Impaired Antifungal Effector Activity but Not Inflammatory Cell Recruitment in Interleukin‐6–Deficient Mice with Invasive Pulmonary Aspergillosis

Cenci, Elio; Mencacci, Antonella; Casagrande, Andrea; Mosci, Paolo; Bistoni, Francesco; Romani, Luigina

doi:10.1086/322793

Cited by 100 publications

(79 citation statements)

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“…As many of these chemokines are synthesized by macrophages, we speculate that their increased expression in mice infected with the Δ gliP mutants was due to reduced death of macrophages in the fungal lesions. In mice infected with the Δ gliP mutant, there was also elevated expression of IL-6 and TNF-α, suggesting that gliotoxin also inhibits the production of these cytokines, both of which are required for the host defense against invasive aspergillosis [36–38]. …”

Section: Discussionmentioning

confidence: 99%

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Liu

Solis

et al. 2018

Virulence

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Gliotoxin contributes to the virulence of the fungus Aspergillus fumigatus in non-neutropenic mice that are immunosuppressed with corticosteroids. To investigate how the absence of gliotoxin affects both the fungus and the host, we used a nanoString nCounter to analyze their transcriptional responses during pulmonary infection of a non-neutropenic host with a gliotoxin-deficient ΔgliP mutant. We found that the ΔgliP mutation led to increased expression of aspf1, which specifies a secreted ribotoxin. Prior studies have shown that aspf1, like gliP, is not required for virulence in a neutropenic infection model, but its role in a non-neutropenic infection model has not been fully investigated. To investigate the functional significance of this up-regulation of aspf1, a Δaspf1 single mutant and a Δaspf1 ΔgliP double mutant were constructed. Both Δaspf1 and ΔgliP single mutants had reduced lethality in non-neutropenic mice, and a Δaspf1 ΔgliP double mutant had a greater reduction in lethality than either single mutant. Analysis of mice infected with these mutants indicated that the presence of gliP is associated with massive apoptosis of leukocytes at the foci of infection and inhibition of chemokine production. Also, the combination of gliP and aspf1 is associated with suppression of CXCL1 chemokine expression. Thus, aspf1 contributes to A. fumigatus pathogenicity in non-neutropenic mice and its up-regulation in the ΔgliP mutant may partially compensate for the absence of gliotoxin.Abbreviations:PAS: periodic acid-Schiff; PBS: phosphate buffered saline; ROS: reactive oxygen species; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling

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Section: Discussionmentioning

confidence: 99%

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Liu

Solis

et al. 2018

Virulence

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“…98 IL-6 knockout mice are more susceptible to invasive aspergillosis than wild-type animals. 99 This is important because IL-6 is a neuroinflammatory cytokine released by cells of the brain, including microglia, astrocytes, and neurons. IL-6 plays a role in sequestering intracellular free iron, an important nutritional source for microbial growth within phagocytes.…”

Section: Aspergillosismentioning

confidence: 99%

Role of microglia in fungal infections of the central nervous system

2016

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Most fungi are capable of disseminating into the central nervous system (CNS) commonly being observed in immunocompromised hosts. Microglia play a critical role in responding to these infections regulating inflammatory processes proficient at controlling CNS colonization by these eukaryotic microorganisms. Nonetheless, it is this inflammatory state that paradoxically yields cerebral mycotic meningoencephalitis and abscess formation. As peripheral macrophages and fungi have been investigated aiding our understanding of peripheral disease, ascertaining the key interactions between fungi and microglia may uncover greater abilities to treat invasive fungal infections of the brain. Here, we present the current knowledge of microglial physiology. Due to the existing literature, we have described to greater extent the opportunistic mycotic interactions with these surveillance cells of the CNS, highlighting the need for greater efforts to study other cerebral fungal infections such as those caused by geographically restricted dimorphic and rare fungi.

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“…Infecting WT mice with SP-D opsonized melanin ghost resulted in a significant increase in the lung TNF-α transcript/protein levels. IL-6 was induced in the BAL of immunocompetent mice infected intranasally with conidia (46), while IL-6-deficient mice were more susceptible to IA than wild-type mice (47). Although the cellular recruitment was not affected in IL-6-deficient mice, the fungicidal activity of the recruited phagocytes was significantly impaired (47).…”

Section: Sp-d Opsonized a Fumigatus Conidia/melanin Ghost Induce Promentioning

confidence: 99%