17 September 2002 21:00 EST

by Bea Perks

Loughborough, UK. - The ability of Staphylococci and other bacteria to evolve ways of evading the antimicrobials deployed against them presents stark warning to microbiologists, inspiring them to develop novel alternatives to these one-time therapeutic mainstays. Their latest efforts to develop suitable non-antimicrobial therapies in the fight against infection are targeting both the innate and acquired host immune responses.

Jos van Strijp, professor of microbiology at the Eijkman Winkler Institute in Utrecht, Holland, is concentrating his research efforts on the innate immune system. Components of innate immunity are particularly well conserved across the animal kingdom, says van Strijp, and the immune system itself relies on the ability to recognize evolutionarily conserved structures borne by pathogens themselves.

"If you can recognize LPS [lipopolysaccharide] you can recognize all gram negative bacteria," said van Strijp; similarly, a system that recognizes the bacterial chemotactic peptide fMLP (formylmethionyl-leucylphenylalanine) can recognize all bacteria. All this, he adds, without the defining components of the acquired immune response, otherwise known as antibodies.

Van Strijp presented his latest findings this morning at the 151st Ordinary Meeting of the Society for General Microbiology here at Loughborough University. When bacteria enter their host, he says, they are surrounded by formylated proteins, such as fMLP, and by one of the complement proteins, C5a. The infected host detects these proteins by means of the formylated peptide receptor (FPR) and the C5a receptor (C5aR), both of which are found on the surface of neutrophils - the "cornerstones of the innate immune system," says van Strijp.

Ligand binding activates the neutrophils while stimulating chemotaxis so that these inflammatory cells are swiftly recruited to the site of infection. Not surprisingly, Staphylococci have evolved a means of hijacking this system in order to prevent being attacked and destroyed by the recruited neutrophils, says van Strijp.

He previously showed that the supernatant fluid surrounding growing Staphylococci downregulates the ability of FPR and C5aR to bind their ligands. Since then, he has been trying to find out what component of the supernatant is responsible for this anti-inflammatory activity.

Now, van Strijp has narrowed it down to a 14 kiloDalton protein with no homology to any known protein. He has named it CHIPS - CHemotaxis Inhibitory Protein of Staphylococci - and established that it is able to block neutrophil chemotaxis and activation both in vitro and in vivo. Crucially, though, CHIPS only blocks neutrophil responses via the two receptors FPR and C5aR; responses to other neutrophil chemoattractants, such as interleukin 8, are unaffected.

Van Strijp excitedly told delegates that CHIPS is due to enter a Phase I clinical trial next month. He hopes that administration of the protein at an early stage of staphylococcal infection will augment the protein's anti-inflammatory effects, preventing progression of the neutrophil-mediated inflammation that gives rise to disease symptoms.

But one possible drawback of a CHIPS therapy, suggested a fellow delegate at this morning's symposium, is that patients' immune systems may well launch an antibody-mediated attack on the protein. CHIPS's discovery may be recent, he argued, but the human immune system has no doubt evolved alongside the protein for millennia and may thus be well equipped with anti-CHIPS antibodies.

Van Strijp argues otherwise. Only 10% of the population have significant levels of anti-CHIPS antibodies, he claims, and these people could safely be given a larger dose of the protein.

Antibodies, so swiftly dismissed by van Strijp, are key to another non-antimicrobial scheme for combatting streptococcal infection. Simon Clarke, a postdoc in the Department of Molecular Biology and Biotechnology at the UK's University of Sheffield, has been hunting for potential vaccine components that are expressed by Staphylococci during active infection.

Clarke has taken sera from people infected with S. aureus and analyzed it for the presence of antigens expressed by the bacterium. This painstaking process has culminated in the construction of a database of in vivo expressed genes, he told delegates.

"We have isolated 355 clones, which has yielded 115 loci," said Clarke. "We have isolated clones of several known surface proteins, a novel hemolysin, and several other novel surface proteins, some of which may be useful as vaccine components." One of the most promising candidates among them, he adds, is a 1.1 megaDalton surface protein called Ebh.

The therapeutic success or failure of van Strijp and Clarke's approaches will be closely monitored by microbiologists worldwide, as the threat posed by resistant bacterial strains spreads wider and wider and the need for alternative, non-antimicrobial therapies has never been greater. This was underscored by a separate talk at today's symposium, which revealed for the first time that one of the most infamous antimicrobial-resistant infections, methicillin-resistant S. aureus (MRSA), is capable of forming fast-growing biofilms - sheets of bacterial cells that can coat the surface of implant devices such as catheters and artificial heart valves and proceed to do some serious harm.

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See also:
Staphylococcal resistance to antimicrobial peptides of mammalian and bacterial origin
[Review]
Andreas Peschel and L. Vincent Collins
Peptides, 2001, 22:10:1651-1659

The emergence and evolution of methicillin-resistant Staphylococcus aureus
[Review]
Keiichi Hiramatsu, Longzhu Cui, Makoto Kuroda et al.
Trends in Microbiology, 2001, 9:10:486-493

The rise and fall of antimicrobial resistance
[Review]
Marc Lipsitch
Trends in Microbiology, 2001, 9:9:438-444
 

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