Resolvin D2 promotes host defense in a 2 - hit model of sepsis with secondary lung infection

To date, no reports have linked the multifunctional protein, staphylococcal nuclease domain-containing protein 1 (SND1), to host defense against intracellular infections. In this study, we investigated the role and mechanisms of SND1, by using SND1 knockout (SND1-/-) mice, in host defense against the lung infection of Chlamydia muridarum, an obligate intracellular bacterium. Our data showed that SND1-/- mice exhibited significantly greater body weight loss, higher organism growth, and more severe pathological changes compared with wild-type mice following the infection. Further analysis showed significantly reduced Chlamydia-specific Th1/17 immune responses in SND1-/- mice after infection. Interestingly, the dendritic cells (DCs) isolated from SND1-/- mice showed lower costimulatory molecules expression and IL-12 production, but higher IL-10 production compared with those from wild-type control mice. In the DC-T cell co-culture system, DCs isolated from SND1-/- infected mice showed significantly reduced ability to promote Chlamydia-specific IFN-γ producing Th1 cells but enhanced capacity to induce CD4+T cells into Foxp3+ Treg cells. Adoptive transfer of DCs isolated from SND1-/- mice, unlike those from wild-type control mice, failed to protect the recipients against challenge infection. These findings provide in vivo evidence that SND1 plays an important role in host defense against intracellular bacterial infection, and suggest that SND1 can promote Th1/17 immunity and inhibit the expansion of Treg cells through modulation of the function of DCs.

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033 Mice lacking neutrophil elastase exhibit impaired host defense against pseudomonas aeruginosa lung infection

Revue des Maladies Respiratoires ◽

10.1016/s0761-8425(05)92445-5 ◽

2005 ◽

Vol 22 (5) ◽

pp. 860

Author(s):

J. Aregbesola ◽

T.O. Hirche ◽

S. Bahr ◽

A. Belaaouaj

Keyword(s):

Pseudomonas Aeruginosa ◽

Host Defense ◽

Neutrophil Elastase ◽

Lung Infection

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Interleukin-17A Enhances Host Defense against Cryptococcal Lung Infection through Effects Mediated by Leukocyte Recruitment, Activation, and Gamma Interferon Production

Infection and Immunity ◽

10.1128/iai.01477-13 ◽

2013 ◽

Vol 82 (3) ◽

pp. 937-948 ◽

Cited By ~ 58

Author(s):

Benjamin J. Murdock ◽

Gary B. Huffnagle ◽

Michal A. Olszewski ◽

John J. Osterholzer

Keyword(s):

T Cells ◽

Host Defense ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Myeloid Cells ◽

Lung Infection ◽

Leukocyte Recruitment ◽

Content Type ◽

Interleukin 17A ◽

Ifn Γ

ABSTRACTInfection of C57BL/6 mice with the moderately virulentCryptococcus neoformansstrain 52D models the complex adaptive immune response observed in HIV-negative patients with persistent fungal lung infections. In this model, Th1 and Th2 responses evolve over time, yet the contribution of interleukin-17A (IL-17A) to antifungal host defense is unknown. In this study, we show that fungal lung infection promoted an increase in Th17 T cells that persisted to 8 weeks postinfection. Our comparison of fungal lung infection in wild-type mice and IL-17A-deficient mice (IL-17A−/−mice; C57BL/6 genetic background) demonstrated that late fungal clearance was impaired in the absence of IL-17A. This finding was associated with reduced intracellular containment of the organism within lung macrophages and deficits in the accumulation of total lung leukocytes, including specific reductions in CD11c+CD11b+myeloid cells (dendritic cells and exudate macrophages), B cells, and CD8+T cells, and a nonsignificant trend in the reduction of lung neutrophils. Although IL-17A did not alter the total number of CD4 T cells, decreases in the total number of CD4 T cells and CD8 T cells expressing gamma interferon (IFN-γ) were observed in IL-17A−/−mice. Lastly, expression of major histocompatibility complex class II (MHC-II) and the costimulatory molecules CD80 and CD86 on CD11c+CD11b+myeloid cells was diminished in IL-17A−/−mice. Collectively, these data indicate that IL-17A enhances host defenses against a moderately virulent strain ofC. neoformansthrough effects on leukocyte recruitment, IFN-γ production by CD4 and CD8 T cells, and the activation of lung myeloid cells.

