Coxiella burnetii Interaction with Neutrophils and Macrophages
            <i>In Vitro</i>
            and in SCID Mice following Aerosol Infection

Elliott, Alexandra; Peng, Ying; Zhang, Guoquan

doi:10.1128/iai.00973-13

Cited by 33 publications

(38 citation statements)

References 28 publications

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“…It has been shown, however, that primary human alveolar macrophages produce mature IL-1␤ in response to NMII but not phase I C. burnetii, suggesting that human and mouse inflammasome sensors or various cell types differ in their responses to NMII infection (54). The finding that NMII does not induce inflammasome activation in mouse cells may provide some insight into the observation that neutrophil recruitment is delayed in mice infected with phase I or phase II C. burnetii until 1 week postinfection (118), as inflammasome-derived IL-1 is a critical regulator of neutrophil recruitment during other bacterial infections, such as pulmonary L. pneumophila infection (68,(90)(91)(92). Further studies are warranted to determine the additional mechanisms by which C. burnetii evades inflammasome activation in mouse macrophages.…”

Section: Discussionmentioning

confidence: 80%

Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages

et al. 2016

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dCoxiella burnetii replicates within permissive host cells by employing a Dot/Icm type IV secretion system (T4SS) to translocate effector proteins that direct the formation of a parasitophorous vacuole. C57BL/6 mouse macrophages restrict the intracellular replication of the C. burnetii Nine Mile phase II (NMII) strain. However, eliminating Toll-like receptor 2 (TLR2) permits bacterial replication, indicating that the restriction of bacterial replication is immune mediated. Here, we examined whether additional innate immune pathways are employed by C57BL/6 macrophages to sense and restrict NMII replication. In addition to the known role of TLR2 in detecting and restricting NMII infection, we found that TLR4 also contributes to cytokine responses but is not required to restrict bacterial replication. Furthermore, the TLR signaling adaptors MyD88 and Trif are required for cytokine responses and restricting bacterial replication. The C. burnetii NMII T4SS translocates bacterial products into C57BL/6 macrophages. However, there was little evidence of cytosolic immune sensing of NMII, as there was a lack of inflammasome activation, T4SS-dependent cytokine responses, and robust type I interferon (IFN) production, and these pathways were not required to restrict bacterial replication. Instead, endogenous tumor necrosis factor (TNF) produced upon TLR sensing of C. burnetii NMII was required to control bacterial replication. Therefore, our findings indicate a primary role for TNF produced upon immune detection of C. burnetii NMII by TLRs, rather than cytosolic PRRs, in enabling C57BL/6 macrophages to restrict bacterial replication.T o initiate innate immune defense against bacterial pathogens, infected host cells utilize pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) (1-3). Toll-like receptors (TLRs) located at the cell surface and within endosomes detect extracellular PAMPs such as bacterial lipoproteins and lipopolysaccharide (LPS) (4). Downstream of TLRs, the adaptor proteins MyD88 and Trif activate several signaling pathways, including NF-B, mitogen-activated protein kinases (MAPKs), and interferon (IFN) regulatory factor 3 (IRF3), which direct the expression of proinflammatory cytokines and other antimicrobial effectors (4). For intracellular bacterial pathogens, cytosolic PRRs, such as those of the nucleotide binding domain/ leucine-rich repeat (NLR) and RIG-I-like receptor (RLR) families, often are critical for host defense as they respond to PAMPs introduced into the host cell cytosol by bacterial pore-forming toxins or specialized secretion systems (5-8). In addition, cytosolic sensing can lead to the assembly of a multiprotein complex termed the inflammasome, which activates the host proteases caspase-1 and caspase-11, resulting in the release of IL-1 family cytokines and a form of cell death known as pyroptosis (9-16). These innate immune pathways collaborate to restrict intracellular bacterial infection through both cell-intrinsic and -extrinsic mechanisms (17)(18...

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Section: Discussionmentioning

confidence: 80%

Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages

et al. 2016

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“…A previous study from our lab found that neutrophils infected with C. burnetii were taken up by macrophages and the bacteria were able to replicate within these macrophages (4). This suggests that neutrophils may not be able to kill C. burnetii directly.…”

Section: Discussionmentioning

confidence: 96%

“…However, a previous study from our lab found that following C. burnetii aerosol infection, neutrophils are not present in the airways until 7 days p.i. (4). The mechanism of this delay is unknown.…”

mentioning

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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“…Studies have shown how bacteria could use neutrophils as an evasive strategy to infect macrophages. 9 The C. burnetii strain that circulates in Spain represents a low risk for Q fever transmission in zoonotic terms. 5,20,23 However, further studies designed to examine the cellular response are needed to clarify the pathogenesis of coxiellosis during acute infection in cattle.…”

Section: Discussionmentioning

confidence: 99%

Coxiella burnetii total immunoglobulin G, phase I and phase II immunoglobulin G antibodies, and bacterial shedding in young dams in persistently infected dairy herds

et al. 2015

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Abstract. The current study examines Coxiella burnetii infection patterns in young dairy dams around the calving period in persistently infected high-producing dairy herds. Infection patterns were determined in terms of total immunoglobulin G (IgG) and phase-specific IgG antibodies by enzyme-linked immunosorbent assay and bacterial shedding by real-time polymerase chain reaction (qPCR). On days 171-177 of gestation, at parturition, and on days 15-21 and 91-97 postpartum, 7 firstparity cows and 7 second-parity cows were sampled for serology and qPCR. Total phase-specific I (PhI) and II (PhII) IgG antibodies were detected in 2 animals at days 171-177 of gestation. Four additional animals underwent seroconversion on days 91-97 postpartum. Three of 6 seropositive dams according to total IgG, showed a PhI+/PhII+ profile, whereas dams that seroconverted exhibited a PhI-/PhII+ (2/6) or PhI+/PhII-(1/6) profile. An indirect fluorescent antibody test for PhI and PhII immunoglobulin M (IgM) was performed on plasma samples from the shedding dams, confirming seropositivity in a first-parity dam that seroconverted, and detecting a sudden spike of PhI-IgM antibodies in 1 further dam. No relationship was detected in young C. burnetii-infected animals between total IgG, PhI and/or PhII antibodies, and bacterial shedding throughout the study period. The highest bacterial load measured by qPCR was recorded in a second-parity dam. This animal presented abnormal peripheral blood counts, which would be an indication of severe peripheral blood alterations in some infected cattle. This study suggests that young shedder cows are mostly seronegative in early stages of infection.

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Coxiella burnetii Interaction with Neutrophils and Macrophages In Vitro and in SCID Mice following Aerosol Infection

Cited by 33 publications

References 28 publications

Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages

Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages

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

Coxiella burnetii total immunoglobulin G, phase I and phase II immunoglobulin G antibodies, and bacterial shedding in young dams in persistently infected dairy herds

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