The Staphylococcus aureus secretome - TI Pharma

Chapter 9
General summary and discussion
The human body functions as a host to many bacteria. Normally, we have no problem
carrying all these bacteria, and some are even beneficial to us. One can think of the bacteria
that are present in our colon that help us by synthesizing vitamins (Vitamine K, biotin), or
bacteria that help to break down food components that we cannot digest, such as starch and
various other fibers. Other bacteria are dangerous pathogens, causing diseases that can be
lethal to human beings. Several of these primary pathogens cause well known diseases, like
Clostridium tetani (tetanus), Corynebacterium diphtheria (diphtheria), Treponema pallidum
(syphilis), Vibrio cholerae (cholera), Mycobacterium leprae (leprosy) and Mycobacterium
tuberculosis (tuberculosis).
Staphylococcus aureus and Staphylococcus epidermdis are two of those bacteria that are
living as commensals in the moist places and the skin of the human body. For healthy
humans, S. aureus is not considered as a serious threat and ~20% of the population carries this
organism in the nose. However, when the host defenses are breached and S. aureus is able to
spread throughout the human body, this organism can turn into a dangerous pathogen. The
infective properties of S. aureus are caused by the arsenal of virulence factors that are
expressed by this organism. As with all pathogens, these virulence factors are often
proteinaceous compounds that are necessary for the bacterium to invade, colonize and spread
throughout the (human) host and compounds that contribute to the symptoms of disease. All
these virulence factors are synthesized in the cytoplasm of the cell and translocated across the
bacterial membrane to an extracytoplasmic location, such as the cell surface or the host
milieu. Well-characterized virulence factors include the many exotoxins of S. aureus.
Most virulence factors are synthesized with an N-terminal signal peptide. This signal peptide
is recognized by cytoplasmic chaperones that lead the protein to translocation pathways that
are present in the cell. At the trans-side of the membrane, the translocated virulence factors
are processed into their mature form and folded into the correct three-dimensional
conformation with or without the help of other proteins. While several proteins are released
into the environment (e.g. exotoxins), other proteins are retained at the surface of the cell. In
Gram-positive bacteria, at least four extracytoplasmic cellular locations are distinguished: the
membrane, the membrane-cell wall interface, the cell wall and the cell surface. All these
locations can contain important virulence factors.
Soon after the introduction of penicillin to eradicate the threat of S. aureus infections,
resistant strains emerged and today the multidrug resistant S. aureus strains are imposing both
therapeutic and financial challenges to our health care. The last resort antibiotic is
vancomycin, but in the last 10-15 years S. aureus strains that are less susceptible or even fully
resistant to vancomycin have been isolated. The need to search for alternatives to antibiotics
such as vaccines and target-directed drugs is therefore increasing. These alternative drugs or
vaccines should be directed against a specific protein or process which decreases the chance
of survival of the pathogenic bacteria in the human host without interfering with the host’s
health.
This thesis describes investigations on the secretome of S. aureus. By definition, the
secretome includes all proteins that are translocated across the bacterial membrane to
extracytoplasmic locations plus all the proteins that make up the protein translocation
machinery.
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