scholarly journals N-Acetylglucosamine Metabolism Promotes Survival of Candida albicans in the Phagosome

mSphere ◽  
2017 ◽  
Vol 2 (5) ◽  
Author(s):  
Elisa M. Vesely ◽  
Robert B. Williams ◽  
James B. Konopka ◽  
Michael C. Lorenz
Keyword(s):  
Amino Acids ◽  
Candida Albicans ◽  
Carboxylic Acids ◽  
Immune Cells ◽  
Carbon Sources ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Content Type ◽  
Macrophage Phagocytosis ◽  
Ph Neutralization

ABSTRACT Candida albicans is the most important medically relevant fungal pathogen, with disseminated candidiasis being the fourth most common hospital-associated bloodstream infection. Macrophages and neutrophils are innate immune cells that play a key role in host defense by phagocytosing and destroying C. albicans cells. To survive this attack by macrophages, C. albicans generates energy by utilizing alternative carbon sources that are available in the phagosome. Interestingly, metabolism of amino acids and carboxylic acids by C. albicans raises the pH of the phagosome and thereby blocks the acidification of the phagosome, which is needed to initiate antimicrobial attack. In this work, we demonstrate that metabolism of a third type of carbon source, the amino sugar GlcNAc, also induces pH neutralization and survival of C. albicans upon phagocytosis. This mechanism is genetically and physiologically distinct from the previously described mechanisms of pH neutralization, indicating that the robust metabolic plasticity of C. albicans ensures survival upon macrophage phagocytosis. Phagocytosis by innate immune cells is one of the most effective barriers against the multiplication and dissemination of microbes within the mammalian host. Candida albicans, a pathogenic yeast, has robust mechanisms that allow survival upon macrophage phagocytosis. C. albicans survives in part because it can utilize the alternative carbon sources available in the phagosome, including carboxylic acids and amino acids. Furthermore, metabolism of these compounds raises the pH of the extracellular environment, which combats the acidification and maturation of the phagolysosome. In this study, we demonstrate that metabolism by C. albicans of an additional carbon source, N-acetylglucosamine (GlcNAc), facilitates neutralization of the phagosome by a novel mechanism. Catabolism of GlcNAc raised the ambient pH through release of ammonia, which is distinct from growth on carboxylic acids but similar to growth on amino acids. However, the effect of GlcNAc metabolism on pH was genetically distinct from the neutralization induced by catabolism of amino acids, as mutation of STP2 or ATO5 did not impair the effects of GlcNAc. In contrast, mutants lacking the dedicated GlcNAc transporter gene NGT1 or the enzymes responsible for catabolism of GlcNAc were defective in altering the pH of the phagosome. This correlated with reduced survival following phagocytosis and decreased ability to damage macrophages. Thus, GlcNAc metabolism represents the third genetically independent mechanism that C. albicans utilizes to combat the rapid acidification of the phagolysosome, allowing for cells to escape and propagate infection. IMPORTANCE Candida albicans is the most important medically relevant fungal pathogen, with disseminated candidiasis being the fourth most common hospital-associated bloodstream infection. Macrophages and neutrophils are innate immune cells that play a key role in host defense by phagocytosing and destroying C. albicans cells. To survive this attack by macrophages, C. albicans generates energy by utilizing alternative carbon sources that are available in the phagosome. Interestingly, metabolism of amino acids and carboxylic acids by C. albicans raises the pH of the phagosome and thereby blocks the acidification of the phagosome, which is needed to initiate antimicrobial attack. In this work, we demonstrate that metabolism of a third type of carbon source, the amino sugar GlcNAc, also induces pH neutralization and survival of C. albicans upon phagocytosis. This mechanism is genetically and physiologically distinct from the previously described mechanisms of pH neutralization, indicating that the robust metabolic plasticity of C. albicans ensures survival upon macrophage phagocytosis.

scholarly journals Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Robert B. Williams ◽  
Michael C. Lorenz
Keyword(s):  
Amino Acids ◽  
Cell Wall ◽  
Candida Albicans ◽  
Stress Resistance ◽  
Innate Immune System ◽  
Carbon Sources ◽  
Innate Immune ◽  
Content Type ◽  
Multiple Alternative ◽  
Carbon Pathways

