scholarly journals Cryptococcus neoformans Chitin Synthase 3 (Chs3) Plays a Critical Role in Dampening Host Inflammatory Responses

2019 ◽  
Author(s):  
Camaron R. Hole ◽  
Woei C. Lam ◽  
Rajendra Upadhya ◽  
Jennifer K. Lodge
Keyword(s):  
Immune Response ◽  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Pathogenic Fungi ◽  
Fungal Cell Wall ◽  
Chitin Synthase ◽  
Aids Patients ◽  
Fungal Cell

ABSTRACTCryptococcus 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 lacking three chitin deacetylases (cda1Δ2Δ3Δ) 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 chs3Δ at a dose previously shown to induce protection with cda1Δ2Δ3Δ die within 36 hours after installation of the organism. Mortality was not dependent on viable fungi as mice inoculated with heat-killed preparation of chs3Δ died at the same rate as mice inoculated with live chs3Δ, suggesting the rapid onset of death was host mediated likely caused by an over exuberant immune response. Histology, cytokine profiling, and flow cytometry indicates a massive neutrophil influx in the mice inoculated with chs3Δ. 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 cryptococcal induced host inflammatory responses.IMPORTANCECryptococcus 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 than 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 chs3Δ, a chitosan-deficient strain, and found mice inoculated with chs3Δ all died within 36 hours and death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response to Cryptococcus.

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

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Camaron R. Hole ◽  
Woei C. Lam ◽  
Rajendra Upadhya ◽  
Jennifer K. Lodge
Keyword(s):  
Immune Response ◽  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Inflammatory Responses ◽  
Pathogenic Fungi ◽  
Fungal Cell Wall ◽  
Chitin Synthase ◽  
Aids Patients ◽  
Fungal Cell ◽  
Content Type

ABSTRACT 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.

Chitin synthase gene FgCHS8 affects virulence and fungal cell wall sensitivity to environmental stress in Fusarium graminearum

2016 ◽  
Vol 120 (5) ◽  
pp. 764-774 ◽  
Author(s):  
Ya-Zhou Zhang ◽  
Qing Chen ◽  
Cai-Hong Liu ◽  
Yu-Bin Liu ◽  
Pan Yi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Environmental Stress ◽  
Fusarium Graminearum ◽  
Fungal Cell Wall ◽  
Chitin Synthase ◽  
Fungal Cell

scholarly journals Cell Wall Integrity Pathway Involved in Morphogenesis, Virulence and Antifungal Susceptibility in Cryptococcus neoformans

2021 ◽  
Vol 7 (10) ◽  
pp. 831
Author(s):  
Haroldo Cesar de Oliveira ◽  
Suelen Andreia Rossi ◽  
Irene García-Barbazán ◽  
Óscar Zaragoza ◽  
Nuria Trevijano-Contador
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Morphological Changes ◽  
Antifungal Susceptibility ◽  
Pathogenic Fungi ◽  
Cell Wall Integrity ◽  
Cell Permeability ◽  
Fungal Cell ◽  
Cell Wall Integrity Pathway ◽  
Fungal Kingdom

Due to its location, the fungal cell wall is the compartment that allows the interaction with the environment and/or the host, playing an important role during infection as well as in different biological functions such as cell morphology, cell permeability and protection against stress. All these processes involve the activation of signaling pathways within the cell. The cell wall integrity (CWI) pathway is the main route responsible for maintaining the functionality and proper structure of the cell wall. This pathway is highly conserved in the fungal kingdom and has been extensively characterized in Saccharomyces cerevisiae. However, there are still many unknown aspects of this pathway in the pathogenic fungi, such as Cryptococcus neoformans. This yeast is of particular interest because it is found in the environment, but can also behave as pathogen in multiple organisms, including vertebrates and invertebrates, so it has to adapt to multiple factors to survive in multiple niches. In this review, we summarize the components of the CWI pathway in C. neoformans as well as its involvement in different aspects such as virulence factors, morphological changes, and its role as target for antifungal therapies among others.

ChemInform Abstract: Novel Nikkomycin Analogues: Inhibitors of the Fungal Cell Wall Biosynthesis Enzyme Chitin Synthase.

ChemInform ◽  
2000 ◽  
Vol 31 (41) ◽  
pp. no-no
Author(s):  
Kikoh Obi ◽  
Jun-ichiro Uda ◽  
Kazuhiko Iwase ◽  
Osamu Sugimoto ◽  
Hiroyuki Ebisu ◽  
...  
Keyword(s):  
Cell Wall ◽  
Fungal Cell Wall ◽  
Chitin Synthase ◽  
Cell Wall Biosynthesis ◽  
Fungal Cell

scholarly journals Iron alters the cell wall composition and intracellular lactate to affect Candida albicans susceptibility to antifungals and host immune response

2020 ◽  
Vol 295 (29) ◽  
pp. 10032-10044 ◽  
Author(s):  
Aparna Tripathi ◽  
Elisabetta Liverani ◽  
Alexander Y. Tsygankov ◽  
Sumant Puri
Keyword(s):  
Immune Response ◽  
Cell Wall ◽  
Candida Albicans ◽  
Signaling Pathways ◽  
Host Immune Response ◽  
Fungal Cell Wall ◽  
Mitogen Activated Protein Kinase ◽  
Fungal Cell ◽  
High Iron ◽  
Cell Wall Architecture

Fungal pathogen Candida albicans has a complex cell wall consisting of an outer layer of mannans and an inner layer of β-glucans and chitin. The fungal cell wall is the primary target for antifungals and is recognized by host immune cells. Environmental conditions such as carbon sources, pH, temperature, and oxygen tension can modulate the fungal cell wall architecture. Cellular signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways, are responsible for sensing environmental cues and mediating cell wall alterations. Although iron has recently been shown to affect β-1,3-glucan exposure on the cell wall, we report here that iron changes the composition of all major C. albicans cell wall components. Specifically, high iron decreased the levels of mannans (including phosphomannans) and chitin; and increased β-1,3-glucan levels. These changes increased the resistance of C. albicans to cell wall-perturbing antifungals. Moreover, high iron cells exhibited adequate mitochondrial functioning; leading to a reduction in accumulation of lactate that signals through the transcription factor Crz1 to induce β-1,3-glucan masking in C. albicans. We show here that iron-induced changes in β-1,3-glucan exposure are lactate-dependent; and high iron causes β-1,3-glucan exposure by preventing lactate-induced, Crz1-mediated inhibition of activation of the fungal MAPK Cek1. Furthermore, despite exhibiting enhanced antifungal resistance, high iron C. albicans cells had reduced survival upon phagocytosis by macrophages. Our results underscore the role of iron as an environmental signal in multiple signaling pathways that alter cell wall architecture in C. albicans, thereby affecting its survival upon exposure to antifungals and host immune response.

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