Chemotaxis Inhibitory Protein of Staphylococcus aureus, a Bacterial Antiinflammatory Agent

Abstract

Leukocyte migration is a key event both in host defense against invading pathogens as well as in inflammation. Bacteria generate chemoattractants primarily by excretion (formylated peptides), complement activation (C5a), and subsequently through activation of leukocytes (e.g., leukotriene B4, platelet-activating factor, and interleukin 8). Here we describe a new protein secreted by Staphylococcus aureus that specifically impairs the response of neutrophils and monocytes to formylated peptides and C5a. This chemotaxis inhibitory protein of S. aureus (CHIPS) is a 14.1-kD protein encoded on a bacteriophage and is found in >60% of clinical isolates. CHIPS reduces the neutrophil recruitment toward C5a in a mouse peritonitis model, even though its activity is much more potent on human than on mouse cells. These findings suggest a new immune escape mechanism of S. aureus and put forward CHIPS as a potential new antiinflammatory therapeutic compound.

Identification and Characterization of the C3 Binding Domain of the Staphylococcus aureus Extracellular Fibrinogen-binding Protein (Efb)

“…Furthermore, S. aureus remains one of the most common causes of infections in the industrialized world, and since the 1980s S. aureus has become the most common nosocomial pathogen due in part to an increasing resistance to multiple antibiotics and to the recent worldwide emergence of highly virulent strains (1,(3)(4)(5)(6)(7)(8)(9)(10)(11). In addition, S. aureus infections can result in a variety of diseases, including skin infections, endocarditis, arthritis, osteomyelitis, or sepsis and is a reflection of the capacity of this organism to colonize a variety of different tissues and of their ability to circumvent a variety of immune surveillance systems resulting in the persistence of S. aureus in different environments within the host organism (1,(12)(13)(14).…”

Tyrosine sulfation in N-terminal domain of human C5a receptor is necessary for binding of chemotaxis inhibitory protein of Staphylococcus aureus

“…The gene encoding for CHIPS, chp, lies at a bacteriophageencoded immune cluster, seen in greater than 60% of S aureus isolates [3] . To examine the prevalence of chp in clinical S aureus isolates in our hospital, one of the major referral medical centers in China, we screened 13 methicillin-resistant strains and 13 methicillin-sensitive isolates (MSSA) from blood stream of infected individuals by PCR.…”

“…Expression and purification of recombinant CHIPS was as previously described with minor modification [3,21,22] . Briefly, chp, with the exclusion of its signal sequence, was amplified by PCR on genomic DNA extracted from methicillinresistant staphylococcus aureus (MRSA) ATCC 29213, cloned into pET32a (+) vector, then transformed into Escherichia coli BL21(DE3) plays (Invitrogen).…”

“…One possible mechanism underlying this may be that staphylococci release chemotaxis inhibitory protein of staphylococci (CHIPS) encoded by chp that contributes to the evasion of these bacteria from the immune system of the host. CHIPS has been shown to be necessary for inhibition of the early immune response by blocking the initial activation and recruitment of neutrophils and monocytes into the site of infection [2,3] .…”

Studying Interactions of <em>Staphylococcus aureus</em> with Neutrophils by Flow Cytometry and Time Lapse Microscopy

“…Using this method, it is possible to study the direct effects of toxic and other components on neutrophils, and determine the lowest concentration at which these are active. For us, it is a very useful tool to study the effect of many proteins produced by S. aureus involved in immune evasion, such as FPR2 inhibitory protein (FLIPr) 8 , FLIPr-like 7 , and Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) 9 . All these proteins have been shown to inhibit the calcium mobilization in neutrophils by binding to the receptor recognizing the agonist.…”