ABSTRACT The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of the phagocyte. C. albicans rapidly adapts to the phagosome by upregulating multiple alternative carbon utilization pathways, particularly those for amino acids, carboxylic acids, and N-acetylglucosamine (GlcNAc). Here, we report that C. albicans recognizes these carbon sources both as crucial nutrients and as independent signals in its environment. Even in the presence of glucose, each carbon source promotes increased resistance to a unique profile of stressors; lactate promotes increased resistance to osmotic and cell wall stresses, amino acids increased resistance to oxidative and nitrosative stresses, and GlcNAc increased resistance to oxidative stress and caspofungin, while all three alternative carbon sources have been shown to induce resistance to fluconazole. Moreover, we show mutants incapable of utilizing these carbon sources, in particular, strains engineered to be defective in all three pathways, are significantly attenuated in both macrophage and mouse models, with additive effects observed as multiple carbon pathways are eliminated, suggesting that C. albicans simultaneously utilizes multiple carbon sources within the macrophage phagosome and during disseminated candidiasis. Taking the data together, we propose that, in addition to providing energy to the pathogen within host environments, alternative carbon sources serve as niche-specific priming signals that allow C. albicans to recognize microenvironments within the host and to prepare for stresses associated with that niche, thus promoting host adaptation and virulence. IMPORTANCE Candida albicans is a fungal pathogen and a significant cause of morbidity and mortality, particularly in people with defects, sometimes minor ones, in innate immunity. The phagocytes of the innate immune system, particularly macrophages and neutrophils, generally restrict this organism to its normal commensal niches, but C. albicans shows a robust and multifaceted response to these cell types. Inside macrophages, a key component of this response is the activation of multiple pathways for the utilization of alternative carbon sources, particularly amino acids, carboxylic acids, and N-acetylglucosamine. These carbon sources are key sources of energy and biomass but also independently promote stress resistance, induce cell wall alterations, and affect C. albicans interactions with macrophages. Engineered strains incapable of utilizing these alternative carbon pathways are attenuated in infection models. These data suggest that C. albicans recognizes nutrient composition as an indicator of specific host environments and tailors its responses accordingly.

scholarly journals Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

2012 ◽  
Vol 81 (1) ◽  
pp. 238-248 ◽  
Author(s):  
Iuliana V. Ene ◽  
Shih-Chin Cheng ◽  
Mihai G. Netea ◽  
Alistair J. P. Brown
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune System ◽  
Carbon Source ◽  
Immune Responses ◽  
Immune Cells ◽  
Carbon Sources ◽  
Innate Immune ◽  
Phagocytic Cells ◽  
Content Type

Candida albicansis a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status.C. albicansregularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses toC. albicanshave been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth ofC. albicanscells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grownC. albicansstimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinicalC. albicansisolates from different host niches and from different epidemiological clades. In addition, lactate-grownC. albicanscells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon theC. albicansinteraction with the innate immune system.

scholarly journals An Interspecies Regulatory Network Inferred from Simultaneous RNA-seq of Candida albicans Invading Innate Immune Cells

2012 ◽  
Vol 3 ◽  
Author(s):  
Lanay Tierney ◽  
Jörg Linde ◽  
Sebastian Müller ◽  
Sascha Brunke ◽  
Juan Camilo Molina ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Immune Cells ◽  
Regulatory Network ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Rna Seq

scholarly journals Copper Chaperone CupA and Zinc Control CopY Regulation of the Pneumococcal cop Operon

mSphere ◽  
2017 ◽  
Vol 2 (5) ◽  
Author(s):  
Miranda J. Neubert ◽  
Elizabeth A. Dahlmann ◽  
Andrew Ambrose ◽  
Michael D. L. Johnson
Keyword(s):  
Streptococcus Pneumoniae ◽  
Immune Cells ◽  
Pathogenic Bacteria ◽  
Copper Toxicity ◽  
Innate Immune ◽  
Copper Chaperone ◽  
Innate Immune Cells ◽  
Content Type ◽  
Copper State ◽  
Intracellular Copper

ABSTRACT As mechanisms of copper toxicity are emerging, bacterial processing of intracellular copper, specifically inside Streptococcus pneumoniae, remains unclear. In this study, we investigated two proteins encoded by the copper export operon: the repressor, CopY, and the copper chaperone, CupA. Zinc suppressed transcription of the copper export operon by increasing the affinity of CopY for DNA. Furthermore, CupA was able to chelate copper from CopY not bound to DNA and reduce it from Cu2+ to Cu1+. This reduced copper state is essential for bacterial copper export via CopA. In view of the fact that innate immune cells use copper to kill pathogenic bacteria, understanding the mechanisms of copper export could expose new small-molecule therapeutic targets that could work synergistically with copper against pathogenic bacteria. Any metal in excess can be toxic; therefore, metal homeostasis is critical to bacterial survival. Bacteria have developed specialized metal import and export systems for this purpose. For broadly toxic metals such as copper, bacteria have evolved only export systems. The copper export system (cop operon) usually consists of the operon repressor, the copper chaperone, and the copper exporter. In Streptococcus pneumoniae, the causative agent of pneumonia, otitis media, sepsis, and meningitis, little is known about operon regulation. This is partly due to the S. pneumoniae repressor, CopY, and copper chaperone, CupA, sharing limited homology to proteins of putative related function and confirmed established systems. In this study, we examined CopY metal crosstalk, CopY interactions with CupA, and how CupA can control the oxidation state of copper. We found that CopY bound zinc and increased the DNA-binding affinity of CopY by roughly an order of magnitude over that of the apo form of CopY. Once copper displaced zinc in CopY, resulting in operon activation, CupA chelated copper from CopY. After copper was acquired from CopY or other sources, if needed, CupA facilitated the reduction of Cu2+ to Cu1+, which is the exported copper state. Taken together, these data show novel mechanisms for copper processing in S. pneumoniae. IMPORTANCE As mechanisms of copper toxicity are emerging, bacterial processing of intracellular copper, specifically inside Streptococcus pneumoniae, remains unclear. In this study, we investigated two proteins encoded by the copper export operon: the repressor, CopY, and the copper chaperone, CupA. Zinc suppressed transcription of the copper export operon by increasing the affinity of CopY for DNA. Furthermore, CupA was able to chelate copper from CopY not bound to DNA and reduce it from Cu2+ to Cu1+. This reduced copper state is essential for bacterial copper export via CopA. In view of the fact that innate immune cells use copper to kill pathogenic bacteria, understanding the mechanisms of copper export could expose new small-molecule therapeutic targets that could work synergistically with copper against pathogenic bacteria.

