679: Host defense defects and inflammation within the nasal airways of CFTR knockout mice

Aspergillus fumigatus is an opportunistic fungal pathogen that causes severe invasive infections in immunocompromised patients. Innate immunity plays a major role in protection against A. fumigatus. The ficolins are a family of soluble pattern recognition receptors that are capable of activating the lectin pathway of complement. Previous in vitro studies reported that ficolins bind to A. fumigatus, but their part in host defense against fungal infections in vivo is unknown. In this study, we used ficolin-deficient mice to investigate the role of ficolins during lung infection with A. fumigatus. Ficolin knockout mice showed significantly higher fungal loads in the lungs 24 h postinfection compared to wild-type mice. The delayed clearance of A. fumigatus in ficolin knockout mice could not be attributed to a compromised recruitment of inflammatory cells. However, it was revealed that ficolin knockout mice exhibited a decreased production of proinflammatory cytokines in the lungs compared to wild-type mice following A. fumigatus infection. The impaired clearance and cytokine production in ficolin knockout mice was independent of complement, as shown by equivalent levels of A. fumigatus-mediated complement activation in ficolin knockout mice and wild-type mice. In conclusion, this study demonstrates that ficolins are important in initial innate host defense against A. fumigatus infections in vivo.

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Urokinase-Type Plasminogen Activator in Inflammatory Cell Recruitment and Host Defense against Pneumocystis carinii in Mice

Infection and Immunity ◽

10.1128/iai.67.2.879-884.1999 ◽

1999 ◽

Vol 67 (2) ◽

pp. 879-884 ◽

Cited By ~ 30

Author(s):

James M. Beck ◽

Angela M. Preston ◽

Margaret R. Gyetko

Keyword(s):

Host Defense ◽

Knockout Mice ◽

Inflammatory Cell ◽

Pneumocystis Carinii ◽

Lavage Fluid ◽

Wild Type ◽

Cell Recruitment ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Inflammatory Cell Recruitment

ABSTRACT Effective host defense against Pneumocystis cariniidepends upon the integrated actions of inflammatory cells and mediators in the lungs. Using immunocompetent and immunosuppressed mice, our laboratory has defined inflammatory changes in the lungs in response toP. carinii. However, the essential molecules and mechanisms required for cellular recruitment and for host defense against P. carinii are undefined. We hypothesized that urokinase-type plasminogen activator (uPA), a protease intimately involved in inflammatory cell migration and activation, is required for clearance of P. carinii. To test this hypothesis in vivo, we compared the intensity of P. carinii infection and inflammation in the lungs of mice lacking the uPA gene (uPA knockout mice) and in the lungs of wild-type mice. After intratracheal inoculation with P. carinii organisms, uPA knockout mice developed uniformly heavyP. carinii pneumonia while wild-type mice cleared theP. carinii inoculum. Bronchoalveolar lavage fluid from uPA knockout mice contained significantly smaller numbers of cells than did lavage fluid from wild-type mice. We conclude that deletion of the uPA gene prevents the clearance of P. carinii and reduces inflammatory cell recruitment. Therefore, uPA is an important participant in the network of inflammatory events required for the clearance of P. carinii, confirming an important role for this molecule in pulmonary host defense against opportunistic pathogens.

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IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity

Mucosal Immunology ◽

10.1038/s41385-020-00348-5 ◽

2020 ◽

Author(s):

Stephen J. Gaudino ◽

Michael Beaupre ◽

Xun Lin ◽

Preet Joshi ◽

Sonika Rathi ◽

...

Keyword(s):

Immune Responses ◽

Host Defense ◽

Knockout Mice ◽

Paneth Cell ◽

Cell Types ◽

Paneth Cells ◽

Lineage Tracing ◽

Interleukin 22 ◽

Serovar Typhimurium ◽

Small Intestinal

Abstract Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1fl/fl;Lgr5-EGFP-creERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.

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Interleukin-17A during Local and Systemic Staphylococcus aureus-Induced Arthritis in Mice

Infection and Immunity ◽

10.1128/iai.00385-10 ◽

2010 ◽

Vol 78 (9) ◽

pp. 3783-3790 ◽

Cited By ~ 24

Author(s):

Louise Henningsson ◽

Pernilla Jirholt ◽

Catharina Lindholm ◽

Tove Eneljung ◽

Elin Silverpil ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Host Defense ◽

Knockout Mice ◽

Joint Destruction ◽

Systemic Infection ◽

Mrna Levels ◽

Wild Type ◽

Bacterial Inoculation ◽

Interleukin 17A

ABSTRACT Staphylococcus aureus is one of the dominant pathogens that induce septic arthritis in immunocompromised hosts, e.g., patients suffering from rheumatoid arthritis treated with immunosuppressive drugs. S. aureus-induced arthritis leads to severe joint destruction and high mortality despite antibiotic treatment. Recently, interleukin-17A (IL-17A) has been discovered to be an important mediator of aseptic arthritis both in mice and humans, but its function in S. aureus-induced arthritis is largely unknown. Here, we investigated the role of IL-17A in host defense against arthritis following systemic and local S. aureus infection in vivo. IL-17A knockout mice and wild-type mice were inoculated systemically (intravenously) or locally (intra-articularly) with S. aureus. During systemic infection, IL-17A knockout mice lost significantly more weight than the wild-type mice did, but no differences were found in the mortality rate. The absence of IL-17A had no impact on clinical arthritis development but led to increased histopathological erosivity late during systemic S. aureus infection. Bacterial clearance in kidneys was increased in IL-17A knockout mice compared to the level in wild-type mice only 1 day after bacterial inoculation. During systemic S. aureus infection, serum IL-17F protein levels and mRNA levels in the lymph nodes were elevated in the IL-17A knockout mice compared to the level in wild-type mice. In contrast to systemic infection, the IL-17A knockout mice had increased synovitis and erosions and locally decreased clearance of bacteria 3 days after local bacterial inoculation. On the basis of these findings, we suggest that IL-17A is more important in local host defense than in systemic host defense against S. aureus-induced arthritis.

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A Role for Interleukin-6 in Host Defense against Murine Chlamydia trachomatis Infection

Infection and Immunity ◽

10.1128/iai.66.9.4564-4567.1998 ◽

1998 ◽

Vol 66 (9) ◽

pp. 4564-4567 ◽

Cited By ~ 42

Author(s):

Dwight M. Williams ◽

Barry G. Grubbs ◽

Toni Darville ◽

Kathleen Kelly ◽

Roger G. Rank

Keyword(s):

Chlamydia Trachomatis ◽

Host Defense ◽

Lung Tissue ◽

Specific Antibody ◽

Knockout Mice ◽

Interleukin 6 ◽

Host Response ◽

Interferon Production ◽

Chlamydia Trachomatis Infection ◽

Antibody Levels

ABSTRACT Interleukin-6-deficient (IL-6−/−) knockout mice had significantly increased Chlamydia trachomatis levels in lung tissue and increased mortality compared to B6129F2/J controls early after intranasal infection. Gamma interferon production and chlamydia-specific antibody levels were consistent with a decreased but reversible Th1-like response in IL-6−/− mice. IL-6 is needed for an optimal early host response to this infection.

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