Strain‐Specific Iron‐Dependent Virulence in<i>Escherichia coli</i>

Telang, Sucheta; Vimr, Eric R.; Mahoney, John R.; Law, I.L.G.; Lundqvist-Gustafsson, Helen; Qian, Mingwei; Eaton, John W.

doi:10.1086/322017

Cited by 9 publications

(4 citation statements)

References 32 publications

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“…However, the relevance of these mechanisms to the virulence of NTHi in the chinchilla model must be speculative, given that chinchilla sera do not support in vitro bactericidal activity in the absence of an exogenous source of complement. Sialylation also modulates microbial interactions with host cells, for example by inhibiting phagocytosis or by sterically impeding the interaction of cell surface molecules such as adhesins and invasins (9,(30)(31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Host-derived sialic acid is incorporated into Haemophilus influenzae lipopolysaccharide and is a major virulence factor in experimental otitis media

Bouchet

Hood

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

191

192

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Otitis media, a common and often recurrent bacterial infection of childhood, is a major reason for physician visits and the prescription of antimicrobials. Haemophilus influenzae is the cause of Ϸ20% of episodes of bacterial otitis media, but most strains lack the capsule, a factor known to play a critical role in the virulence of strains causing invasive H. influenzae disease. Here we show that in capsule-deficient (nontypeable) strains, sialic acid, a terminal residue of the core sugars of H. influenzae lipopolysaccharide (LPS), is a critical virulence factor in the pathogenesis of experimental otitis media in chinchillas. We used five epidemiologically distinct H. influenzae isolates, representative of the genetic diversity of strains causing otitis media, to inoculate the middle ear of chinchillas. All animals developed acute bacterial otitis media that persisted for up to 3 wk, whereas isogenic sialic acid-deficient mutants (disrupted sialyltransferase or CMP-acetylneuraminic acid synthetase genes) were profoundly attenuated. MS analysis indicated that WT bacteria used to inoculate animals lacked any sialylated LPS glycoforms. In contrast, LPS of ex vivo organisms recovered from chinchilla middle ear exudates was sialylated. We conclude that sialylated LPS glycoforms play a key role in pathogenicity of nontypeable H. influenzae and depend on scavenging the essential precursors from the host during the infection.ex vivo isolate ͉ phylogeny ͉ mass spectrometry C arried by up to 80% of humans, Haemophilus influenzae (Hi) is a common nasopharyngeal commensal. Capsule-deficient or nontypeable (NT) Hi can cause upper and lower respiratory tract infections, the most common being episodes of otitis media (OM) in young children. On average, children experience two or more episodes of acute OM by age 2 yr (1), making OM a major cause of physician visits (24 million per year in the U.S.) and of the profligate use of antibiotics in general practice. OM causes sequelae, including impaired hearing (Ϸ20% cases) and cognitive development (2). NTHi is also the most frequent pathogen recovered from the middle ear in children with recurrent OM (3). Although immunity against infection due to NTHi appears to develop after acute OM (4, 5), protection is strain specific, therefore permitting recurrent episodes due to distinct isolates.We have reported that all NTHi OM isolates have the potential to incorporate sialic acid [N-acetylneuraminic acid (Neu5Ac)] into their lipopolysaccharide (LPS), and that strains expressing this sugar are more resistant to the bactericidal activity of normal human serum in vitro (6-8). Although sialylation of LPS has been implicated in bacterial virulence (9), the contribution of sialylated LPS glycoforms of Hi has not been investigated in vivo.We have investigated the role of sialic acid as a virulence factor of NTHi in a well described chinchilla model of OM (10, 11). By comparing isogenic sialic acid-proficient and sialic acid-deficient strains, we show that sialylation of LPS is a major factor in...

