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Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection.

Jhingran A, Kasahara S, Shepardson KM, Junecko BA, Heung LJ, Kumasaka DK, Knoblaugh SE, Lin X, Kazmierczak BI, Reinhart TA, Cramer RA, Hohl TM - PLoS Pathog. (2015)

Bottom Line: Aspergillus fumigatus forms ubiquitous airborne conidia that humans inhale on a daily basis.Herein, we demonstrate that MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense.Exogenous CXCL1 administration reverses murine mortality in MyD88-deficient mice.

View Article: PubMed Central - PubMed

Affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT
Aspergillus fumigatus forms ubiquitous airborne conidia that humans inhale on a daily basis. Although respiratory fungal infection activates the adaptor proteins CARD9 and MyD88 via C-type lectin, Toll-like, and interleukin-1 family receptor signals, defining the temporal and spatial pattern of MyD88- and CARD9-coupled signals in immune activation and fungal clearance has been difficult to achieve. Herein, we demonstrate that MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense. The first phase depends on MyD88 signaling because genetic deletion of MyD88 leads to delayed induction of the neutrophil chemokines CXCL1 and CXCL5, delayed neutrophil lung trafficking, and fatal pulmonary damage at the onset of respiratory fungal infection. MyD88 expression in lung epithelial cells restores rapid chemokine induction and neutrophil recruitment via interleukin-1 receptor signaling. Exogenous CXCL1 administration reverses murine mortality in MyD88-deficient mice. The second phase depends predominately on CARD9 signaling because genetic deletion of CARD9 in radiosensitive hematopoietic cells interrupts CXCL1 and CXCL2 production and lung neutrophil recruitment beyond the initial MyD88-dependent phase. Using a CXCL2 reporter mouse, we show that lung-infiltrating neutrophils represent the major cellular source of CXCL2 during CARD9-dependent recruitment. Although neutrophil-intrinsic MyD88 and CARD9 function are dispensable for neutrophil conidial uptake and killing in the lung, global deletion of both adaptor proteins triggers rapidly progressive invasive disease when mice are challenged with an inoculum that is sub-lethal for single adapter protein knockout mice. Our findings demonstrate that distinct signal transduction pathways in the respiratory epithelium and hematopoietic compartment partially overlap to ensure optimal chemokine induction, neutrophil recruitment, and fungal clearance within the respiratory tract.

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MyD88 is critical for survival, fungal clearance, and lung integrity during A. fumigatus challenge.WT and MyD88(−/−) mice were challenged with 7 × 107 conidia and (A) monitored for survival (Kaplan-Meier survival plot of WT (black circles; n = 9) and MyD88(−/−) (grey circles; n = 9) mice), assayed for (B) lung fungal burden, (C) BALF albumin, and (D) BALF LDH levels at 48 h p.i. (A) One of three experiments shown. (B-D) The bar graphs show mean (+SEM) values from an experiment with 6–7 mice per genotype. (C) nd = none detected. The value was below the limit of detection of the albumin assay (dashed line).
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ppat.1004589.g001: MyD88 is critical for survival, fungal clearance, and lung integrity during A. fumigatus challenge.WT and MyD88(−/−) mice were challenged with 7 × 107 conidia and (A) monitored for survival (Kaplan-Meier survival plot of WT (black circles; n = 9) and MyD88(−/−) (grey circles; n = 9) mice), assayed for (B) lung fungal burden, (C) BALF albumin, and (D) BALF LDH levels at 48 h p.i. (A) One of three experiments shown. (B-D) The bar graphs show mean (+SEM) values from an experiment with 6–7 mice per genotype. (C) nd = none detected. The value was below the limit of detection of the albumin assay (dashed line).

Mentions: To define the role of MyD88 during respiratory fungal challenge, MyD88(−/−) and C57BL/6 control mice were challenged with 7 × 107A. fumigatus Af293 conidia and monitored for survival. The median survival time for MyD88(−/−) mice was 3 days, while all C57BL/6 mice survived the 17 day observation period (Fig. 1A). Mortality in MyD88(−/−) mice correlated with an increased fungal burden (Fig. 1B) and greater lung damage, as measured by bronchoalveolar lavage fluid (BALF) albumin (Fig. 1C) and lactate dehydrogenase (LDH) release (Fig. 1D), compared to control mice at 48 h p.i.


Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection.

