scholarly journals Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice fromCryptococcus gattiiIndependently of T Cells

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Michael J. Davis ◽  
Shannon Moyer ◽  
Elizabeth S. Hoke ◽  
Edward Sionov ◽  
Katrin D. Mayer-Barber ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Cryptococcus Gattii ◽  
Iron Limitation ◽  
Type I ◽  
Type I Ifn ◽  
Aids Patients ◽  
Content Type ◽  
Immune Pathways

ABSTRACTCryptococcus neoformanscauses deadly mycosis primarily in AIDS patients, whereasCryptococcus gattiiinfects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence ofC. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome ofC. neoformansandC. gattiiinfections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. InC. neoformans-infected mice, pICLC activity was associated withC. neoformanscontainment and classical Th1 immunity. In contrast, pICLC activity againstC. gattiidid not require any immune factors previously associated withC. neoformansimmunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly,C. gattiipICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggestingC. gattiipICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcusin vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection byC. gattiiandC. neoformansbut by distinct mechanisms; theC. gattiieffect was mediated by iron limitation, while the effect onC. neoformansinfection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for differentCryptococcusspecies suggests a possible mechanism by which HIV infection may select againstC. gattiibut notC. neoformans.IMPORTANCECryptococcus neoformansandCryptococcus gattiicause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species,C. gattiiinfects very few AIDS patients, whileC. neoformansinfection is an AIDS-defining illness, suggesting that the host response to HIV selectsC. neoformansoverC. gattii. We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action againstC. neoformanswas due to activation of well-defined immune pathways known to deterC. neoformans, whereas these immune pathways were dispensable for pICLC treatment ofC. gattii. Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to controlC. neoformansinfection but is protective againstC. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibitedC. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.

scholarly journals Altered Immune Response Differentially Enhances Susceptibility to Cryptococcus neoformans and Cryptococcus gattii Infection in Mice Expressing the HIV-1 Transgene

2013 ◽  
Vol 81 (4) ◽  
pp. 1100-1113 ◽  
Author(s):  
Kassandre Leongson ◽  
Vincent Cousineau-Côté ◽  
Mathieu Goupil ◽  
Francine Aumont ◽  
Serge Sénéchal ◽  
...  
Keyword(s):  
Immune Response ◽  
Cryptococcus Neoformans ◽  
Transgene Expression ◽  
Inflammatory Cell ◽  
Differential Susceptibility ◽  
Lung Parenchyma ◽  
Cryptococcus Gattii ◽  
Content Type ◽  
Altered Immune Response ◽  
Hiv 1

ABSTRACTCryptococcus neoformansvar.grubiiis the most frequent cause of AIDS-associated cryptococcosis worldwide, whileCryptococcus gattiiusually infects immunocompetent people. To understand the mechanisms which cause differential susceptibility to these cryptococcal species in HIV infection, we established and characterized a model of cryptococcosis in CD4C/HIVMutAtransgenic (Tg) mice expressing gene products of HIV-1 and developing an AIDS-like disease. Tg mice infected intranasally withC. neoformansvar.grubiistrain H99 or C23 consistently displayed reduced survival compared to non-Tg mice at three graded inocula, while shortened survival of Tg mice infected withC. gattiistrain R265 or R272 was restricted to a single high inoculum. HIV-1 transgene expression selectively augmented systemic dissemination to the liver and spleen for strains H99 and C23 but not strains R265 and R272. Histopathologic examination of lungs of Tg mice revealed large numbers of widely scattered H99 cells, with a minimal inflammatory cell response, while in the non-Tg mice H99 was almost completely embedded within extensive mixed inflammatory cell infiltrates. In contrast to H99, R265 was dispersed throughout the lung parenchyma and failed to induce a strong inflammatory response in both Tg and non-Tg mice. HIV-1 transgene expression reduced pulmonary production of CCL2 and CCL5 after infection with H99 or R265, and production of these two chemokines was lower after infection with R265. These results indicate that an altered immune response in these Tg mice markedly enhancesC. neoformansbut notC. gattiiinfection. This model therefore provides a powerful new tool to further investigate the immunopathogenesis of cryptococcosis.

scholarly journals Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing Cryptococcus Alkaline Extracts

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Charles A. Specht ◽  
Chrono K. Lee ◽  
Haibin Huang ◽  
Donald J. Tipper ◽  
Zu T. Shen ◽  
...  
Keyword(s):  
At Risk ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Delivery System ◽  
Cell Walls ◽  
Vaccine Development ◽  
Cryptococcus Gattii ◽  
Content Type ◽  
Alkaline Extract ◽  
Virulent Strains

