Interaction with immune cells
Phagocytes such as macrophages and neutrophils are key players of the innate immune system and represent a crucial line of defense against pathogenic Candida species such as C. albicans and C. glabrata. This is particularly illustrated by the fact that invasive Candida infections rarely occur in healthy hosts, and a compromised immune system is one of the major predisposing factors for disease.
Recognition of Candida cells by phagocytes leads to cytokine production, phagocytosis, and the activation of antimicrobial effector functions to induce killing of the fungus. On the other hand, pathogenic Candida spp. are well adapted to their host and have developed mechanisms to evade or counteract the anti-microbial activities of phagocytes. One of these mechanisms is the adaptation of fungal metabolism to cope with nutrient limitation inside the phagosome. This and other strategies allow C. albicans and C. glabrata to not only survive phagocytosis by macrophages, but even proliferate intracellularly and escape. C. albicans escapes by rapid hyphal growth and host cell damage. In contrast, C. glabrata replicates as yeast cells inside macrophages and persists for days, before macrophages burst and fungal cells are released.
We want to characterize the interaction of C. albicans, C. glabrata, and C. auris with phagocytes. We are especially interested in the fungal factors and activities that help Candida to cope with these immune cells, survive and escape. Moreover, in close collaboration with the Junior Research Group Adaptive Pathogenicity Strategies we investigate how immunotherapy impacts on the interactions between C. albicans and macrophages and mitigates escape of C. albicans from macrophages. Therapies that aim at improving the innate immune system are increasingly recognized as essential in improving the outcome of fungal infections. Particularly interferon-γ is a promising candidate due to its potential of improving macrophage microbicidal activity.
(2021) Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis. Cell Host Microbe S1931-3128(21), 00280-8.
(2021) Neuraminidase and SIGLEC15 modulate the host defense against pulmonary aspergillosis. Cell Rep Med 2(5), 100289.
(2021) In vitro infection models to study fungal-host interactions. FEMS Microbiol Rev [Epub ahead of print]
(2020) I want to break free - macrophage strategies to recognize and kill Candida albicans, and fungal counter-strategies to escape. Curr Opin Microbiol 58, 15-23. (Review)
(2020) The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives. FEMS Microbiol Rev , fuaa060. (Review)
(2020) The dual Function of the fungal toxin candidalysin during Candida albicans-macrophage interaction and virulence. Toxins 12(8), 469. (Review)
(2020) Fungal factors involved in host immune evasion, modulation and exploitation during infection. Cell Microbiol 23(1), e13272. (Review)
(2020) Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence. Cell Microbiol 22(7), e13197.
(2020) Lysosome fusion maintains phagosome integrity during fungal infection. Cell Host Microbe 28(6), 798-812.
(2019) Human anti-fungal Th17 immunity and pathology rely on cross-reactivity against Candida albicans. Cell 176(6), 1340-1355.
(2019) The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab 29(1), 211-220.e5.
(2019) CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. Nat Immunol 20(5), 559-570.
(2019) Frontline science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst. J Leukoc Biol 106(1), 11-25.
(2019) Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor. Nat Commun 10(1), 2297.
(2019) RNAi as a tool to study virulence in the pathogenic yeast Candida glabrata. Front Microbiol 10, 1679.
(2019) A genome-wide functional genomics approach identifies susceptibility pathways to fungal bloodstream infection in humans. J Infect Dis 220(5), 862-872.
(2019) A systems genomics approach identifies SIGLEC15 as a susceptibility factor in recurrent vulvovaginal candidiasis. Sci Transl Med 11(496), eaar3558.
(2019) Candidalysin: Discovery and function in Candida albicans infections. Curr Opin Microbiol 52, 100-109. (Review)
(2019) Candidalysin is required for neutrophil recruitment and virulence during systemic Candida albicans infection. J Infect Dis 220(9), 1477-1488.
(2019) Integrity under stress: Host membrane remodelling and damage by fungal pathogens. Cell Microbiol 21(4), e13016.
(2018) Adjunctive interferon-γ immunotherapy in a pediatric case of Aspergillus terreus infection. Eur J Clin Microbiol Infect Dis 37(10), 1915-1922.
(2018) The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nat Commun 9(1), 4260.
(2018) IL-36 and IL-1/IL-17 drive immunity to oral candidiasis via parallel mechanisms. J Immunol 201(2), 627-634.
(2016) Aspartyl proteinases of eukaryotic microbial pathogens: From eating to heating. PLOS Pathog 12(12), e1005992. (Review)
(2016) In vivo induction of neutrophil chemotaxis by secretory aspartyl proteinases of Candida albicans. Virulence 7(7), 819-825.
(2016) Candida albicans induces metabolic reprogramming in human NK cells and responds to perforin with a Zinc depletion response. Front Microbiol 7, 750.
(2015) Induction of Caspase-11 by aspartyl proteinases of Candida albicans and implication in promoting inflammatory response. Infect Immun 83(5), 1940-1948.
(2015) Intracellular survival of Candida glabrata in macrophages: immune evasion and persistence. FEMS Yeast Res 15(5), fov042.
(2014) One small step for a yeast - Microevolution within macrophages renders Candida glabrata hypervirulent due to a single point mutation. PLOS Pathog 10(10), e1004478.
(2014) Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages. PLOS One 9(5), e96015.
(2014) A family of glutathione peroxidases contributes to oxidative stress resistance in Candida albicans. Med Mycol 52(3), 223-239.
(2014) Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice. Eur J Immunol 44(8), 2405-2414.
(2014) Immune evasion, stress resistance, and efficient nutrient acquisition are crucial for intracellular survival of Candida glabrata within macrophages. Eukaryot Cell 13(1), 170-183.
(2014) Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis 209(4), 616-626.
(2013) Thriving within the host: Candida spp. interactions with phagocytic cells. Med Microbiol Immunol 202(3), 183-195. (Review)
(2013) Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome. Eur J Immunol 43(3), 679-692.
(2012) Complement plays a central role in Candida albicans-induced cytokine production by human PBMCs. Eur J Immunol 42(4), 993-991004.
(2011) The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J Immunol 187(6), 3072-3086.
(2010) Candida glabrata tryptophan-based pigment production via the Ehrlich pathway. Mol Microbiol 76(1), 25-47.
(2010) Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy. Infect Immun 78(3), 1066-1077.
(2010) Interaction of pathogenic yeasts with phagocytes: survival, persistence and escape. Curr Opin Microbiol 13(4), 392-400. (Review)
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Dr. Mark S Gresnigt
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Dr. Lydia Kasper
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