Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection

Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers.

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Decision letter: Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection

10.7554/elife.58855.sa1 ◽

2020 ◽

Author(s):

Frank L van de Veerdonk ◽

Agostinho Carvalho ◽

Mark Gresnigt

Keyword(s):

Aspergillus Fumigatus ◽

Ethanol Consumption ◽

Neutrophil Function ◽

Chronic Ethanol ◽

Chronic Ethanol Consumption

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Author response: Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection

10.7554/elife.58855.sa2 ◽

2020 ◽

Author(s):

Nathalia Luisa Sousa de Oliveira Malacco ◽

Jessica Amanda Marques Souza ◽

Flavia Rayssa Braga Martins ◽

Milene Alvarenga Rachid ◽

Janaina Aparecida Simplicio ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Ethanol Consumption ◽

Neutrophil Function ◽

Chronic Ethanol ◽

Author Response ◽

Chronic Ethanol Consumption

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Increased susceptibility of hepatic mitochondria to the toxicity of acetaldehyde after chronic ethanol consumption

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(77)91489-9 ◽

1977 ◽

Vol 75 (4) ◽

pp. 1059-1065 ◽

Cited By ~ 67

Author(s):

Shohei Matsuzaki ◽

Charles S. Lieber

Keyword(s):

Ethanol Consumption ◽

Chronic Ethanol ◽

Chronic Ethanol Consumption ◽

Increased Susceptibility

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Distinct Innate Immune Phagocyte Responses to Aspergillus fumigatus Conidia and Hyphae in Zebrafish Larvae

Eukaryotic Cell ◽

10.1128/ec.00080-14 ◽

2014 ◽

Vol 13 (10) ◽

pp. 1266-1277 ◽

Cited By ~ 48

Author(s):

Benjamin P. Knox ◽

Qing Deng ◽

Mary Rood ◽

Jens C. Eickhoff ◽

Nancy P. Keller ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Host Defense ◽

Leukocyte Adhesion ◽

Human Leukocyte ◽

Invasive Disease ◽

Neutrophil Function ◽

Innate Immune ◽

Infection Model ◽

Zebrafish Model ◽

Content Type

ABSTRACTAspergillus fumigatusis the most common filamentous fungal pathogen of immunocompromised hosts, resulting in invasive aspergillosis (IA) and high mortality rates. Innate immunity is known to be the predominant host defense againstA. fumigatus; however, innate phagocyte responses toA. fumigatusin an intact host and their contributions to host survival remain unclear. Here, we describe a larval zebrafishA. fumigatusinfection model amenable to real-time imaging of host-fungal interactions in live animals. Following infection withA. fumigatus, innate phagocyte populations exhibit clear preferences for different fungal morphologies: macrophages rapidly phagocytose conidia and form aggregates around hyphae, while the neutrophil response is dependent upon the presence of hyphae. Depletion of macrophages rendered host larvae susceptible to invasive disease. Moreover, a zebrafish model of human leukocyte adhesion deficiency with impaired neutrophil function also resulted in invasive disease and impaired host survival. In contrast, macrophage-deficient but not neutrophil-deficient larvae exhibited attenuated disease following challenge with a less virulent (ΔlaeA) strain ofA. fumigatus, which has defects in secondary metabolite production. Taking these results together, we have established a new vertebrate model for studying innate immune responses toA. fumigatusthat reveals distinct roles for neutrophils and macrophages in mediating host defense against IA.

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Inflammatory consequences of inherited disorders affecting neutrophil function

Blood ◽

10.1182/blood-2018-11-844563 ◽

2019 ◽

Vol 133 (20) ◽

pp. 2130-2139 ◽

Cited By ~ 13

Author(s):

Mary C. Dinauer

Keyword(s):

Immune Responses ◽

Fungal Infections ◽

Leukocyte Adhesion ◽

Neutrophil Function ◽

Innate Immune ◽

Innate Immune Responses ◽

Inherited Disorders ◽

Molecular Defects ◽

Inflammatory Stimuli ◽

Increased Susceptibility

Abstract Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.

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