Killing of<i>Klebsiella pneumoniae</i>by human alveolar macrophages

Hickman-Davis, Judy M.; O’Reilly, Philip; Davis, Ian C.; Peti‐Peterdi, Janos; Davis, Glenda C.; Young, K. Randall; Devlin, Robert B.; Matalon, Sadis

doi:10.1152/ajplung.00216.2001

Cited by 63 publications

(53 citation statements)

References 56 publications

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“…Klebsiella administration (42). Other investigators have likewise established the essential role that alveolar macrophages play in clearing bacterial pathogens from the lung via their phagocytic and bactericidal functions (43)(44)(45)(46)(47). In this study, we demonstrate yet another potentially important function of alveolar macrophages in innate immunity: as an early source of IFN-␥.…”

Section: Discussionsupporting

confidence: 59%

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

Deng

Zeng

Newstead

et al. 2004

The Journal of Immunology

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Bacterial pneumonia is a leading cause of morbidity and mortality in the U.S. An effective innate immune response is critical for the clearance of bacteria from the lungs. IL-12, a key T1 cytokine in innate immunity, signals through STAT4. Thus, understanding how STAT4 mediates pulmonary immune responses against bacterial pathogens will have important implications for the development of rational immunotherapy targeted at augmenting innate immunity. We intratracheally administered Klebsiella pneumoniae to wild-type BALB/c and STAT4 knockout (STAT4−/−) mice. Compared with wild-type controls, STAT4−/− mice had decreased survival following intratracheal Klebsiella administration, which was associated with a higher lung and blood bacterial burden. STAT4−/− animals also displayed impaired pulmonary IFN-γ production and decreased levels of proinflammatory cytokines, including the ELR− CXC chemokines IFN-γ-inducible protein-10 and monokine induced by IFN-γ. Although total lung leukocyte populations were similar between STAT4−/− and wild-type animals following infection, alveolar macrophages isolated from infected STAT4−/− mice had decreased production of proinflammatory cytokines, including IFN-γ, compared with infected wild-type mice. The intrapulmonary overexpression of IFN-γ concomitant with the systemic administration of IFN-γ partially reversed the immune deficits observed in STAT4−/− mice, resulting in improved bacterial clearance from the blood. Collectively, these studies demonstrate that STAT4 is required for the generation of an effective innate host defense against bacterial pathogens of the lung.

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Section: Discussionsupporting

confidence: 59%

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

Deng

Zeng

Newstead

et al. 2004

The Journal of Immunology

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“…AMs comprise the first line of host defense against microorganisms, but their potency in killing K. pneumoniae remains incompletely understood (25). Our data showed that internalization (phagocytosis) into AMs was significantly decreased by MbCD pretreatment ( Figure 4B), indicating that cholesterol-containing membrane microdomains may be related to the phagocytosis of this pathogen.…”

Section: Raft-dependent Bacterial Internalization Is Enhanced By Delementioning

confidence: 77%

Lipid-Based Signaling Modulates DNA Repair Response and Survival against Klebsiella pneumoniae Infection in Host Cells and in Mice