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The calcineurin-NFAT axis contributes to host defense during Pseudomonas aeruginosa lung infection

Journal of Leukocyte Biology ◽

10.1189/jlb.4a0517-197r ◽

2017 ◽

Vol 102 (6) ◽

pp. 1461-1469 ◽

Cited By ~ 2

Author(s):

Zheng Pang ◽

Robert D. Junkins ◽

Adam J. MacNeil ◽

Craig McCormick ◽

Zhenyu Cheng ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Host Defense ◽

Lung Infection

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Synthetic host defense peptide IDR-1002 reduces inflammation in Pseudomonas aeruginosa lung infection

PLoS ONE ◽

10.1371/journal.pone.0187565 ◽

2017 ◽

Vol 12 (11) ◽

pp. e0187565 ◽

Cited By ~ 11

Author(s):

Kelli C. Wuerth ◽

Reza Falsafi ◽

Robert E. W. Hancock

Keyword(s):

Pseudomonas Aeruginosa ◽

Host Defense ◽

Lung Infection ◽

Host Defense Peptide

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CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3

Blood ◽

10.1182/blood-2018-10-878082 ◽

2019 ◽

Vol 133 (12) ◽

pp. 1335-1345 ◽

Cited By ~ 15

Author(s):

Sagar Paudel ◽

Pankaj Baral ◽

Laxman Ghimire ◽

Scott Bergeron ◽

Liliang Jin ◽

...

Keyword(s):

Bone Marrow ◽

Streptococcus Pneumoniae ◽

Host Defense ◽

Bacterial Pneumonia ◽

Bacterial Infections ◽

Neutrophil Migration ◽

Lung Infection ◽

Neutrophil Influx ◽

Bacterial Dissemination

Abstract Neutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1−/− mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1−/− mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.

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Early Growth Response 1 Deficiency Protects the Host against Pseudomonas aeruginosa Lung Infection

Infection and Immunity ◽

10.1128/iai.00678-19 ◽

2019 ◽

Vol 88 (1) ◽

Cited By ~ 1

Author(s):

Zheng Pang ◽

Renee Raudonis ◽

Craig McCormick ◽

Zhenyu Cheng

Keyword(s):

Host Defense ◽

Growth Response ◽

Lung Infection ◽

Early Growth ◽

Nitric Oxide Production ◽

Bacterial Clearance ◽

Content Type ◽

Early Growth Response ◽

Early Growth Response 1 ◽

Deficient Mice

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is a common cause of nosocomial infections. The molecular mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Early growth response 1 (Egr-1) is a zinc-finger transcription factor that controls inflammatory responses. Here, we characterized the role of Egr-1 in host defense against P. aeruginosa infection in a mouse model of acute bacterial pneumonia. Egr-1 expression was rapidly and transiently induced in response to P. aeruginosa infection. Egr-1-deficient mice displayed decreased mortality, reduced levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-1β [IL-1β], IL-6, IL-12, and IL-17), and enhanced bacterial clearance from the lung. Egr-1 deficiency caused diminished NF-κB activation in P. aeruginosa-infected macrophages independently of IκBα phosphorylation. A physical interaction between Egr-1 and NF-κB p65 was found in P. aeruginosa-infected macrophages, suggesting that Egr-1 could be required for assembly of heterodimeric transcription factors that direct synthesis of inflammatory mediators. Interestingly, Egr-1 deficiency had no impact on neutrophil recruitment in vivo due to its differential effects on chemokine production, which included diminished accumulation of KC (CXCL1), MIP2 (CXCL2), and IP-10 (CXCL10) and increased accumulation of LIX (CXCL5). Importantly, Egr-1-deficient macrophages and neutrophils displayed significant increases in nitric oxide production and bacterial killing ability that correlated with enhanced bacterial clearance in Egr-1-deficient mice. Together, these findings suggest that Egr-1 plays a detrimental role in host defense against P. aeruginosa acute lung infection by promoting systemic inflammation and negatively regulating the nitric oxide production that normally assists with bacterial clearance.

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