Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung

ABSTRACT Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We invest...

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Autores principales: Seyedmojtaba Seyedmousavi, Michael J. Davis, Janyce A. Sugui, Tzvia Pinkhasov, Shannon Moyer, Andres M. Salazar, Yun C. Chang, Kyung J. Kwon-Chung
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Publicado: American Society for Microbiology 2018
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spelling oai:doaj.org-article:a4d609af11e54c1b9d0098a728cb089a2021-11-15T15:53:26ZExogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung10.1128/mBio.00422-182150-7511https://doaj.org/article/a4d609af11e54c1b9d0098a728cb089a2018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00422-18https://doaj.org/toc/2150-7511ABSTRACT Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by three Aspergillus species, A. fumigatus, A. nidulans, and A. tanneri, in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the three Aspergillus species. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection with A. nidulans germlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA. IMPORTANCE Patients with chronic granulomatous disease (CGD) are highly susceptible to invasive aspergillosis (IA). While Aspergillus fumigatus is the most-studied Aspergillus species, CGD patients often suffer IA caused by A. nidulans, A. tanneri, and other rare species. These non-fumigatus Aspergillus species are more resistant to antifungal drugs and cause higher fatality rates than A. fumigatus. Therefore, alternative therapies are needed to protect CGD patients. We report an effective immunotherapy of mice infected with three Aspergillus species via PICLC dosing. While protection from IA was long lasting, PICLC induction of type I IFN surged but quickly returned to baseline levels, suggesting that PICLC was altering early events in IA. Interestingly, we found responding immune cells to be similar between PICLC-treated and untreated-infected mice. However, PICLC immunotherapy resulted in an earlier recruitment of the leukocytes and suppressed fungal growth. This study highlights the value of type I IFN induction in CGD patients.Seyedmojtaba SeyedmousaviMichael J. DavisJanyce A. SuguiTzvia PinkhasovShannon MoyerAndres M. SalazarYun C. ChangKyung J. Kwon-ChungAmerican Society for MicrobiologyarticleAspergillus fumigatusAspergillus nidulansAspergillus tanneripoly(I:C) (PICLC)chronic granulomatous disease (CGD)conidiaMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution DOAJ
collection DOAJ
language EN
topic Aspergillus fumigatus
Aspergillus nidulans
Aspergillus tanneri
poly(I:C) (PICLC)
chronic granulomatous disease (CGD)
conidia
Microbiology
QR1-502
spellingShingle Aspergillus fumigatus
Aspergillus nidulans
Aspergillus tanneri
poly(I:C) (PICLC)
chronic granulomatous disease (CGD)
conidia
Microbiology
QR1-502
Seyedmojtaba Seyedmousavi
Michael J. Davis
Janyce A. Sugui
Tzvia Pinkhasov
Shannon Moyer
Andres M. Salazar
Yun C. Chang
Kyung J. Kwon-Chung
Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung
description ABSTRACT Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by three Aspergillus species, A. fumigatus, A. nidulans, and A. tanneri, in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the three Aspergillus species. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection with A. nidulans germlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA. IMPORTANCE Patients with chronic granulomatous disease (CGD) are highly susceptible to invasive aspergillosis (IA). While Aspergillus fumigatus is the most-studied Aspergillus species, CGD patients often suffer IA caused by A. nidulans, A. tanneri, and other rare species. These non-fumigatus Aspergillus species are more resistant to antifungal drugs and cause higher fatality rates than A. fumigatus. Therefore, alternative therapies are needed to protect CGD patients. We report an effective immunotherapy of mice infected with three Aspergillus species via PICLC dosing. While protection from IA was long lasting, PICLC induction of type I IFN surged but quickly returned to baseline levels, suggesting that PICLC was altering early events in IA. Interestingly, we found responding immune cells to be similar between PICLC-treated and untreated-infected mice. However, PICLC immunotherapy resulted in an earlier recruitment of the leukocytes and suppressed fungal growth. This study highlights the value of type I IFN induction in CGD patients.
format article
author Seyedmojtaba Seyedmousavi
Michael J. Davis
Janyce A. Sugui
Tzvia Pinkhasov
Shannon Moyer
Andres M. Salazar
Yun C. Chang
Kyung J. Kwon-Chung
author_facet Seyedmojtaba Seyedmousavi
Michael J. Davis
Janyce A. Sugui
Tzvia Pinkhasov
Shannon Moyer
Andres M. Salazar
Yun C. Chang
Kyung J. Kwon-Chung
author_sort Seyedmojtaba Seyedmousavi
title Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung
title_short Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung
title_full Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung
title_fullStr Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung
title_full_unstemmed Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung
title_sort exogenous stimulation of type i interferon protects mice with chronic granulomatous disease from aspergillosis through early recruitment of host-protective neutrophils into the lung
publisher American Society for Microbiology
publishDate 2018
url https://doaj.org/article/a4d609af11e54c1b9d0098a728cb089a
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