RESUMEN
The current paradigm suggests that Yersinia enterocolitica (Ye) adheres to host cells via the outer membrane proteins Yersinia adhesin A (YadA) or invasin (Inv) to facilitate injection of Yops by the type III secretion system. In this process Inv binds directly to ß1 integrins of host cells while YadA may bind indirectly via extracellular matrix proteins to ß1 integrins. Here we challenged this paradigm and investigated the requirements for Yop injection. We demonstrate that Inv- but not YadA-mediated adhesion depends on ß1 integrin binding and activation, and that tight adhesion is a prerequisite for Yop injection. By means of novel transgenic cell lines, shRNA approaches and RGD peptides, we found that YadA, in contrast to Inv, may use a broad host cell receptor repertoire for host cell adhesion. In the absence of ß1 integrins, YadA mediates Yop injection by interaction with αV integrins in cooperation with yet unknown cofactors expressed by epithelial cells, but not fibroblasts. Electron microscopic and flow chamber studies revealed that a defined intimate contact area between Ye and host cells resulting in adhesion forces resisting shear stress is required for Yop injection. Thus, the indirect binding of YadA to a broad extracellular matrix (ECM) binding host cell receptor repertoire of different cell types makes YadA a versatile tool to ensure Yop injection. In conclusion, given the differential expression of the outer membrane proteins Inv and YadA in the course of Ye infection and differential expression of integrins by various host cell populations, the data demonstrate that Ye is flexibly armed to accomplish Yop injection in different host cell types, a central event in its immune evasion strategy.
Asunto(s)
Adhesinas Bacterianas/metabolismo , Adhesión Bacteriana , Toxinas Bacterianas/metabolismo , Interacciones Huésped-Patógeno , Yersinia enterocolitica/fisiología , Células Epiteliales/microbiología , Fibroblastos/metabolismo , Citometría de Flujo , Integrina alfaV/metabolismo , Integrina beta1/metabolismo , Microscopía Electrónica , Unión Proteica , Transporte de ProteínasRESUMEN
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are the cause of a severe pandemic consisting primarily of skin and soft tissue infections. The underlying pathomechanisms have not been fully understood and we report here a mechanism that plays an important role for the elevated virulence of CA-MRSA. Surprisingly, skin abscess induction in an animal model was correlated with the amount of a major cell wall component of S. aureus, termed wall teichoic acid (WTA). CA-MRSA exhibited increased cell-wall-associated WTA content (WTAhigh) and thus were more active in inducing abscess formation via a WTA-dependent and T-cell-mediated mechanism than S. aureus strains with a WTAlow phenotype. We show here that WTA is directly involved in S. aureus strain-specific virulence and provide insight into the underlying molecular mechanisms that could guide the development of novel anti-infective strategies.
Asunto(s)
Absceso/microbiología , Pared Celular/química , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Infecciones Cutáneas Estafilocócicas/microbiología , Ácidos Teicoicos/biosíntesis , Animales , Antibacterianos/farmacología , Infecciones Comunitarias Adquiridas/microbiología , Masculino , Staphylococcus aureus Resistente a Meticilina/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Ratones , Piel/microbiología , Piel/patología , Ácidos Teicoicos/análisis , Virulencia , Factores de Virulencia/biosíntesisRESUMEN
Cell wall glycopolymers (CWGs) of gram-positive bacteria have gained increasing interest with respect to their role in colonization and infection. In most gram-positive pathogens they constitute a large fraction of the cell wall biomass and represent major cell envelope determinants. Depending on their chemical structure they modulate interaction with complement factors and play roles in immune evasion or serve as nonprotein adhesins that mediate, especially under dynamic conditions, attachment to different host cell types. In particular, covalently peptidoglycan-attached CWGs that extend well above the cell wall seem to interact with glyco-receptors on host cell surfaces. For example, in the case of Staphylococcus aureus, the cell wall-attached teichoic acid (WTA) has been identified as a major CWG adhesin. A recent report indicates that a type-F scavenger receptor, termed SR-F1 (SREC-I), is the predominant WTA receptor in the nasal cavity and that WTA-SREC-I interaction plays an important role in S. aureus nasal colonization. Therefore, understanding the role of CWGs in complex processes that mediate colonization and infection will allow novel insights into the mechanisms of host-microbiota interaction.