The Staphylococcus aureus Map protein is an immunomodulator that interferes with T cell–mediated responses

Abstract

Staphylococcus aureus (SA) is an opportunistic pathogen that affects a variety of organ systems and is responsible for many diseases worldwide. SA express an MHC class II analog protein (Map), which may potentiate SA survival by modulating host immunity. We tested this hypothesis in mice by generating Map-deficient SA (Map(-)SA) and comparing disease outcome to wild-type Map(+)SA-infected mice. Map(-)SA-infected mice presented with significantly reduced levels of arthritis, osteomyelitis, and abscess formation compared with control animals. Furthermore, Map(-)SA-infected nude mice developed arthritis and osteomyelitis to a severity similar to Map(+)SA-infected controls, suggesting that T cells can affect disease outcome following SA infection and Map may attenuate cellular immunity against SA. The capacity of Map to alter T cell function was tested more specifically in vitro and in vivo using native and recombinant forms of Map. T cells or mice treated with recombinant Map had reduced T cell proliferative responses and a significantly reduced delayed-type hypersensitivity response to challenge antigen, respectively. These data suggest a role for Map as an immunomodulatory protein that may play a role in persistent SA infections by affecting protective cellular immunity.

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

“…The recombinant proteins rEfb (17), rEfb104, rEfb120, and rEfb165 were expressed as recombinant N-terminal His-tagged proteins that allowed for purification using metal ion-chelating chromatography as described previously (12,59). Proteins were expressed and purified as previously described (59,60).…”

“…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).…”

“…The ability of S. aureus to affect such diverse tissues and cause persistent infections is in part related to their ability to manipulate or evade multiple defense mechanisms (1,(12)(13)(14)(15)(16)(17). Pathogens associated with persistent infections often produce multiple microbial immunomodulatory molecules (12,17) to counter the immune systems of the host (i.e.…”

“…Pathogens associated with persistent infections often produce multiple microbial immunomodulatory molecules (12,17) to counter the immune systems of the host (i.e. adaptive and innate immunity) (12,17), and this strategy results in the effective avoidance or delay of the pathogen clearance while concomitantly affecting the development of a protective memory response. Well characterized members of the S. aureus microbial immunomodulatory molecule family of proteins are the super antigens and protein A, which can affect T cell and antibody responses, respectively (1).…”

“…Well characterized members of the S. aureus microbial immunomodulatory molecule family of proteins are the super antigens and protein A, which can affect T cell and antibody responses, respectively (1). Recent additions to this rapidly growing protein family are the secreted extracellular fibrinogen-binding protein (Efb) 1 (18 -23), which we identified as an inhibitor of various complement-mediated processes (17), the major histocompatibility complex class II analog protein (Map), which interferes with T cell function and neutrophil migration (12,24), and the chemotaxis inhibitory protein from S. aureus (CHIPS) (13,25), which interferes with the inflammatory response early in the infection process by binding to the C5a-and formylated peptide receptors.…”