Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections

Dellière, Sarah; Guéry, Romain; Candon, Sophie; Rammaert, Blandine; Aguilar, Claire; Lanternier, Fanny; Chatenoud, Lucienne; Lortholary, Olivier

doi:10.3390/jof4040139

Cited by 39 publications

(55 citation statements)

References 141 publications

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“…Too little of a response can lead to patient death due to the fungus, whereas a hyperactive response can lead to death caused by immunopathology. AIDS patients treated with antiretroviral therapy often develop cryptococcal immune reconstitution inflammatory syndrome (IRIS), which is an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency (19). Cryptococcal IRIS emphasizes the potential role of the host immune system in mediating host damage and disease symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…There is reason to study mutants that induce an aberrant hyperinflammatory immune response, as similar responses like increased cytokine levels and strong neutrophil responses have been observed with fungal IRIS (19)(20)(21)(22). Cryptococcal IRIS develops in 8 to 49% of patients with known cryptococcal disease before antiretroviral therapy (23).…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of IRIS is poorly understood, and prediction of IRIS is not currently possible. Innate immune cells, such as monocytes and neutrophils, are of increasing interest in IRIS pathophysiology, since granuloma appears to be frequently found in IRIS lesions (19). Additionally, at the time of IRIS onset, multiple proinflammatory cytokine are detected, including IL-6 (20).…”

Section: Discussionmentioning

confidence: 99%

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Cryptococcus neoformans Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses

Hole

Lam

Upadhya

et al. 2020

mBio

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Cryptococcus neoformans infections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal cell wall is unusual among human-pathogenic fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan-deficient strains of C. neoformans were found to be avirulent and rapidly cleared from the murine lung. Moreover, infection with a chitosan-deficient C. neoformans strain lacking three chitin deacetylases (cda1Δcda2Δcda3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild-type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase-mediated formation of chitosan. Mice inoculated with the chs3Δ strain at a dose previously shown to induce protection with the cda1Δcda2Δcda3Δ strain die within 36 h after installation of the organism. Mortality was not dependent on viable fungi, as mice inoculated with a heat-killed preparation of the chs3Δ strain died at the same rate as mice inoculated with a live chs3Δ strain, suggesting that the rapid onset of death was host mediated, likely caused by an overexuberant immune response. Histology, cytokine profiling, and flow cytometry indicate a massive neutrophil influx in the mice inoculated with the chs3Δ strain. Mice depleted of neutrophils survived chs3Δ inoculation, indicating that death was neutrophil mediated. Altogether, these studies lead us to conclude that Chs3, along with chitosan, plays critical roles in dampening cryptococcus-induced host inflammatory responses. IMPORTANCE Cryptococcus neoformans is the most common disseminated fungal pathogen in AIDS patients, resulting in ∼200,000 deaths each year. There is a pressing need for new treatments for this infection, as current antifungal therapy is hampered by toxicity and/or the inability of the host’s immune system to aid in resolution of the disease. An ideal target for new therapies is the fungal cell wall. The cryptococcal cell wall is different from the cell walls of many other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan are less pathogenic and strains that are deficient in chitosan are avirulent and can induce protective responses. In this study, we investigated the host responses to a chs3Δ strain, a chitosan-deficient strain, and found that mice inoculated with the chs3Δ strain all died within 36 h and that death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response to Cryptococcus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cryptococcus neoformans Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses

Hole

Lam

Upadhya

et al. 2020

mBio

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“…Too little of a response can lead to patient death due to the fungus, whereas a hyperactive response can lead to death caused by immunopathology. AIDS patients treated with antiretroviral therapy often develop cryptococcal immune reconstitution inflammatory syndrome (IRIS) which is an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency (15). Cryptococcal IRIS emphasizes the potential role of the host immune system in mediating host damage and disease symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of IRIS is poorly understood, and prediction of IRIS is not currently possible. Innate immune cells, such as monocytes and neutrophils, are of increasing interest in IRIS pathophysiology, since granuloma appears to be frequently found in IRIS lesions (15). Additionally, at the time of IRIS onset multiple proinflammatory cytokine are detected, including IL-6 (17).…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformansChitin Synthase 3 (Chs3) Plays a Critical Role in Dampening Host Inflammatory Responses

Hole¹,

Lam²,

Upadhya³

et al. 2019

Preprint

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1Cryptococcus neoformans infections are significant causes of morbidity and 2 mortality among AIDS patients and the third most common invasive fungal infection in 3 organ transplant recipients. One of the main interfaces between the fungus and the host 4 is the fungal cell wall. The cryptococcal cell wall is unusual among human pathogenic 5 fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan deficient strains 6 of C. neoformans were found to be avirulent and rapidly cleared from the murine lung. 7 Moreover, infection with a chitosan deficient C. neoformans lacking three chitin 8 deacetylases (cda1D2D3D) was found to confer protective immunity to a subsequent 9 challenge with a virulent wild type counterpart. In addition to the chitin deacetylases, it 10 was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase 11 mediated formation of chitosan. Mice inoculated with chs3D at a dose previously shown 12 to induce protection with cda1D2D3D die within 36 hours after installation of the organism. 13 Mortality was not dependent on viable fungi as mice inoculated with heat-killed 14 preparation of chs3D died at the same rate as mice inoculated with live chs3D, suggesting 15 the rapid onset of death was host mediated likely caused by an over exuberant immune 16 response. Histology, cytokine profiling, and flow cytometry indicates a massive neutrophil 17 influx in the mice inoculated with chs3D. Mice depleted of neutrophils survived chs3D 18 inoculation indicating that death was neutrophil mediated. Altogether, these studies lead 19 us to conclude that Chs3, along with chitosan, plays critical roles in dampening 20 cryptococcal induced host inflammatory responses. 21 22 23 24 IMPORTANCE:25 Cryptococcus neoformans is the most common disseminated fungal pathogen in 26 AIDS patients, resulting in ~200,000 deaths each year. There is a pressing need for new 27 treatments for this infection, as current antifungal therapy is hampered by toxicity and/or 28 the inability of the host's immune system to aid in resolution of the disease. An ideal target 29 for new therapies is the fungal cell wall. The cryptococcal cell wall is different than many 30 other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan 31 are less pathogenic and strains that are deficient in chitosan are avirulent and can induce 32 protective responses. In this study we investigated the host responses to chs3∆, a 33 chitosan-deficient strain, and found mice inoculated with chs3∆ all died within 36 hours 34 and death was associated with an aberrant hyperinflammatory immune response driven 35 by neutrophils, indicating that chitosan is critical in modulating the immune response to 36 Cryptococcus. 37 38 Introduction: 39 Cryptococcus neoformans is a ubiquitous encapsulated fungal pathogen that 40 causes pneumonia and meningitis in immunocompromised individuals. C. neoformans is 41 the most common disseminated fungal pathogen in AIDS patients, with an estimated 42 quarter...

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Histoplasma stomatitis unveiled: Not all opportunistic infections get better after initiation of antiretroviral therapy

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Singhania

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et al. 2021

Clinical Case Reports

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Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections

Cited by 39 publications

References 141 publications

Cryptococcus neoformans Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses

Cryptococcus neoformans Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses

Cryptococcus neoformansChitin Synthase 3 (Chs3) Plays a Critical Role in Dampening Host Inflammatory Responses

Histoplasma stomatitis unveiled: Not all opportunistic infections get better after initiation of antiretroviral therapy

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