Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

Caffrey-Carr, Alayna K.; Kowalski, Caitlin H.; Beattie, Sarah R; Blaseg, Nathan A.; Upshaw, Chanell R.; Thammahong, Arsa; Lust, Hannah E; Tang, Yi‐Wei; Hohl, Tobias M.; Cramer, Robert A.; Obar, Joshua J.

doi:10.1128/iai.00661-17

Cited by 61 publications

(90 citation statements)

References 84 publications

(128 reference statements)

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“…infection biology and characterization of strains that were isolated from immunocompromised patients under different conditions have received considerable attention in recent years (24,37,47), whereas similar studies into other pathogenic Aspergillus spp. have been neglected although it is becoming apparent that non-A.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans

Bastos

Valero

Silva

et al. 2020

mSphere

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Aspergillus nidulans is an opportunistic fungal pathogen in patients with immunodeficiency, and virulence of A. nidulans isolates has mainly been studied in the context of chronic granulomatous disease (CGD), with characterization of clinical isolates obtained from non-CGD patients remaining elusive. This study therefore carried out a detailed biological characterization of two A. nidulans clinical isolates (CIs), obtained from a patient with breast carcinoma and pneumonia and from a patient with cystic fibrosis that underwent lung transplantation, and compared them to the reference, nonclinical FGSC A4 strain. Both CIs presented increased growth in comparison to that of the reference strain in the presence of physiologically relevant carbon sources. Metabolomic analyses showed that the three strains are metabolically very different from each other in these carbon sources. Furthermore, the CIs were highly susceptible to cell wall-perturbing agents but not to other physiologically relevant stresses. Genome analyses identified several frameshift variants in genes encoding cell wall integrity (CWI) signaling components. Significant differences in CWI signaling were confirmed by Western blotting among the three strains. In vivo virulence studies using several different models revealed that strain MO80069 had significantly higher virulence in hosts with impaired neutrophil function than the other strains. In summary, this study presents detailed biological characterization of two A. nidulans sensu stricto clinical isolates. Just as in Aspergillus fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits. Further studies are required to fully characterize A. nidulans strain-specific virulence traits and pathogenicity. IMPORTANCE Immunocompromised patients are susceptible to infections with opportunistic filamentous fungi from the genus Aspergillus. Although A. fumigatus is the main etiological agent of Aspergillus species-related infections, other species, such as A. nidulans, are prevalent in a condition-specific manner. A. nidulans is a predominant infective agent in patients suffering from chronic granulomatous disease (CGD). A. nidulans isolates have mainly been studied in the context of CGD although infection with A. nidulans also occurs in non-CGD patients. This study carried out a detailed biological characterization of two non-CGD A. nidulans clinical isolates and compared the results to those with a reference strain. Phenotypic, metabolomic, and genomic analyses highlight fundamental differences in carbon source utilization, stress responses, and maintenance of cell wall integrity among the strains. One clinical strain had increased virulence in models with impaired neutrophil function. Just as in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits.

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Section: Discussionmentioning

confidence: 99%

Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans

Bastos

Valero

Silva

et al. 2020

mSphere

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“…IL-1 receptor deficiency results in profound susceptibility to A. fumigatus as a result of IL-1␣-mediated early (day 1) neutrophil recruitment and IL-1␤-mediated macrophage antifungal responses (46). More recently, IL-1␣ was found to be required for the elimination of highly virulent, highly germinating A. fumigatus strains (47). Likewise, we recently reported that another function of IL-1 receptor signaling during A. fumigatus exposure is the induction of IL-17A and IL-22 (32), both of which we have shown to be essential for A. fumigatus elimination from the lungs (48) (49).…”

Section: Discussionmentioning

confidence: 99%

Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

et al. 2018

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Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) () deficiency on host defense during acute exposure to the fungal pathogen as well as its contribution to-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in conidia, which emerged at the highest level during hyphal transition. In response to acute challenge, mice unexpectedly demonstrated lower lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E (PGE) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronic exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.

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“…Studies on A. nidulans virulence have been carried out in CGD models (animal and cell culture) and virulence characteristics have been compared to the primary human opportunistic fungus A. fumigatus (20,21,45,46). A. fumigatus infection biology and characterization of strains that were isolated from immunocompromised patients with different conditions have received considerable attention in recent years (24,37,47), whereas similar studies into other pathogenic Aspergillus spp. have been neglected, although it is becoming apparent that non- A. fumigatus species, including cryptic Aspergillus species, also contribute to host infection and invasion (7).…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of clinical isolates of the opportunistic fungal pathogenAspergillus nidulans

Bastos

Valero²,

Silva³

et al. 2020

Preprint

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AbstractAspergillus nidulans is an opportunistic fungal pathogen in patients with immunodeficiency and virulence of A. nidulans isolates has mainly been studied in the context of the chronic granulomatous disease (CGD), with characterization of clinical isolates obtained from non-CGD patients remaining elusive. This study therefore carried out a detailed biological characterization of two A. nidulans clinical isolates (CIs), obtained from a patient with breast carcinoma and pneumonia and from a patient with cystic fibrosis that underwent lung transplantation, and compared them to the reference, non-clinical A4 strain. Both CIs presented increased growth in comparison to the reference strain in the presence of physiologically-relevant carbon sources. Metabolomic analyses showed that the three strains are metabolically very different from each other in these carbon sources. Furthermore, the CIs were highly susceptible to cell wall perturbing agents but not to other physiologically-relevant stresses. Genome analyses identified several frame-shift variants in genes encoding cell wall integrity (CWI) signalling components. Significant differences in CWI signalling were confirmed by western blotting among the three strains. In vivo virulence studies using several different models revealed that strain MO80069 had significantly higher virulence in hosts with impaired neutrophil function when compared to the other strains. In summary, this study presents detailed biological characterization of two A. nidulans sensu stricto clinical isolates. Just like in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits. Further studies are required to fully characterize A. nidulans strain-specific virulence traits and pathogenicity.ImportanceImmunocompromised patients are susceptible to infections with opportunistic filamentous fungi from the genus Aspergillus. Although A. fumigatus is the main etiological agent of Aspergillus spp.-related infections, other species, such as A. nidulans are prevalent in a condition-specific manner. A. nidulans is a predominant infective agent in patients suffering from chronic granulomatous disease (CGD). A. nidulans isolates have mainly been studied in the context of CGD, although infection with A. nidulans also occurs in non-CGD patients. This study carried out a detailed biological characterization of two non-CGD A. nidulans clinical isolates and compared it to a reference strain. Phenotypic, metabolomic and genomic analyses highlight fundamental differences in carbon source utilization, stress responses and maintenance of cell wall integrity among the strains. One clinical strain had increased virulence in models with impaired neutrophil function. Just as in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits.

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Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

Cited by 61 publications

References 84 publications

Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans

Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans

Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure

Functional characterization of clinical isolates of the opportunistic fungal pathogenAspergillus nidulans

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