Chapter 12 : Inflammation and Host Defense

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To detect potential harmful microorganisms, higher eukaryotes have evolved two types of systems, i.e., innate immunity and adaptive immunity. Monocytes and macrophage express both CD14 and Toll-like receptors (TLRs) on their surfaces. Polymorphonuclear cells were shown to express CD14 and at least TLR2. Peptidoglycan-recognizing proteins (PGRPs) are a new family of pathogen-associated molecular pattern (PAMP)-recognizing molecules that are conserved from insects to mammals. PGRPs have several attributed functions, including direct antimicrobial activity or triggering the production of antimicrobial molecules, signaling via the TLR system, and peptidoglycan degradation. The major and most conserved constituent of the envelope of gram-positive organisms is peptidoglycan. One possible explanation is the dissimilar natures of the bacterial components used. Lipopolysaccharide (LPS) is made of noncovalently linked glycolipid subunits that are emulsified by plasma lipoproteins and lipopolysaccharide-binding protein (LBP), which presents them to the cell receptor CD14. The inflammatory activity might also depend on other constraints, including the secondary structure of the components and/or the stereochemistry of their amino acid constituents. Mesodiaminopimelic acid is a precursor of L-lysine. Therefore, it is tempting to make the provocative speculation that gram-positive animal colonizers have evolved an L-lysine peptidoglycan in order be less well detected by innate immunity. The constant inflammatory response to bacterial surface component might be profitable. As far as disease is concerned, the real problem might not be so much the ability of the host to recognize bacterial intruders as much as the capacity of pathogens to escape early recognition by innate immunity.

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12

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Cell Wall Components
Bacterial Cell Wall
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Image of FIGURE 1

Diagram presenting the pneumococcal peptidoglycan and the sites of hydrolysis of naturally occurring -acetylmuramic--alanine amidase (amidase) and muramidase (glycosidase), respectively. Mature pneumococci usually do not contain the terminal -alanine. It is noteworthy that numerous bacteria, including both grampositive and gram-negative genera, contain mesodiaminopimelic acid or even ornithine instead of lysine in position 3 of the stem peptide. G, -acetylglucosamine; M, -acetylmuramic acid. The two first (gray) circles hooked to M represent -alanine and -isoglutamine. The third (white) circle represents -lysine. The fourth (black) circle represents the penultimate -alanine. (Reproduced with permission from reference .)

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Image of FIGURE 2

Assembly of the bacterial cell wall and production of penicillin-induced soluble peptidoglycan. Cell wall precursor disaccharide-pentapeptides are translocated through the plasma membrane and processed by membrane-anchored penicillin-binding proteins (PBP). High-molecular-weight PBPs ensure both a transglycosidase function (upper curved arrow) that elongates the glycan chain and a transpeptidase activity (lower curved arrow) that transfers the peptide bond of the penultimate -alanine (penultimate closed circle) to a diamino acid acceptor at position 3 of the stem peptide (open circle; lysine or lysine-bound glycine side chains in the case of ). Subinhibitory concentrations of penicillin block transpeptidation (see lower curved arrow) but not transglycosylation. As a result, large uncross-linked glycan chains, i.e., soluble peptidoglycan (A), are released in the supernatant. Polymeric soluble peptidoglycan can be hydrolyzed by muramidase (see Fig. 1 ) to disaccharide-pentapeptide subunits (B). Muramyl-dipeptide (C) containing only -acetylmuramic acid and the two first amino acids -alanine and -isoglutamate (or isoglutamine) is the simplest common structure of all bacterial peptidoglycans. Details are as in Fig. 1 . The bars linking Llysines and -alanines represent the pentaglycine side chain typical of staphylococcal peptidoglycan. (Reproduced with permission from reference .)

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Image of FIGURE 3

Molecular structures of one inactive and two active internal fragments of the pneumococcal peptidoglycan. Pneumococcal peptidoglycan was solubilized with amidase, subjected to high-pressure liquid chromatography fractionation, and analyzed by a combination of mass spectrometry, amino acid determination, and TNF-releasing activity on human PBMCs. The TNF-triggering activity is expressed as the minimal concentration of wall materials required to increase the release of TNF by ≥10 times over background. The stem-peptide dimer was poorly active (>0.1 µg/ml), whereas the two stem-peptide trimers were almost as active (0.01 to 0.001 mg/ml) as LPS. (Reproduced with permission from reference .)

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Image of FIGURE 4

Possible structural constraints ensuring high TNF-releasing activity of peptidoglycan of gram-positive organisms. On the left side, soluble peptidoglycan is a large multimer (triplets times n) that is not more inflammatory than whole insoluble peptidoglycan. Hydrolyzing soluble peptidoglycan to disaccharide-pentapeptide results in complete loss of TNF release. On the right side, trimers of pneumococcal stem peptides are the minimal structures conferring high TNF-triggering activity. Shorter structures are inactive, and larger polymers are less active in a weight-to-weight ratio. Thus, trimeric stem peptides might be the most active complexes, whether they are cross-linked via glycan bonds, as in soluble peptidoglycan, or peptide bonds, as in pneumococcal stem peptides. Circles highlight the peptide structures. Details are as in Fig. 1 . (Reproduced with permission from reference .)

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Image of FIGURE 5

Stem peptides are highly unstable structures. The diagram depicts a simple stem peptide with the four-carbon side chain of the diamino acid lysine implicated in peptide cross-links (right) and the multiple possible planar and axial rotations of this very side chain, as well as the amino acids in the stem peptide. Cross-linkage to a second or a third stem peptide may limit free movement to a certain extent, but not enough to stabilize the structure in a fixed position. (Reproduced with permission from reference .)

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Major host molecules recognizing PAMPs

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Threshold bioactivities of cell wall components from different organisms tested in different models

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Anatomy of gram-negative and gram-positive bacteria and major conserved and strain-specific proinflammatory determinants

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12
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Some landmark studies in understanding the structure-activity relationship of inflammation induced by walls of gram-positive organisms

Citation: Majcherczyk P, Moreillon P. 2004. Inflammation and Host Defense, p 183-200. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch12

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