Chapter 15 : Attachment and Invasion of the Respiratory Tract

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The description of the patient with lobar pneumococcal pneumonia is considered one of the classics of medicine. The history and physical findings usually establish the diagnosis of pneumonia. The major effect of different genetic backgrounds of animals on the course of infection has been particularly apparent in mice. CbpA is the most abundant of the choline-binding proteins and functions as an adhesin in the upper and lower respiratory tract. Of these, PAFr and epithelium derived C3 play essential roles in pneumococcal interactions with cells in the lung that lead to progression from pneumonia to bacteremia and meningitis. In leukopenic animals, the bacterial load in the lung increases but there is no decrease in the incidence of bacteremia, indicating that events in this stage of consolidation are sufficient to lead to invasion without the effects of leukocytes. In vitro studies have demonstrated that invasion of alveolar cells involves recognition of PAFr by pneumococci. Using COS cells transfected with components of the PAFr, it has been shown that the presence of PAFr is necessary for pneumococcal invasion. This choline-dependent invasion mechanism appears to apply to a large number of respiratory pathogens. Pneumococcal pneumonia is very common and causes a dramatic clinical picture due to intense inflammation in the lung.

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15
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Image of FIGURE 1

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.)

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15
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Image of FIGURE 2

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 ( ). The peptidoglycan portion bound to a soluble peptidoglycan recognition protein (for example, lipopolysaccharidebinding protein [LBP] [ ]) is presented to toll-like receptor 2 (TLR2). TLR2 also binds lipoteichoic acid ( ), and TLR4 has been found to bind pneumolysin ( ). 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.

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15
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Image of FIGURE 3

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.)

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15
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Image of FIGURE 4

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).

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15
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Activities of pneumococcal cell wall in the lung

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15
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Pulmonary virulence determinants

Citation: Tuomanen E. 2004. Attachment and Invasion of the Respiratory Tract, p 221-237. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch15

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