co-infected with vancomycin-resistant enterococci. Hence, scientists all over the world are extensively searching for and studying new approaches to prevent, to treat and to eliminate this rogue bacterium.
So far, there is no approved vaccine against S. aureus infections despite several clinical trials. While some of the vaccine candidates have shown immune protection, others impaired immune responses. In 2005, the phase III trial of StaphVax vaccine by Nabi Biopharmaceuticals failed and further development was stopped. Merck’s V710 vaccine trial was terminated during phase II/III due to the higher mortality and morbidity among patients who developed S. aureus infection. Lastly, S. aureus four-antigen vaccine SA4Ag developed by Pfizer has commenced a phase 2b trial in 2015 with yet unpublished results.
There are many speculations why design of anti-S. aureus vaccine is so difficult. Firstly, most of the research on S. aureus infections is based on mouse models; however, mouse is not a natural host of human S. aureus isolates. Furthermore, distinct mechanisms play a role during activation of protective immunity in mice and in humans. Secondly, the long-term interaction between S. aureus in the microflora and our immune system has probably induce a natural protection already. Lastly, S. aureus has a great arsenal of manipulative strategies which enables it to escape from our immune system. Hence, the question is whether it is possible to design a universal vaccine against S. aureus. Perhaps, we should focus on prevention of infection and reduction of complications during S. aureus infections since it seems that S. aureus is so far winning this battle.
Fig. 1: Haemolysis caused by S.aureus.