Host defense against fungal pathogens: Adaptable neutrophil responses and the promise of therapeutic opportunities?

Hopke, Alex; Sykes, David B.; Irimia, Daniel; Mansour, Michael K.

doi:10.1371/journal.ppat.1009691

Cited by 5 publications

(4 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Generation and maturation characterization of clones. (a) Illustration of potential areas of neutrophil heterogeneity where 1) homogeneous populations of granulocyte monocyte progenitors (GMPs) mature into homogeneous neutrophils (PMNs) which respond equally to stimuli, 2) GMPs are pre-programmed to mature into neutrophils which respond to specific stimuli, or 3) GMPs belong to a homogeneous population which become heterogeneous during neutrophil maturation (adapted from (Scherer et al, 2021) with BioRender.com. (b) Outline of the experimental method in which clonal GMPs were kept in culture, matured in the absence of βestradiol, and then subsequentially used for transcriptional and epigenetic studies or challenged with a fungal pathogen.…”

Section: Data and Materials Availabilitymentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 1, 2022. ; https://doi.org/10.1101/2022.11.01.514676 doi: bioRxiv preprint RESULTS Conditional immortalization of granulocyte monocyte progenitors for clonally derived neutrophils Heterogeneity of the granulocyte monocyte progenitors (GMPs) and their ensuing neutrophils have been defined in several ways (Scherer et al, 2021). Figure 1a illustrates potential mechanisms through which neutrophil heterogeneity may arise: 1) GMPs may be homogeneous in the bone marrow compartment and result in mature neutrophils which respond equally to stimuli, 2) neutrophils arise from heterogeneous GMPs and maintain distinct characteristics through maturation, or 3) GMPs are homogenous but result in heterogeneous neutrophils which respond differently to various stimuli.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Hopke

Viens

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Once perceived to be homogenous effector cells, neutrophils have since been shown to exhibit population heterogeneity. Here, we established an experimental model of clonal neutrophil heterogeneity using conditionally immortalized clonal granulocyte monocyte progenitors (GMPs) and their mature neutrophil progeny. Transcriptional and epigenetic profiling showed conserved genome-wide signatures of transcription and chromatin accessibility that were specific to individual GMP clones and their paired neutrophil progeny, suggesting that clone specificity is established as early as the GMP stage. Clone-specific genes in vital regulatory pathways were pre-programmed and exhibited delayed expression in the mature neutrophil stage. The clone specific gene expression in the mature neutrophils paired to enhancer activation in their parental GMPs. To determine whether transcriptional heterogeneity predicted the response to fungal pathogens, neutrophil clones were functionally profiled. Clones demonstrated heterogeneous responses to fungal pathogens in vitro and revealed neutrophil subsets with evidence for tailored functional responses to Candida spp. as well as specific transcriptional and epigenetic patterns that may explain these differences. Together, this work establishes that heterogenous GMP and neutrophil compartments exist under homeostatic conditions and that these represent predefined clusters that are uniquely adapted to control invasive fungal pathogens.

show abstract

Section: Data and Materials Availabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Hopke

Viens

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Following infection, neutrophils, another innate phagocyte, can infiltrate into the pulmonary tissue. Although C. neoformans can be phagocytosed by neutrophils, depletion of these cells in murine models leads to increased clearance of C. neoformans , suggesting that neutrophils may be detrimental ( 31 – 33 ). For cryptococcal clearance, the adaptive immune system relies on a Th1 and Th17 profile while Th2 cytokines correlate with fungal dissemination ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Protective interaction of human phagocytic APC subsets with Cryptococcus neoformans induces genes associated with metabolism and antigen presentation