ABSTRACTA vaccine capable of protecting at-risk persons against infections due toCryptococcus neoformansandCryptococcus gattiicould reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purifiedSaccharomyces cerevisiaecell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains ofC. neoformansandC. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4+T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine.IMPORTANCEThe encapsulated yeastCryptococcus neoformansand its closely related sister species,Cryptococcus gattii, are major causes of morbidity and mortality, particularly in immunocompromised persons. This study reports on the preclinical development of vaccines to protect at-risk populations from cryptococcosis. Antigens were extracted fromCryptococcusby treatment with an alkaline solution. The extracted antigens were then packaged into glucan particles, which are hollow yeast cell walls composed mainly of β-glucans. The glucan particle-based vaccines elicited robust T cell immune responses and protected mice from otherwise-lethal challenge with virulent strains ofC. neoformansandC. gattii. The technology used for antigen extraction and subsequent loading into the glucan particle delivery system is relatively simple and can be applied to vaccine development against other pathogens.

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.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection

2014 ◽  
Vol 7 (5) ◽  
pp. 1151-1164 ◽  
Author(s):  
A Jayaraman ◽  
D J Jackson ◽  
S D Message ◽  
R M Pearson ◽  
J Aniscenko ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Type I ◽  
Type I Ifn ◽  
Cell Responses ◽  
Rhinovirus Infection

scholarly journals Failure To Recruit Anti-Inflammatory CD103+Dendritic Cells and a Diminished CD4+Foxp3+Regulatory T Cell Pool in Mice That Display Excessive Lung Inflammation and Increased Susceptibility to Mycobacterium tuberculosis

2012 ◽  
Vol 80 (3) ◽  
pp. 1128-1139 ◽  
Author(s):  
Chaniya Leepiyasakulchai ◽  
Lech Ignatowicz ◽  
Andrzej Pawlowski ◽  
Gunilla Källenius ◽  
Markus Sköld
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Bacterial Growth ◽  
Lung Inflammation ◽  
Chronic Infection ◽  
Host Immune Response ◽  
Content Type ◽  
Tnf Α

Susceptibility toMycobacterium tuberculosisis characterized by excessive lung inflammation, tissue damage, and failure to control bacterial growth. To increase our understanding of mechanisms that may regulate the host immune response in the lungs, we characterized dendritic cells expressing CD103 (αEintegrin) (αE-DCs) and CD4+Foxp3+regulatory T (Treg) cells duringM. tuberculosisinfection. In resistant C57BL/6 and BALB/c mice, the number of lung αE-DCs increased dramatically duringM. tuberculosisinfection. In contrast, highly susceptible DBA/2 mice failed to recruit αE-DCs even during chronic infection. Even though tumor necrosis factor alpha (TNF-α) is produced by multiple DCs and macrophage subsets and is required for control of bacterial growth, αE-DCs remained TNF-α negative. Instead, αE-DCs contained a high number of transforming growth factor beta-producing cells in infected mice. Further, we show that Tregcells in C57BL/6 and DBA/2 mice induce gamma interferon during pulmonary tuberculosis. In contrast to resistant mice, the Tregcell population was diminished in the lungs, but not in the draining pulmonary lymph nodes (PLN), of highly susceptible mice during chronic infection. Tregcells have been reported to inhibitM. tuberculosis-specific T cell immunity, leading to increased bacterial growth. Still, despite the reduced number of lung Tregcells in DBA/2 mice, the bacterial load in the lungs was increased compared to resistant animals. Our results show that αE-DCs and Tregcells that may regulate the host immune response are increased inM. tuberculosis-infected lungs of resistant mice but diminished in infected lungs of susceptible mice.

scholarly journals DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans

2016 ◽  
Vol 84 (6) ◽  
pp. 1879-1886 ◽  
Author(s):  
Lena J. Heung ◽  
Tobias M. Hohl
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Cryptococcus Neoformans ◽  
Molecular Mechanisms ◽  
Content Type ◽  
Effector Cells ◽  
Opportunistic Fungal Pathogen ◽  
Efficient Uptake ◽  
Bacteria And Fungi

Cryptococcus neoformansis an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response toC. neoformans. Infectious outcomes in DAP12−/−mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12−/−mice. In contrast to WT NK cells, DAP12−/−NK cells are able to repressC. neoformansgrowthin vitro. Additionally, DAP12−/−macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing ofC. neoformans. These findings suggest that DAP12 acts as a brake on the pulmonary immune response toC. neoformansby promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.

EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi181-vi181
Author(s):  
Yuanfan Yang ◽  
Michael Brown ◽  
Kevin Stevenson ◽  
Giselle lopez ◽  
Reb Kornahrens ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Cd8 T Cell ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Acute Type ◽  
Type I Ifn ◽  
Term Survival

Abstract Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.

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