Huang

Weaver

et al. 2013

Am J Respir Cell Mol Biol

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Klebsiella pneumoniae causes serious infections in the urinary tract, respiratory tract, and blood. Lipid rafts, also known as membrane microdomains, have been linked to the pathogenesis of bacterial infection. However, whether lipid rafts affect K. pneumoniae internalization into host cells remains unknown. Here, we show for the first time that K. pneumoniae was internalized into lung cells by activating lipid rafts. Disrupting lipid rafts by methyl-b-cyclodextrin inhibited pathogen internalization, impairing host defense. A deficient mutant of capsule polysaccharide (CPS) showed a higher internalization rate than a wild-type strain, indicating that CPS may inhibit bacterial entry to host cells. Furthermore, lipid rafts may affect the function of extracellular regulated kinase (ERK)-1/2, and knocking down ERK1/ 2 via short, interfering RNA increased apoptosis in both alveolar macrophages and epithelial cells after infection. To gain insights into bacterial pathogenesis, we evaluated the impact of lipid rafts on DNA integrity, and showed that raft aggregates also affect DNA damage and DNA repair responses (i.e., 8-oxoguanine DNA glycosylase [Ogg1]) through the regulation of reactive oxygen species. Importantly, cells overexpressing Ogg1 demonstrated reduced cytotoxicity during bacterial infection. Taken together, these results suggest that lipid rafts may modulate bacterial internalization, thereby affecting DNA damage and repair, which is critical to host defense against K. pneumoniae.Keywords: Klebsiella pneumoniae infection; internalization; alveolar epithelial cells; lipid rafts; capsule polysaccharide Klebsiella pneumoniae causes serious infections in multiorgan systems, and is the third most commonly isolated bacterium from the blood of patients with sepsis (1). Because K. pneumoniae rapidly develops multidrug-resistant strains, this "superbug" can also cause outbreaks in intensive care units, imposing significant financial burdens and dangerous health threats (2, 3). Despite intensive research during the past few decades, the pathogenesis of K. pneumoniae, including its internalization of alveolar cells, is incompletely understood. K. pneumoniae expresses two critical antigens on its cell surface, LPS (an O antigen) and capsule polysaccharide (CPS; a K antigen) (4). These two antigens contribute to pathogenicity through interactions with host cells in different manners (5). LPS is a major component of Gramnegative bacterial cell walls with high immunogenicity, but its role in pathogenesis remains elusive. Early studies suggest that LPS-deficient strains failed to show significantly different pathogenesis from the wild-type (WT) strain (5). By contrast, CPS demonstrates the most distinguished characteristic of virulence factors for K. pneumoniae, and is implicated in the internalization of pathogens into epithelial cells (6). The capsule may protect the bacterium from phagocytosis by macrophages, through an escape from bactericidal serum factors (6). Other studies also demonstrated that isogenic CPS mutant...

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“…The intracellular killing of K. pneumoniae is likely mediated by several microbicidal molecules, including antimicrobial peptides, reactive nitrogen intermediates, and ROIs (21,(38)(39)(40)(41). However the individual contributions of such molecules are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, in vivo treatments of mice with the nitric oxide synthase inhibitor, L-NAME, impaired host defense against K. pneumoniae (41). Interestingly, HickmanDavis and colleagues (40) demonstrated (in a cell-free system) that, although neither ROIs nor nitric oxide alone were toxic to K. pneumoniae, potent bacterial killing could be observed when a combination of nitric oxide and superoxide was present (at a pH of 5.0), suggesting that optimal bactericidal activity can be achieved when peroxynitrite is formed in an acidic milieu. Our data support this result, as we find requirements for both nitric oxide and NADPHox activation in macrophage killing of K. pneumoniae.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E₂Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase

Serezani

Chung²,

Ballinger³

et al. 2007

Am J Respir Cell Mol Biol

157

150

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Prostaglandin E 2 (PGE 2 ) is a potent lipid mediator that effects changes in cell functions through ligation of four distinct G proteincoupled E prostanoid (EP) receptors (EP1-EP4). PGE 2 inhibits bacterial killing and reactive oxygen intermediate (ROI) production by alveolar macrophages (AMs), although little is known about the operative molecular mechanisms. The aims of this study were to evaluate the molecular mechanisms and the specific EP receptors through which PGE 2 inhibits killing of Klebsiella pneumoniae by AMs. The treatment of AMs with PGE 2 suppressed the killing of K. pneumoniae, and this effect was blocked by an adenylyl cyclase inhibitor and mimicked by agonists for the stimulatory G protein (G s )-coupled EP2 and EP4 receptors. Conversely, microbicidal activity was augmented by pretreatment with the cyclooxygenase inhibitor, indomethacin, and antagonists of EP2 and EP4. Similar results were found when ROI production was examined. PGE 2 inhibition of killing and ROI generation was associated with its activation of the cAMP effectors, protein kinase A and exchange protein directly activated by cAMP-1, as well as attenuation of the phosphorylation and translocation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase component, p47phox, to the phagosomal membrane. We conclude that PGE 2 suppresses the microbicidal activity of AMs through the G s -coupled EP2/EP4 receptors, with increased cAMP inhibiting the assembly and activation of p47phox.

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Killing ofKlebsiella pneumoniaeby human alveolar macrophages

Cited by 63 publications

References 56 publications

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

Lipid-Based Signaling Modulates DNA Repair Response and Survival against Klebsiella pneumoniae Infection in Host Cells and in Mice

Prostaglandin E₂Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase

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Killing ofKlebsiella pneumoniaeby human alveolar macrophages

Cited by 63 publications

References 56 publications

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

Lipid-Based Signaling Modulates DNA Repair Response and Survival against Klebsiella pneumoniae Infection in Host Cells and in Mice

Prostaglandin E2Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase

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Prostaglandin E₂Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase