Inhibition of the human neutrophil NADPH oxidase by Coxiella burnetii

Siemsen, Daniel W.; Kirpotina, Liliya N.; Jutila, Mark A.; Quinn, Mark T.

doi:10.1016/j.micinf.2009.04.005

Cited by 59 publications

(40 citation statements)

References 35 publications

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“…This suggests that neutrophils may not be able to kill C. burnetii directly. It has been shown that C. burnetii uptake by neutrophils decreases the amount of reactive oxygen species (ROS) produced by the neutrophils (24). If the role of neutrophils in C. burnetii infection is not associated with direct killing, there are two other possible roles, based on the increased disease severity observed when neutrophils are depleted: (i) C. burnetii infects neutrophils, which are then taken up by macrophages.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Play an Important Role in Protective Immunity against Coxiella burnetii Infection

et al. 2015

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Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes the zoonotic disease Q fever. Although Q fever is mainly transmitted by aerosol infection, study of the immune responses in the lung following pulmonary C. burnetii infection is lacking. Neutrophils are considered the first immune cell to migrate into the lung and play an important role in host defense against aerosol infection with microbial pathogens. However, the role of neutrophils in the host defense against C. burnetii infection remains unclear. To determine the role of neutrophils in protective immunity against C. burnetii infection, the RB6-8C5 antibody was used to deplete neutrophils in mice before intranasal infection with C. burnetii. The results indicated that neutrophil-depleted mice developed more severe disease than their wild-type counterparts, suggesting that neutrophils play an important role in host defense against C. burnetii pulmonary infection. We also found that neither CXC chemokine receptor 2 (CXCR2) nor interleukin-17 (IL-17) receptor (IL-17R) deficiency changed the severity of disease following intranasal C. burnetii challenge, suggesting that keratinocyte-derived chemokine and IL-17 may not play essential roles in the response to C. burnetii infection. However, significantly higher C. burnetii genome copy numbers were detected in the lungs of IL-1R ؊/؊ mice at 14 days postinfection. This indicates that IL-1 may be important for the clearance of C. burnetii from the lungs following intranasal infection. Our results also suggest that neutrophils are involved in protecting vaccinated mice from C. burnetii challenge-induced disease. This is the first study to demonstrate an important role for neutrophils in protective immunity against C. burnetii infection.

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Section: Discussionmentioning

confidence: 99%

Neutrophils Play an Important Role in Protective Immunity against Coxiella burnetii Infection

et al. 2015

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“…This lack of response was thought to be caused, in part, by acid phosphatase activity that was detected in C. burnetii extracts (4,25). Recently, Siemsen et al reported that PMN challenged with opsonized NMII did not activate the translocation of p47 phox or p60 phox to the membrane (42). This suggested that C. burnetii actively inhibited the phosphorylation of p47 phox and p60 phox , although it was not determined if C. burnetii components acted directly or indirectly upon p47 phox and p60 phox phosphorylation.…”

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confidence: 99%

Coxiella burnetiiAcid Phosphatase Inhibits the Release of Reactive Oxygen Intermediates in Polymorphonuclear Leukocytes

Hill

Samuel

2011

Infect Immun

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Coxiella burnetii, the etiological agent of Q fever, is a small, Gram-negative, obligate intracellular bacterium. Replication of C. burnetii during infection has been shown to be increased by decreasing oxidative stress using p47 phox ؊/؊ and iNOS ؊/؊ mice in vivo and by pharmacologic inhibitors in vitro. Building upon this model, we investigated the role polymorphonuclear leukocytes (PMN) play in the control of infection, since NADPH oxidase-mediated release of reactive oxygen intermediates (ROI) is a primary bactericidal mechanism for these cells that is critical for early innate clearance. Earlier studies suggested that C. burnetii actively inhibited release of ROI from PMN through expression of an unidentified acid phosphatase (ACP). Recent genomic annotations identified one open reading frame (CBU0335) which may encode a Sec-and type II-dependent secreted ACP. To test this model, viable C. burnetii propagated in tissue culture host cells or axenic media, C. burnetii extracts, or purified recombinant ACP (rACP) was combined with human PMN induced with 4-phorbol 12-myristate 13-acetate (PMA). The release of ROI was inhibited when PMN were challenged with viable C. burnetii, C. burnetii extracts, or rACP but not when PMN were challenged with electron beam-inactivated C. burnetii. C. burnetii extracts and rACP were also able to inhibit PMA-induced formation of NADPH oxidase complex on PMN membranes, suggesting a molecular mechanism responsible for this inhibition. These data support a model in which C. burnetii eludes the primary ROI killing mechanism of activated PMN by secreting at least one acid phosphatase.Coxiella burnetii, the etiological agent of Q fever, is a small, Gram-negative, obligate intracellular bacterium. Human Q fever is most commonly acquired through aerosol inhalation of soil contaminated with livestock birth products (43). There are two distinct disease progressions associated with Q fever: acute and chronic infection. The acute infection presents as a flu-like illness often including severe periorbital headache, and clinical presentations have included the neurological, gastrointestinal, endocrine, and renal systems (34, 35). Chronic Q fever has been characterized by the development of endocarditis, with less common manifestations of hepatitis and osteoarticular or vascular infections (3). C. burnetii resides within specialized phagolysosomes (27) of host cells during infection, including macrophages (22, 26) and potentially polymorphonuclear leukocytes (PMN). The ability of C. burnetii to survive and replicate within the phagolysosome requires it to either inhibit or withstand degradative enzymes and an oxidative burst from PMNs that generate reactive oxygen intermediates (ROI), such as superoxide anions. Earlier studies suggested that PMN challenged with C. burnetii Nine Mile phase I (NMI) did not stimulate an oxidative burst (1). Additionally, C. burnetii extracts have acid phosphatase activity that can serve as an inhibitor of an oxidative burst in N-formyl-Met-Leu-Phe (fMLP)-stimulate...

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“…Previous work suggests that catalase and SOD are potential persistence factors for Coxiella bacteria residing in the intracellular niche (1,14). In addition, a secreted acid phosphatase possibly reduces the respiratory burst of the host cell by inhibiting NADPH oxidase (4,23). in silico analysis of the C. burnetii RSA 493 genome (22) revealed predicted Mn-and Cu/Zn-SODs, catalase, and four peroxiredoxins (Prxs), which are antioxidant enzymes (EC 1.11.1.15) that are thiol-containing reductants used to detoxify hydroperoxides.…”

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confidence: 99%

A DNA-Binding Peroxiredoxin of Coxiella burnetii Is Involved in Countering Oxidative Stress during Exponential-Phase Growth

et al. 2010

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Coxiella burnetii is a Gram-negative, obligate intracellular bacterial pathogen that resides within the harsh, acidic confines of a lysosome-like compartment of the host cell that is termed a parasitophorous vacuole. In this study, we characterized a thiol-specific peroxidase of C. burnetii that belongs to the atypical 2-cysteine subfamily of peroxiredoxins, commonly referred to as bacterioferritin comigratory proteins (BCPs). Coxiella BCP was initially identified as a potential DNA-binding protein by two-dimensional Southwestern (SW) blots of the pathogen's proteome, probed with biotinylated C. burnetii genomic DNA. Confirmation of the identity of the DNA-binding protein as BCP (CBU_0963) was established by matrix-assisted laser desorption ionizationtandem time of flight mass spectrometry (MALDI-TOF/TOF MS). Recombinant Coxiella BCP (rBCP) was generated, and its DNA binding was demonstrated by two independent methods, including SW blotting and electrophoretic mobility shift assays (EMSAs). rBCP also demonstrated peroxidase activity in vitro that required thioredoxin-thioredoxin reductase (Trx-TrxR). Both the DNA-binding and peroxidase activities of rBCP were lost upon heat denaturation (100°C, 10 min). Functional expression of Coxiella bcp was demonstrated by trans-complementation of an Escherichia coli bcp mutant, as evidenced by the strain's ability to grow in an oxidative-stress growth medium containing tert-butyl hydroperoxide to levels that were indistinguishable from, or significantly greater than, those observed with its wild-type parental strain and significantly greater than bcp mutant levels (P < 0.05). rBCP was also found to protect supercoiled plasmid DNA from oxidative damage (i.e., nicking) in vitro. Maximal expression of the bcp gene coincided with the pathogen's early (day 2 to 3) exponential-growth phase in an experiment involving synchronized infection of an epithelial (Vero) host cell line. Taken as a whole, the results show that Coxiella BCP binds DNA and likely serves to detoxify endogenous hydroperoxide byproducts of Coxiella's metabolism during intracellular replication.

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Inhibition of the human neutrophil NADPH oxidase by Coxiella burnetii

Cited by 59 publications

References 35 publications

Neutrophils Play an Important Role in Protective Immunity against Coxiella burnetii Infection

Neutrophils Play an Important Role in Protective Immunity against Coxiella burnetii Infection

Coxiella burnetiiAcid Phosphatase Inhibits the Release of Reactive Oxygen Intermediates in Polymorphonuclear Leukocytes

A DNA-Binding Peroxiredoxin of Coxiella burnetii Is Involved in Countering Oxidative Stress during Exponential-Phase Growth

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