Biomedical subjects

Fredric Carlsson

Publications and source records attributed to Fredric Carlsson.

6 recordsLinked to original sources

PubMed2006

Signal sequence directs localized secretion of bacterial surface proteins.

All living cells require specific mechanisms that target proteins to the cell surface. In eukaryotes, the first part of this process involves recognition in the endoplasmic reticulum of amino-terminal signal sequences and translocation through Sec translocons, whereas subsequent targeting to different surface locations is promoted by internal sorting signals. In bacteria, N-terminal signal sequences promote translocation across the cytoplasmic membrane, which surrounds the entire cell, but some proteins are nevertheless secreted in one part of the cell by poorly understood mechanisms. Here we analyse localized secretion in the Gram-positive pathogen Streptococcus pyogenes, and show that the signal sequences of two surface proteins, M protein and protein F (PrtF), direct secretion to different subcellular regions. The signal sequence of M protein promotes secretion at the division septum, whereas that of PrtF preferentially promotes secretion at the old pole. Our work therefore shows that a signal sequence may contain information that directs the secretion of a protein to one subcellular region, in addition to its classical role in promoting secretion. This finding identifies a new level of complexity in protein translocation and emphasizes the potential of bacterial systems for the analysis of fundamental cell-biological problems.

Adhesins, Bacterial↗

PubMed2006

Actin-based motility of intracellular bacteria, and polarized surface distribution of the bacterial effector molecules.

Several intracellular bacterial pathogens, including species of Listeria, Rickettsia, Shigella, Mycobacteria, and Burkholderia, have evolved mechanisms to exploit the actin polymerization machinery of their hosts to induce actin-based motility, enabling these pathogens to spread between host cells without exposing themselves to the extracellular milieu. Efficient cell-to-cell spread requires directional motility, which the bacteria may achieve by concentrating the effector molecules at one pole of their cell body, thereby restricting polymerization of monomeric actin into actin tails to this pole. The study of the molecular processes involved in the initiation of actin tail formation at the bacterial surface, and subsequent actin-based motility, has provided much insight into the pathogenesis of infections caused by these bacteria and into the cell biology of actin dynamics. Concomitantly, this field of research has provided an opportunity to understand the mechanisms whereby bacteria can achieve a polarized distribution of surface proteins. This review will describe the process of actin-based motility of intracellular bacteria, and the mechanisms by which bacteria can obtain a polarized distribution of their surface proteins.

Actins↗

PubMed2006

Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes.

Antibodies directed against a pathogenic microorganism may recognize either protective or non-protective epitopes. Because antibodies elicited by a vaccine must be directed against protective epitopes, it is essential to understand the molecular properties that distinguish the two types of epitope. Here we analyse this problem for the antiphagocytic M protein of Streptococcus pyogenes, using the opsonizing capacity of antibodies to estimate their ability to confer protection in vivo. Our studies were focused on the M5 protein, which has three surface-exposed regions: the amino-terminal hypervariable region (HVR) and the B- and C-repeat regions. We first analysed the role of different M5 regions in phagocytosis resistance under non-immune conditions, employing chromosomal mutants expressing M5 proteins with internal deletions, and demonstrate that only the B-repeat region is essential for phagocytosis resistance. However, only antibodies to the HVR were opsonic. This apparent paradox could be explained by the ability of fibrinogen and albumin to specifically bind to the B- and C-repeats, respectively, causing inhibition of antibody binding under physiological conditions, while antibodies to the HVR could bind and promote deposition of complement. These data indicate that binding of human plasma proteins plays an important role in determining the location of opsonic and non-opsonic epitopes in streptococcal M protein.

Animals↗

PubMed2005

Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway.

Human fibrinogen (Fg) binds to surface proteins expressed by many pathogenic bacteria and has been implicated in different host-pathogen interactions, but the role of bound Fg remains unclear. Here, we analyse the role of Fg bound to Streptococcus pyogenes M protein, a major virulence factor that confers resistance to phagocytosis. Studies of the M5 system showed that a chromosomal mutant lacking the Fg-binding region was completely unable to resist phagocytosis, indicating that bound Fg plays a key role in virulence. Deposition of complement on S. pyogenes occurred via the classical pathway even under non-immune conditions, but was blocked by M5-bound Fg, which reduced the amount of classical pathway C3 convertase on the bacterial surface. This property of M protein-bound Fg may explain its role in phagocytosis resistance. Previous studies have shown that many M proteins do not bind Fg, but interfere with complement deposition and phagocytosis by recruiting human C4b-binding protein (C4BP), an inhibitor of the classical pathway. Thus, all M proteins may share ability to recruit a human plasma protein, Fg or C4BP, which inhibits complement deposition via the classical pathway. Our data identify a novel function for surface-bound Fg and allow us to propose a unifying mechanism by which M proteins interfere with innate immunity.

Antigens, Bacterial↗

PubMed2004

Host-pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development.

Streptococcus pyogenes (group A streptococcus) causes a variety of diseases, including acute pharyngitis, impetigo, rheumatic fever and the streptococcal toxic shock syndrome. Moreover, S. pyogenes was responsible for the classical example of a nosocomial infection, the epidemics of puerperal fever (childbed fever) that caused the death of numerous women in earlier centuries. The most extensively studied virulence factor of S. pyogenes is the surface M protein, which inhibits phagocytosis and shows antigenic variation. Recent data indicate that many M proteins confer phagocytosis resistance because the variable N-terminal region has non-overlapping sites that specifically bind two components of the human immune system, the complement inhibitor C4b-binding protein (C4BP) and IgA-Fc. Concerning puerperal fever, molecular and epidemiological analysis suggests that the S. pyogenes surface protein R28 may have played a pathogenetic role in these epidemics. This article summarizes the properties of M protein and the R28 protein and considers a potential problem encountered in connection with the use of animal models for vaccine development.

Antigens, Bacterial↗

PubMed2003

Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein.

The M protein of Streptococcus pyogenes is a major bacterial virulence factor that confers resistance to phagocytosis. To analyze how M protein allows evasion of phagocytosis, we used the M22 protein, which has features typical of many M proteins and has two well-characterized regions binding human plasma proteins: the hypervariable NH2-terminal region binds C4b-binding protein (C4BP), which inhibits the classical pathway of complement activation; and an adjacent semivariable region binds IgA-Fc. Characterization of chromosomal S. pyogenes mutants demonstrated that each of the ligand-binding regions contributed to phagocytosis resistance, which could be fully explained as cooperation between the two regions. Deposition of complement on S. pyogenes occurred almost exclusively via the classical pathway, even under nonimmune conditions, but was down-regulated by bacteria-bound C4BP, providing an explanation for the ability of bound C4BP to inhibit phagocytosis. Different opsonizing antisera shared the ability to block binding of both C4BP and IgA, suggesting that the two regions in M22 play important roles also under immune conditions, as targets for protective antibodies. These data indicate that M22 and similar M proteins confer resistance to phagocytosis through ability to bind two components of the human immune system.

Amino Acid Sequence↗