Protection against Cryptococcosis by Using a Murine Gamma Interferon-Producing<i>Cryptococcus neoformans</i>Strain

Wormley, Floyd L.; Perfect, John R.; Steele, Chad; Cox, Gary M.

doi:10.1128/iai.00274-06

Cited by 168 publications

(208 citation statements)

References 46 publications

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“…Gene expression was measured three times in each of the three samples per group. virulent strain [35]. Moreover, mice vaccinated with either heat-killed Cryptococcus cells or culture filtrate antigens showed significant T-cell-dependent delayed-type hypersensitivity reaction and were better protected against subsequent challenge with a virulent strain [36,37].…”

Section: Discussionmentioning

confidence: 91%

Cryptococcus inositol utilization modulates the host protective immune response during brain infection

Liu

Subbian

Pan

et al. 2014

Cell Communication and Signaling

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Background: Cryptococcus neoformans is the most common cause of fungal meningitis among individuals with HIV/AIDS, which is uniformly fatal without proper treatment. The underlying mechanism of disease development in the brain that leads to cryptococcal meningoencephalitis remains incompletely understood. We have previously demonstrated that inositol transporters (ITR) are required for Cryptococcus virulence. The itr1aΔ itr3cΔ double mutant of C. neoformans was attenuated for virulence in a murine model of intra-cerebral infection; demonstrating that Itr1a and Itr3c are required for full virulence during brain infection, despite a similar growth rate between the mutant and wild type strains in the infected brain.

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Section: Discussionmentioning

confidence: 91%

Cryptococcus inositol utilization modulates the host protective immune response during brain infection

Liu

Subbian

Pan

et al. 2014

Cell Communication and Signaling

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“…No studies have previously assessed the impact of the inflammasome on the Th1 defense mechanisms during PCM. Because IFN-g is an important cytokine involved in the resistance to P. brasiliensis and other several fungi (11,27,(44)(45)(46)(47)(48)(49)(50), we speculated that IFN-g could play a role in the central mechanism regulated by caspase-1 after P. brasiliensis infection. Confirming this hypothesis, IFN-g production and the Th1 response were lower in infected Asc 2/2 , Casp1 2/2 , and Nlrp3 mice were susceptible to experimental PCM because they exhibited reduced Th1 (and not Th17) immunity.…”

Section: Discussionmentioning

confidence: 99%

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Ketelut-Carneiro

Silva

Rocha

et al. 2015

The Journal of Immunology

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Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain–like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1β). In this study, we showed that NLR family pyrin domain–containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1β and IL-18 by P. brasiliensis–infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18–dependent proinflammatory response.

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“…This strain grows in the lungs in an uncontrolled fashion, readily disseminates into CNS, and causes 100% mortality in a variety of immunocompetent mouse strains such as C57BL/6, BALB/c, CB6129F2, and CBA/J mice. 8,13,[31][32][33] The infections with H99 were previously shown to result in upregulation of several hallmarks of Th2 immunity in the lungs. This was associated with the expression of virulence factors by H99 including urease and PLB1.…”

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confidence: 99%

Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

Zhang

Wang

Tompkins

et al. 2009

The American Journal of Pathology

153

184

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The present study dissected the role of a Th2 bias in pathogenesis of Cryptococcus neoformans H99 infection by comparing inhalational H99 infections in wild-type BALB/c and IL-4/IL-13 double knockout mice. H99-infected wild-type mice showed all major hallmarks of Th2 but not Th1/Th17 immunity in the lungs and lung-associated lymph nodes. In contrast, the IL-4/13 ؊/؊ mice developed robust hallmarks of Th1 and Th17 but not Th2 polarization. The IL-4/IL-13 deletion prevented pulmonary eosinophilia, goblet cell metaplasia in the airways and resulted in elevated serum IgE, and a switch from alternative to classical activation of macrophages. The development of a robust Th1/Th17 response and classical activation of macrophages resulted in significant containment of H99 in the lungs of IL-4/13 ؊/؊ mice compared with unopposed growth of H99 in the lungs of wild-type mice. However, IL-4/13 ؊/؊ mice showed only 1-week longer survival compared with wild-type mice. The comparison of brain and spleen cryptococcal loads at weeks 2, 3, and 4 postinfection revealed that the systemic dissemination in IL-4/13 ؊/؊ mice occurred with an approximate 1-week delay but subsequently progressed with similar rate as in the wild-type mice. Furthermore, wild-type and IL-4/13 ؊/؊ mice developed equivalently severe meningitis/encephalitis at the time of death. These data indicate that the Th2 immune bias is a crucial mechanism for pulmonary virulence of H99, whereas other mechanisms are largely responsible for its central nervous system tropism and systemic dissemination.

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Protection against Cryptococcosis by Using a Murine Gamma Interferon-ProducingCryptococcus neoformansStrain

Cited by 168 publications

References 46 publications

Cryptococcus inositol utilization modulates the host protective immune response during brain infection

Cryptococcus inositol utilization modulates the host protective immune response during brain infection

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

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