Biology subjects

Andrianopoulos, A.

Publications and source records attributed to Andrianopoulos, A..

4 recordsLinked to original sources

bioRxiv2026

A Tenebrio molitor model for Talaromyces marneffei infection and the importance of host cues for dimorphic switching

There is a growing body of research demonstrating the utility of invertebrate models for studies of fungal pathogenesis. In this study we evaluated Tenebrio molitor larvae as a model for studying talaromycosis, the infection caused by Talaromyces marneffei. T. marneffei is a thermally dimorphic opportunistic pathogen of humans, which transitions from hyphae to yeast when exposed to human body temperature (37{degrees}C). Using a combination of virulence assays and histopathology techniques, we have found T. molitor larvae to be useful simple hosts for modelling the yeast-associated disease at 37{degrees}C, as well as for studying the influence of temperature on T. marneffei biology. Infection establishment was found to be temperature-dependent: Larval infections could be established at both 37{degrees}C and 25{degrees}C, however 10-fold higher doses of conidia were required to cause significant disease at 25{degrees}C. Infections were also established more quickly when directly injecting larvae with the yeast cells, indicating that the yeast form has an increased capacity for host damage. T. marneffei in vivo yeast cell development was observed within larval tissues and hemolymph primarily at 37{degrees}C, but also at 25{degrees}C along with filamentous hyphal growth. The larval host environment therefore strongly supports yeast development, even partially in the absence of the 37{degrees}C signal, emphasising the combined importance of temperature and host environment for maintenance of the pathogenic morphology. This work provides a new model to assist future studies of this neglected tropical disease and improves our understanding of the complex relationship between morphology and pathogenicity in T. marneffei.

microbiology↗

bioRxiv2024

AcuM and AcuK: the global regulators controlling multiple cellular metabolisms in a dimorphic fungus Talaromyces marneffei

Talaromycosis is a fungal infection caused by an opportunistic dimorphic fungus Talaromyces marneffei. During infection, T. marneffei resides inside phagosomes of human host macrophages where the fungus encounters nutrient scarcities and host-derived oxidative stressors. Previously, we showed that the deletion of acuK, a gene encoding Zn(2)Cys(6) transcription factor, caused a decreased ability for T. marneffei to defend against macrophages, as well as a growth impairment in T. marneffei on both low iron-containing medium and gluconeogenic substrate-containing medium. In this study, a paralogous gene acuM was deleted and characterized. The {Delta}acuM mutant showed similar defects with the {Delta}acuK mutant, suggesting their common role in gluconeogenesis and iron homeostasis. Unlike the pathogenic mold Aspergillus fumigatus, the {Delta}acuK and {Delta}acuM mutants unexpectedly exhibited normal siderophore production and did not show lower expression levels of genes involved in iron uptake and siderophore synthesis. To identify additional target genes of AcuK and AcuM, RNA-sequencing analysis was performed in the {Delta}acuK and {Delta}acuM strains growing in a synthetic dextrose medium with 1% glucose at 25 {degrees}C for 36 hours. Downregulated genes in both mutants participated in iron-consuming processes, especially in mitochondrial metabolism and anti-oxidative stress. Importantly, the {Delta}acuM mutant was sensitive to the oxidative stressors menadione and hydrogen peroxide while the {Delta}acuK mutant was sensitive to only hydrogen peroxide. The yeast form of both mutants demonstrated a more severe defect in antioxidant properties than the mold form. Moreover, ribosomal and ribosomal biogenesis genes were expressed at significantly lower levels in both mutants, suggesting that AcuK and AcuM could affect the protein translation process in T. marneffei. Our study highlighted the role of AcuK and AcuM as global regulators that control multiple cellular adaptations under various harsh environmental conditions during host infection. These transcription factors could be potentially exploited as therapeutic targets for the treatment of this neglected infectious disease. AUTHOR SUMMARYTalaromyces marneffei invades host macrophages to establish infection. Major stressors inside the macrophage compartments are nutrient deprivation and oxidative substances. Here, we demonstrated that AcuK and AcuM transcription factors are necessary for T. marneffei to grow under iron and glucose limitation, and to survive oxidative stress and macrophage killing. AcuK and AcuM regulate non-glucose carbon utilization via the transcriptional control of gluconeogenic genes. For iron homeostasis, the two proteins regulate the expression of genes involved in iron-utilization pathways. Lastly, the AcuK and AcuM play a role in oxidative stress response likely by regulating the expression of genes encoding antioxidant enzymes and alternative respiration enzymes. Thus, AcuK and AcuM control multiple cellular adaptations that allow T. marneffei to cope with major stressors occurring during macrophage infection. Since AcuK and AcuM are critical for cellular metabolism and macrophage engulfment, this new information could lead to a better understanding of host-pathogen interaction and could be ultimately developed into fungal-specific diagnostic tools and therapeutic agents.

microbiology↗

bioRxiv2019

β-glucan dependent shuttling of conidia from neutrophils to macrophages occurs during fungal infection establishment

The initial host response to fungal pathogen invasion is critical to infection establishment and outcome. However, the diversity of leukocyte-pathogen interactions is only recently being appreciated. We describe a new form of interleukocyte conidial exchange called \"shuttling\". In Talaromyces marneffei and Aspergillus fumigatus zebrafish in vivo infections, live imaging demonstrated conidia initially phagocytosed by neutrophils were transferred to macrophages. Shuttling is unidirectional, not a chance event, involves alterations of phagocyte mobility, inter-cellular tethering, and phagosome transfer. Shuttling kinetics were fungal species-specific, implicating a fungal determinant. {beta}-glucan serves as a fungal-derived signal sufficient for shuttling. Murine phagocytes also shuttled in vitro. The impact of shuttling for microbiological outcomes of in vivo infections is difficult to specifically assess experimentally, but for these two pathogens, shuttling augments initial conidial redistribution away from fungicidal neutrophils into the favourable macrophage intracellular niche. Shuttling is a frequent host/pathogen interaction contributing to fungal infection establishment patterns.

cell biology↗

bioRxiv2018

The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

Microbial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37{degrees}C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

cell biology↗