et al. 2022

View full text Add to dashboard Cite

Cryptococcal meningitis is the most common cause of meningitis among HIV/AIDS patients in sub-Saharan Africa, and worldwide causes over 223,000 cases leading to more than 181,000 annual deaths. Usually, the fungus gets inhaled into the lungs where the initial interactions occur with pulmonary phagocytes such as dendritic cells and macrophages. Following phagocytosis, the pathogen can be killed or can replicate intracellularly. Previous studies in mice showed that different subsets of these innate immune cells can either be antifungal or permissive for intracellular fungal growth. Our studies tested phagocytic antigen-presenting cell (APC) subsets from the human lung against C. neoformans. Human bronchoalveolar lavage was processed for phagocytic APCs and incubated with C. neoformans for two hours to analyze the initial interactions and fate of the fungus, living or killed. Results showed all subsets (3 macrophage and 3 dendritic cell subsets) interacted with the fungus, and both living and killed morphologies were discernable within the subsets using imaging flow cytometry. Single cell RNA-seq identified several different clusters of cells which more closely related to interactions with C. neoformans and its protective capacity against the pathogen rather than discrete cellular subsets. Differential gene expression analyses identified several changes in the innate immune cell’s transcriptome as it kills the fungus including increases of TNF-α (TNF) and the switch to using fatty acid metabolism by upregulation of the gene FABP4. Also, increases of TNF-α correlated to cryptococcal interactions and uptake. Together, these analyses implicated signaling networks that regulate expression of many different genes – both metabolic and immune - as certain clusters of cells mount a protective response and kill the pathogen. Future studies will examine these genes and networks to understand the exact mechanism(s) these phagocytic APC subsets use to kill C. neoformans in order to develop immunotherapeutic strategies to combat this deadly disease.

show abstract

“…Equipped with a wide-array of anti-microbial factors, neutrophils use three mechanisms, to eliminate invading micro-organisms: phagocytosis, degranulation, and NETosis [37, 38]. Historically, neutrophils were considered a type of non-specific immune cell, but more recent findings show that neutrophils react to their microenvironments to provide more specific and efficient responses [39, 40]. For example, signals including different pathogen-associated molecular patterns (PAMPs), cytokines, intercellular interactions, and even surface material can determine the specific responses triggered in neutrophils [41, 42].…”

Section: Introductionmentioning

confidence: 99%

Enterococcus faecalis and Staphylococcus aureus mixed species infection attenuates pathogen-specific neutrophil responses and impairs bacterial clearance

Kao

Ch'ng

Chong

et al. 2022

Preprint

View full text Add to dashboard Cite

Enterococcus faecalis is an opportunistic pathogen that is frequently co-isolated with other microbes in catheterized urinary tract infections and chronically infected wounds. While E. faecalis can subvert the host immune response and promote the survival of other microbes via interbacterial synergy, little is known about the impact of immune suppression mediated by E. faecalis and how E. faecalis impacts the survival of co-infecting microbes. We hypothesized that E. faecalis can attenuate neutrophil-mediated responses in mixed-species infection to promote survival of the co-infecting species. Here, we show that E. faecalis and Staphylococcus aureus mono-species infection activates intracellular ROS production and NET formation, respectively, enabling effective neutrophil-mediated control of the microbial infection. Growth of both bacterial species was enhanced during co-infection in neutrophils in vitro and in wounds in vivo. E. faecalis reduced S. aureus-induced NET formation and S. aureus suppressed E. faecalis-induced intracellular ROS production. When the species ratios were skewed, the neutrophil reaction profile resembled that elicited by the more abundant species, favoring enhanced survival of the less abundant species. These findings highlight the complexity of the immune response to polymicrobial infections and show that attenuated pathogen-specific immune responses contribute to microbial survival in the mammalian host.

show abstract

Host defense against fungal pathogens: Adaptable neutrophil responses and the promise of therapeutic opportunities?

Cited by 5 publications

References 35 publications

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Protective interaction of human phagocytic APC subsets with Cryptococcus neoformans induces genes associated with metabolism and antigen presentation

Enterococcus faecalis and Staphylococcus aureus mixed species infection attenuates pathogen-specific neutrophil responses and impairs bacterial clearance

Contact Info

Product

Resources

About