Chapter 15 : Attachment and Invasion of the Respiratory Tract

Diagnosis of pneumonia. (A) Chest X ray. Bilateral lower lobe (R > L) airspace disease in a 14-year-old-boy with sudden onset of fever and cough. (B) Top, axial contrast-enhanced CT through the lung bases and filmed with lung windows demonstrates patchy bilateral lower lobe air space disease (R > L). There are no associated pleural effusions. Bottom, axial contrast-enhanced CT through the mid-chest and filmed with mediastinal windows demonstrates a right hilar lymph node (arrow). (Images courtesy of S. Kaste, St. Jude Children's Research Hospital.) (C) Sputum Gram stain. Gram-positive cocci are visible in meshwork of sputum and cellular debris. (Image courtesy of R. Hayden, St. Jude Children's Research Hospital.)

Model for the inflammatory response to cell wall in the lung. In the alveolar space, pneumococcal cell wall (PCW) (shown as layers of peptidoglycan decorated by projecting choline-containing teichoic acids) interacts with two different signaling pathways. The choline on the teichoic acid binds to PAFr that initiates bacterial uptake into vacuoles supported by the scaffold protein β arrestin and activation of Erk kinases ( 19 , 119 ). The peptidoglycan portion bound to a soluble peptidoglycan recognition protein (for example, lipopolysaccharidebinding protein [LBP] [ 142 ]) is presented to toll-like receptor 2 (TLR2). TLR2 also binds lipoteichoic acid ( 118 ), and TLR4 has been found to bind pneumolysin ( 78 ). Engagement of TLRs elicits production of TNF (shown in inset by immunostaining) and IL-1, resulting in separation of epithelial cells and accumulation of a serous exudate in alveoli.

Schematic domain structure of CbpA. Domains labeled A, R1, and R2 contain multiple repeats of the classical leucine zipper heptad repeat that is found in coiled-coil proteins. PPP is a proline-rich region, and TMH is a putative transmembrane α-helix that serves as a signal sequence for secretion. Ten repeats of the choline-binding motif are found within the C-terminal choline-binding domain (CBD). (Annotated from the TIGR4 sequence.)

Kinetics of events during progression of pneumococcal pneumonia. Bacterial multiplication proceeds unimpeded during the stages of engorgement and red hepatization, peaking at 36 h in the stage of grey hepatization. Bacteremia is a result of pneumococcal adherence to and invasion of alveolar cells. The edema characteristic of engorgement arises from cell-wall induced signaling in epithelial cells and activation of the alternative pathway of the complement cascade by cell wall. Cytokines begin to appear in bronchoalveolar lavage fluid in the first few hours of engorgement but do not reach a maximum until the phase of red hepatization (18 to 24 h). At this stage, the activated endothelium expresses tissue factor forming a platform for procoagulant activity, and the cytolytic activity of pneumolysin is prominent. During the stage of grey hepatization, polymorphonuclear leukocytes (PLN) are recruited and begin to control pneumococcal multiplication. Complement activation by pneumolysin aids in this clearance. The outcome of the infection depends at least in part on the ability of the host to withstand the inflammation associated with bacterial death (i.e., tipping point).