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Section: Discussionmentioning

confidence: 99%

Host-derived sialic acid is incorporated into Haemophilus influenzae lipopolysaccharide and is a major virulence factor in experimental otitis media

Bouchet

Hood

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

191

192

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“…However, chinchillas lack a bactericidal mechanism in the absence of exogenously added complement, suggesting that the function of sialylation as a disease factor in this model may have another explanation (22). One important alternative function may be to block phagocytosis through steric hindrance of charge repulsion conferred by the host-derived sialic acid expressed at the cell surface (136). Despite the ambiguous function of sialylation in the otitis media model, therapeutics aimed at blocking the TRAP transporter for sialic acid uptake may have utility in treating H. influenzae infections or other infections where the pathogen relies on precursor scavenging for the host-pathogen interaction.…”

Section: Precursor Scavengingmentioning

confidence: 94%

Diversity of Microbial Sialic Acid Metabolism

Vimr

Kalivoda

Deszo

et al. 2004

Microbiol Mol Biol Rev

516

663

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Sialic acids are structurally unique nine-carbon keto sugars occupying the interface between the host and commensal or pathogenic microorganisms. An important function of host sialic acid is to regulate innate immunity, and microbes have evolved various strategies for subverting this process by decorating their surfaces with sialylated oligosaccharides that mimic those of the host. These subversive strategies include a de novo synthetic pathway and at least two truncated pathways that depend on scavenging host-derived intermediates. A fourth strategy involves modification of sialidases so that instead of transferring sialic acid to water (hydrolysis), a second active site is created for binding alternative acceptors. Sialic acids also are excellent sources of carbon, nitrogen, energy, and precursors of cell wall biosynthesis. The catabolic strategies for exploiting host sialic acids as nutritional sources are as diverse as the biosynthetic mechanisms, including examples of horizontal gene transfer and multiple transport systems. Finally, as compounds coating the surfaces of virtually every vertebrate cell, sialic acids provide information about the host environment that, at least in Escherichia coli, is interpreted by the global regulator encoded by nanR. In addition to regulating the catabolism of sialic acids through the nan operon, NanR controls at least two other operons of unknown function and appears to participate in the regulation of type 1 fimbrial phase variation. Sialic acid is, therefore, a host molecule to be copied (molecular mimicry), eaten (nutrition), and interpreted (cell signaling) by diverse metabolic machinery in all major groups of mammalian pathogens and commensals

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“…Teleologically, such responses to oxidized Hb may make sense; the presence of a hemorrhagic focus implies that the integument has been breached. Such an incident may permit the entry of adventitious bacteria, most of which can use Hb iron as fertilizer and with which they can grow rapidly [80]. In this light, it may be no surprise that Hp can suppress the Hb-driven growth of pathogenic bacteria [44].…”

Section: Biological Effects Of Oxidized Hbmentioning

confidence: 99%

Natural History of the Bruise: Formation, Elimination, and Biological Effects of Oxidized Hemoglobin

Jeney

Eaton

Balla

et al. 2013

Oxidative Medicine and Cellular Longevity

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Numerous disease states are associated with hemolysis or hemorrhage. Because red cells in the extravascular space tend to lyse quickly, hemoglobin (Hb) is released and is prone to autoxidation producing MetHb. Inorganic and organic peroxides may convert Hb and MetHb to higher oxidation states such as ferrylHb. FerrylHb is not a single chemical entity but is a mixture of globin- and porphyrin-centered radicals and covalently cross-linked Hb multimers. Oxidized Hb species are potent prooxidants caused mainly by heme release from oxidized Hb. Moreover, ferrylHb is a strong proinflammatory agonist that targets vascular endothelial cells. This proinflammatory effect of ferrylHb requires actin polymerization, is characterized by the upregulation of proinflammatory adhesion molecules, and is independent of heme release. Deleterious effects of native Hb are controlled by haptoglobin (Hp) that binds cell-free Hb avidly and facilitates its removal from circulation through the CD163 macrophage scavenger receptor-mediated endocytosis. Under circumstances of Hb oxidation, Hp can prevent heme release from MetHb, but unfortunately the Hp-mediated removal of Hb is severely compromised when Hb is structurally altered such as in ferrylHb allowing deleterious downstream reactions to occur even in the presence of Hp.

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Strain‐Specific Iron‐Dependent Virulence inEscherichia coli

Cited by 9 publications

References 32 publications

Host-derived sialic acid is incorporated into Haemophilus influenzae lipopolysaccharide and is a major virulence factor in experimental otitis media

Host-derived sialic acid is incorporated into Haemophilus influenzae lipopolysaccharide and is a major virulence factor in experimental otitis media

Diversity of Microbial Sialic Acid Metabolism

Natural History of the Bruise: Formation, Elimination, and Biological Effects of Oxidized Hemoglobin

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