Mucorales spores induce a proinflammatory cytokine response in human mononuclear phagocytes and harbor no rodlet hydrophobins

Wurster, Sebastian; Thielen, V; Weis, Philipp; Walther, Paul; Elias, Johannes; Waaga-Gasser, Ana Maria; Dragan, Mariola; Dandekar, Thomas; Einsele, Hermann; Löffler, Jürgen; Ullmann, Andrew J.

doi:10.1080/21505594.2017.1342920

Cited by 27 publications

(34 citation statements)

References 29 publications

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“…This layer is shed when spores swell and germinate, providing an opportunity for phagocyte detection. There is no evidence of hydrophobins similar to RodA in the mucormycete lineage 73 , however resting and swollen Rhizopus spores demonstrate limited immunogenicity 62 . We hypothesized that masking of the spore surface might allow R. microsporus spores to evade host detection.…”

Section: Resultsmentioning

confidence: 99%

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Itabangi

Pcs

Zhou

et al. 2019

Preprint

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Environmentally ubiquitous fungal spores of the Mucorales order cause acute invasive infections through germination and evasion of the mammalian host immune system. Early phagocyte control of spore germination plays a key role in controlling infection, yet swelling Mucorales spores evade phagocytosis through an unknown mechanism. Here we investigate fungal immune evasion in a clinical isolate of Rhizopus microsporus and reveal the role of a bacterial endosymbiont, Ralsonia pickettii, in fungal pathogenesis. Analysis of phagocytosis rates in wild type and cured fungal isolates demonstrates a role for the endosymbiont in immune cell evasion through disruption of the cytoskeleton and phagosome maturation. Further analysis of bacterial secreted products revealed the presence of a previously uncharacterized secondary metabolite whose production is induced by the presence of the fungus. Analysis of the bacterial genome and condition-dependent RNAseq implicate a cryptic type I polyketide synthase. Subsequent analysis of wild type and cured spores in a zebrafish larvae model of infection demonstrate a role for the endosymbiont in suppressing macrophage and neutrophil recruitment to the site of infection. Finally, we demonstrate that this has implications for fungal clearance in an immunocompetent murine model of infection. Together, these findings identify for the first time a role for a bacterial endosymbiont in the pathogenesis of Rhizopus microsporus during animal infection.

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Section: Resultsmentioning

confidence: 99%

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Itabangi

Pcs

Zhou

et al. 2019

Preprint

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“…We have presented a novel interdisciplinary strategy to understanding the interplay between the host immune response and mucormycetes. Recent work has shown that spores induce proinflammatory responses upon encountering macrophages ( 17 , 47 ). Our data suggested that proinflammatory signals are beneficial in controlling mucormycosis by inducing phagocyte recruitment, and both phagocyte number and activity were found to be required for protection from disease onset.…”

Section: Discussionmentioning

confidence: 99%

Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen Mucor circinelloides in Innate Granulomas In Vivo

Inglesfield

Jasiulewicz

Hopwood

et al. 2018

mBio

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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 real-time 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.

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“…In a model of invasive Mucorales infection, peripheral blood mononuclear cells (PBMCs), monocytes, and monocyte-derived dendritic cells (mDCs) from healthy donors were stimulated with resting and germinated stages of Mucorales and Ascomycota. Both inactivated germ tubes and resting spores of Mucorales species significantly stimulated mRNA synthesis and secretion of proinflammatory cytokines, including IL-6 and TNFα, and induced the upregulation of co-stimulatory molecules on mDCs and a T-helper cell response [57]. Another model of stimulated mononuclear cells examined TNFα and IL-6 secretion to cells exposed to different pathogenic fungi.…”

Section: Anti-mold Immune Response: the Impact Of The Host And The Pamentioning

confidence: 99%

Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

Jenks

Rawlings

García-Vidal

et al. 2019

JoF

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Infections caused by invasive molds, including Aspergillus spp., can be difficult to diagnose and remain associated with high morbidity and mortality. Thus, early diagnosis and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals with invasive mold infections. Diagnosis remains difficult due to low sensitivities of diagnostic tests including culture and other mycological tests for mold pathogens, particularly in patients on mold-active antifungal prophylaxis. As a result, antifungal treatment is rarely targeted and reliable markers for treatment monitoring and outcome prediction are missing. Thus, there is a need for improved markers to diagnose invasive mold infections, monitor response to treatment, and assist in determining when antifungal therapy should be escalated, switched, or can be stopped. This review focuses on the role of immunologic markers and specifically cytokines in diagnosis and treatment monitoring of invasive mold infections.

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Mucorales spores induce a proinflammatory cytokine response in human mononuclear phagocytes and harbor no rodlet hydrophobins

Cited by 27 publications

References 29 publications

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen Mucor circinelloides in Innate Granulomas In Vivo

Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

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