Jhingran A, Kasahara S, Shepardson KM, Junecko BA, Heung LJ, Kumasaka DK, Knoblaugh SE, Lin X, Kazmierczak BI, Reinhart TA, Cramer RA, Hohl TM - PLoS Pathog. (2015)

MyD88 is critical for survival, fungal clearance, and lung integrity during A. fumigatus challenge.WT and MyD88(−/−) mice were challenged with 7 × 107 conidia and (A) monitored for survival (Kaplan-Meier survival plot of WT (black circles; n = 9) and MyD88(−/−) (grey circles; n = 9) mice), assayed for (B) lung fungal burden, (C) BALF albumin, and (D) BALF LDH levels at 48 h p.i. (A) One of three experiments shown. (B-D) The bar graphs show mean (+SEM) values from an experiment with 6–7 mice per genotype. (C) nd = none detected. The value was below the limit of detection of the albumin assay (dashed line).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306481&req=5

ppat.1004589.g001: MyD88 is critical for survival, fungal clearance, and lung integrity during A. fumigatus challenge.WT and MyD88(−/−) mice were challenged with 7 × 107 conidia and (A) monitored for survival (Kaplan-Meier survival plot of WT (black circles; n = 9) and MyD88(−/−) (grey circles; n = 9) mice), assayed for (B) lung fungal burden, (C) BALF albumin, and (D) BALF LDH levels at 48 h p.i. (A) One of three experiments shown. (B-D) The bar graphs show mean (+SEM) values from an experiment with 6–7 mice per genotype. (C) nd = none detected. The value was below the limit of detection of the albumin assay (dashed line).
Mentions: To define the role of MyD88 during respiratory fungal challenge, MyD88(−/−) and C57BL/6 control mice were challenged with 7 × 107A. fumigatus Af293 conidia and monitored for survival. The median survival time for MyD88(−/−) mice was 3 days, while all C57BL/6 mice survived the 17 day observation period (Fig. 1A). Mortality in MyD88(−/−) mice correlated with an increased fungal burden (Fig. 1B) and greater lung damage, as measured by bronchoalveolar lavage fluid (BALF) albumin (Fig. 1C) and lactate dehydrogenase (LDH) release (Fig. 1D), compared to control mice at 48 h p.i.

Bottom Line: Aspergillus fumigatus forms ubiquitous airborne conidia that humans inhale on a daily basis.Herein, we demonstrate that MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense.Exogenous CXCL1 administration reverses murine mortality in MyD88-deficient mice.

View Article: PubMed Central - PubMed

Affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

ABSTRACT
Aspergillus fumigatus forms ubiquitous airborne conidia that humans inhale on a daily basis. Although respiratory fungal infection activates the adaptor proteins CARD9 and MyD88 via C-type lectin, Toll-like, and interleukin-1 family receptor signals, defining the temporal and spatial pattern of MyD88- and CARD9-coupled signals in immune activation and fungal clearance has been difficult to achieve. Herein, we demonstrate that MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense. The first phase depends on MyD88 signaling because genetic deletion of MyD88 leads to delayed induction of the neutrophil chemokines CXCL1 and CXCL5, delayed neutrophil lung trafficking, and fatal pulmonary damage at the onset of respiratory fungal infection. MyD88 expression in lung epithelial cells restores rapid chemokine induction and neutrophil recruitment via interleukin-1 receptor signaling. Exogenous CXCL1 administration reverses murine mortality in MyD88-deficient mice. The second phase depends predominately on CARD9 signaling because genetic deletion of CARD9 in radiosensitive hematopoietic cells interrupts CXCL1 and CXCL2 production and lung neutrophil recruitment beyond the initial MyD88-dependent phase. Using a CXCL2 reporter mouse, we show that lung-infiltrating neutrophils represent the major cellular source of CXCL2 during CARD9-dependent recruitment. Although neutrophil-intrinsic MyD88 and CARD9 function are dispensable for neutrophil conidial uptake and killing in the lung, global deletion of both adaptor proteins triggers rapidly progressive invasive disease when mice are challenged with an inoculum that is sub-lethal for single adapter protein knockout mice. Our findings demonstrate that distinct signal transduction pathways in the respiratory epithelium and hematopoietic compartment partially overlap to ensure optimal chemokine induction, neutrophil recruitment, and fungal clearance within the respiratory tract.

Show MeSH
Related in: MedlinePlus