Antifungal Activity of Plasmacytoid Dendritic Cells against Cryptococcus neoformans
            <i>In Vitro</i>
            Requires Expression of Dectin-3 (CLEC4D) and Reactive Oxygen Species

Hole, Camaron R.; Wager, Chrissy M. Leopold; Mendiola, Andrew S.; Wozniak, Karen L.; Campuzano, Althea; Lin, Xin; Wormley, Floyd L.

doi:10.1128/iai.00103-16

Cited by 35 publications

(44 citation statements)

References 51 publications

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“…Plasmacytoid dendritic cells (pDCs) can produce large amounts of t1IFN. Also, a recent study suggested that these cells may be relevant in mouse models of cryptococcosis (41). pICLC-treated pDC-depleted mice showed a lung fungal burden that was indistinguishable from that of pICLC-treated nondepleted mice ( Fig.…”

Section: Resultsmentioning

confidence: 88%

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Davis

Moyer

Hoke

et al. 2019

mBio

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Cryptococcus neoformans causes deadly mycosis primarily in AIDS patients, whereas Cryptococcus gattii infects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence of C. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome of C. neoformans and C. gattii infections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. In C. neoformans-infected mice, pICLC activity was associated with C. neoformans containment and classical Th1 immunity. In contrast, pICLC activity against C. gattii did not require any immune factors previously associated with C. neoformans immunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly, C. gattii pICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggesting C. gattii pICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcus in vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection by C. gattii and C. neoformans but by distinct mechanisms; the C. gattii effect was mediated by iron limitation, while the effect on C. neoformans infection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for different Cryptococcus species suggests a possible mechanism by which HIV infection may select against C. gattii but not C. neoformans. IMPORTANCE Cryptococcus neoformans and Cryptococcus gattii cause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species, C. gattii infects very few AIDS patients, while C. neoformans infection is an AIDS-defining illness, suggesting that the host response to HIV selects C. neoformans over C. 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 against C. neoformans was due to activation of well-defined immune pathways known to deter C. neoformans, whereas these immune pathways were dispensable for pICLC treatment of C. 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 control C. neoformans infection but is protective against C. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibited C. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.

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Section: Resultsmentioning

confidence: 88%

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Davis

Moyer

Hoke

et al. 2019

mBio

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“…However, C. neoformans and C. deuterogattii induced small amounts of cytokines and large amounts of ROS in the first hour of infection, showing the ability to escape and survive inside macrophages, in accordance with previous studies (56, 57-61). Hole and coworkers observed that ROS produced by human plasmacytoid dendritic cells are required for C. neoformans sensu stricto growth inhibition but are not the only mechanism used to control C. neoformans sensu stricto (62). The control of the interspecies hybrid, C. gattii sensu stricto, and C. decagattii may be mediated by cytokine pathways in an ROS-independent manner.…”

Section: Discussionmentioning

confidence: 99%

Differential In Vitro Cytokine Induction by the Species of Cryptococcus gattii Complex

et al. 2018

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Cryptococcal species vary in capsule and cell size, thermotolerance, geographic distribution, and affected populations. and affect mainly immunocompetent hosts; however, ,, and cause infections mainly in immunocompromised hosts. This study aimed to compare the capacities of different species of the species complex to induce cytokines and antimicrobial molecules in human peripheral blood mononuclear cells (PBMCs). and induced the lowest levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 among the five species of the complex. induced higher levels of IL-22 than those induced by and the environmental species In addition, and proliferated inside human monocyte-derived macrophages after 24 h of infection. All species were able to generate reactive oxygen species (ROS) in human PBMCs, with and being more efficient than the other species. In conclusion, and induce lower levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and higher ROS levels than those induced by the other species. Species of the complex have different abilities to induce cytokine and ROS production by human PBMCs.

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“…Pulmonary pDCs infiltrate into the lungs during cryptococcal infection, and pDCs isolated from murine bone marrow have anti-cryptococcal activity (Hole et al, 2016). The recognition and uptake of C. neoformans by pDCs is dependent on expression of Dectin-3 and the chemokine receptor CXCR3, and the fungicidal activity of pDCs is attributed to the production of reactive oxygen species (ROS) within the lysosome (Hole et al, 2016).…”

Section: Murine Pulmonary Pdcsmentioning

confidence: 99%

Pulmonary Macrophage and Dendritic Cell Responses to Cryptococcus neoformans

Nelson

Hawkins

Wozniak

2020

Front. Cell. Infect. Microbiol.

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The fungal pathogen Cryptococcus neoformans can cause life-threatening infections in immune compromised individuals. This pathogen is typically acquired via inhalation, and enters the respiratory tract. Innate immune cells such as macrophages and dendritic cells (DCs) are the first host cells that encounter C. neoformans, and the interactions between Cryptococcus and innate immune cells play a critical role in the progression of disease. Cryptococcus possesses several virulence factors and evasion strategies to prevent its killing and destruction by pulmonary phagocytes, but these phagocytic cells can also contribute to anti-cryptococcal responses. This review will focus on the interactions between Cryptococcus and primary macrophages and dendritic cells (DCs), dealing specifically with the cryptococcal/pulmonary cell interface.

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Antifungal Activity of Plasmacytoid Dendritic Cells against Cryptococcus neoformans In Vitro Requires Expression of Dectin-3 (CLEC4D) and Reactive Oxygen Species

Cited by 35 publications

References 51 publications

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Differential In Vitro Cytokine Induction by the Species of Cryptococcus gattii Complex

Pulmonary Macrophage and Dendritic Cell Responses to Cryptococcus neoformans

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