Metabolic adaptation of intracellular bacteria and fungi to macrophages

Sprenger, Marcel; Kasper, Lydia; Hensel, Michael; Hube, Bernhard

doi:10.1016/j.ijmm.2017.11.001

Cited by 29 publications

(20 citation statements)

References 204 publications

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“…Macrophages are important effectors of the innate immune system, which can recognise, ingest, and kill microbes including Candida species (Erwig & Gow, ; Miramón, Kasper, & Hube, ). The compartmentalisation in phagosomes is assumed to be a major mechanism to control microbial growth by increasing the efficiency of antimicrobial activities, but also by restricting nutrients (Haas, ; Sprenger, Kasper, Hensel, & Hube, ). Indeed, transcriptional profiling of fungal responses to macrophage phagocytosis suggests that C. albicans and C. glabrata experience nutrient limitation inside the phagosome (Chew et al, ; Childers et al, ; Kaur, Ma, & Cormack, ; Lorenz, Bender, & Fink, ; Roetzer, Gratz, Kovarik, & Schüller, ).…”

Section: Introductionmentioning

confidence: 99%

Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence

Sprenger

Hartung

Allert

et al. 2020

Cellular Microbiology

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Biotin is an important cofactor for multiple enzymes in central metabolic processes.While many bacteria and most fungi are able to synthesise biotin de novo, Candida spp. are auxotrophic for this vitamin and thus require efficient uptake systems to facilitate biotin acquisition during infection. Here we show that Candida glabrata and Candida albicans use a largely conserved system for biotin uptake and regulation, consisting of the high-affinity biotin transporter Vht1 and the transcription factor Vhr1. Both species induce expression of biotin-metabolic genes upon in vitro biotin depletion and following phagocytosis by macrophages, indicating low biotin levels in the Candida-containing phagosome. In line with this, we observed reduced intracellular proliferation of both Candida cells pre-starved of biotin and deletion mutants lacking VHR1 or VHT1 genes. VHT1 was essential for the full virulence of C. albicans during systemic mouse infections, and the lack of VHT1 led to reduced fungal burden in C. glabrata-infected brains and C. albicans-infected brains and kidneys. Together, our data suggest a critical role of Vht1-mediated biotin acquisition for C. glabrata and C. albicans during intracellular growth in macrophages and systemic infections. K E Y W O R D S biotin, Candida albicans, Candida glabrata, macrophage, metabolism, virulence

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Section: Introductionmentioning

confidence: 99%

Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence

Sprenger

Hartung

Allert

et al. 2020

Cellular Microbiology

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“…To do so, microbes need to adapt to complex host niches which demand for metabolic modifications and strategies to evade immune surveillance. Some of these adaptations involve adjusting to nutrient quality or scarcity and adjusting to stresses, such as different oxygen levels ( 1 , 2 ). The oxygen levels inside the body vary from oxygen-rich (normoxic, 20% O 2 ) to oxygen-depleted (anoxic, <0.2% O 2 ) niches ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence

Lopes

Stylianou

Backman

et al. 2018

mBio

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Successful human colonizers have evolved mechanisms to bypass immune surveillance. Infiltration of PMNs to the site of infection led to the generation of a low oxygen niche. Exposure to low oxygen levels induced fungal cell wall masking, which in turn hindered pathogen sensing and antifungal responses by PMNs. The cell wall masking effect was prolonged by increasing lactate amounts produced by neutrophil metabolism under oxygen deprivation. In an invertebrate infection model, C. albicans was able to kill infected C. elegans nematodes within 2 days under low oxygen conditions, whereas the majority of uninfected controls and infected worms under normoxic conditions survived. These results suggest that C. albicans benefited from low oxygen niches to increase virulence. The interplay of C. albicans with innate immune cells under these conditions contributed to the overall outcome of infection. Adaption to low oxygen levels was in addition beneficial for C. albicans by reducing susceptibility to selected antifungal drugs. Hence, immunomodulation of host cells under low oxygen conditions could provide a valuable approach to improve current antifungal therapies.

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“…Investigation of the role of metabolism in virulence was recently recognized as a priority equivalent to studying classical virulence factors (24, 26, 53). While cysteine levels in eukaryotes need to be tightly regulated by controlling the degradation of this amino acid (54, 55) and transport of it from the extracellular milieu into the cell and vice versa (56), bacterial cysteine uptake has not yet been elucidated in detail (57–60).…”

Section: Discussionmentioning

confidence: 99%

The Meningococcal Cysteine Transport System Plays a Crucial Role in Neisseria meningitidis Survival in Human Brain Microvascular Endothelial Cells

Takahashi

Watanabe

Kim

et al. 2018

mBio

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Neisseria meningitidis colonizes at a nasopharynx of human as a unique host and has many strains that are auxotrophs for amino acids for their growth. To cause invasive meningococcal diseases (IMD) such as sepsis and meningitis, N. meningitidis passes through epithelial and endothelial barriers and infiltrates into blood and cerebrospinal fluid as well as epithelial and endothelial cells. However, meningococcal nutrients, including cysteine, become less abundant when it more deeply infiltrates the human body even during inflammation, such that N. meningitidis has to acquire nutrients in order to survive/persist, disseminate, and proliferate in humans. This was the first study to examine the relationship between meningococcal cysteine acquisition and the pathogenesis of meningococcal infections. The results of the present study provide insights into the mechanisms by which pathogens with auxotrophs acquire nutrients in hosts and may also contribute to the development of treatments and prevention strategies for IMD.

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Metabolic adaptation of intracellular bacteria and fungi to macrophages

Cited by 29 publications

References 204 publications

Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence

Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence

Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence

The Meningococcal Cysteine Transport System Plays a Crucial Role in Neisseria meningitidis Survival in Human Brain Microvascular Endothelial Cells

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