Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo

Sarah Inglesfield, Aleksandra Jasiulewicz, Matthew Hopwood, James Tyrrell, George Youlden, Maria Mazon-Moya, Owain R. Millington, Serge Mostowy, Sara Jabbari, Kerstin Voelz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and realtime in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. IMPORTANCE Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.

LanguageEnglish
Article numbere02010-17
Number of pages20
JournalmBio
Volume9
Issue number2
DOIs
Publication statusPublished - 27 Mar 2018

Fingerprint

Mucor
Mycoses
Phagocytes
Granuloma
Spores
Mucormycosis
Computer Simulation
Infection
Fungal Spores
Fungi
Zebrafish
Infection Control
Germination
Innate Immunity
Immunosuppression
Leukocytes
Theoretical Models
Oxygen
Mortality

Keywords

  • fungal infection
  • fungal pathogenesis
  • host-pathogen interactions
  • innate immunity
  • macrophages
  • mathematical modeling
  • mucormycosis
  • neutrophils
  • phagocytes
  • zebrafish

Cite this

Inglesfield, S., Jasiulewicz, A., Hopwood, M., Tyrrell, J., Youlden, G., Mazon-Moya, M., ... Voelz, K. (2018). Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo. mBio, 9(2), [e02010-17]. https://doi.org/10.1128/mBio.02010-17
Inglesfield, Sarah ; Jasiulewicz, Aleksandra ; Hopwood, Matthew ; Tyrrell, James ; Youlden, George ; Mazon-Moya, Maria ; Millington, Owain R. ; Mostowy, Serge ; Jabbari, Sara ; Voelz, Kerstin. / Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo. In: mBio. 2018 ; Vol. 9, No. 2.
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Inglesfield, S, Jasiulewicz, A, Hopwood, M, Tyrrell, J, Youlden, G, Mazon-Moya, M, Millington, OR, Mostowy, S, Jabbari, S & Voelz, K 2018, 'Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo' mBio, vol. 9, no. 2, e02010-17. https://doi.org/10.1128/mBio.02010-17

Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo. / Inglesfield, Sarah; Jasiulewicz, Aleksandra; Hopwood, Matthew; Tyrrell, James; Youlden, George; Mazon-Moya, Maria; Millington, Owain R.; Mostowy, Serge; Jabbari, Sara; Voelz, Kerstin.

In: mBio, Vol. 9, No. 2, e02010-17, 27.03.2018.

Research output: Contribution to journalArticle

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T1 - Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo

AU - Inglesfield, Sarah

AU - Jasiulewicz, Aleksandra

AU - Hopwood, Matthew

AU - Tyrrell, James

AU - Youlden, George

AU - Mazon-Moya, Maria

AU - Millington, Owain R.

AU - Mostowy, Serge

AU - Jabbari, Sara

AU - Voelz, Kerstin

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N2 - Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and realtime in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. IMPORTANCE Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.

AB - Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and realtime in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. IMPORTANCE Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.

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KW - fungal pathogenesis

KW - host-pathogen interactions

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KW - macrophages

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KW - mucormycosis

KW - neutrophils

KW - phagocytes

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Inglesfield S, Jasiulewicz A, Hopwood M, Tyrrell J, Youlden G, Mazon-Moya M et al. Robust phagocyte recruitment controls the opportunistic fungal pathogen Mucor circinelloides in innate granulomas In Vivo. mBio. 2018 Mar 27;9(2). e02010-17. https://doi.org/10.1128/mBio.02010-17