scholarly journals The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

2016 ◽  
Vol 84 (11) ◽  
pp. 3195-3205 ◽  
Author(s):  
Heather M. Evans ◽  
Grady L. Bryant ◽  
Beth A. Garvy
Keyword(s):  
Cell Wall ◽  
Life Cycle ◽  
Immune Responses ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Content Type ◽  
Life Cycle Stages ◽  
Ifn Γ

The cell wall β-glucans of Pneumocystis cysts have been shown to stimulate immune responses in lung epithelial cells, dendritic cells, and alveolar macrophages. Little is known about how the trophic life forms, which do not have a fungal cell wall, interact with these innate immune cells. Here we report differences in the responses of both neonatal and adult mice to the trophic and cystic life cycle stages of Pneumocystis murina . The adult and neonatal immune responses to infection with Pneumocystis murina trophic forms were less robust than the responses to infection with a physiologically normal mixture of cysts and trophic forms. Cysts promoted the recruitment of nonresident innate immune cells and T and B cells into the lungs. Cysts, but not trophic forms, stimulated increased concentrations of the cytokine gamma interferon (IFN-γ) in the alveolar spaces and an increase in the percentage of CD4 + T cells that produce IFN-γ. In vitro , bone marrow-derived dendritic cells (BMDCs) stimulated with cysts produced the proinflammatory cytokines interleukin 1β (IL-1β) and IL-6. In contrast, trophic forms suppressed antigen presentation to CD4 + T cells, as well as the β-glucan-, lipoteichoic acid (LTA)-, and lipopolysaccharide (LPS)-induced production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) by BMDCs. The negative effects of trophic forms were not due to ligation of mannose receptor. Our results indicate that optimal innate and adaptive immune responses to Pneumocystis species are dependent on stimulation with the cyst life cycle stage. Conversely, trophic forms suppress β-glucan-induced proinflammatory responses in vitro , suggesting that the trophic forms dampen cyst-induced inflammation in vivo .

scholarly journals The Fungal Quorum-Sensing Molecule Farnesol Activates Innate Immune Cells but Suppresses Cellular Adaptive Immunity

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Ines Leonhardt ◽  
Steffi Spielberg ◽  
Michael Weber ◽  
Daniela Albrecht-Eckardt ◽  
Markus Bläss ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Immune Cells ◽  
Innate Immune ◽  
Interleukin 12 ◽  
Innate Immune Cells ◽  
Content Type ◽  
Gm Csf ◽  
Immature Dendritic Cells ◽  
Macrophage Colony ◽  
Quorum Sensing Molecule

ABSTRACTFarnesol, produced by the polymorphic fungusCandida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α] and macrophage inflammatory protein 1 alpha [MIP-1α]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance.IMPORTANCEFarnesol is a quorum-sensing molecule which controls morphological plasticity of the pathogenic yeastCandida albicans. As such, it is a major mediator of intraspecies communication. Here, we investigated the impact of farnesol on human innate immune cells known to be important for fungal clearance and protective immunity. We show that farnesol is able to enhance inflammation by inducing activation of neutrophils and monocytes. At the same time, farnesol impairs differentiation of monocytes into immature dendritic cells (iDC) by modulating surface phenotype, cytokine release and migrational behavior. Consequently, iDC generated in the presence of farnesol are unable to induce proper T cell responses and fail to secrete Th1 promoting interleukin 12 (IL-12). As farnesol induced down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, desensitization to GM-CSF could potentially explain transcriptional reprofiling of iDC effector molecules. Taken together, our data show that farnesol can also mediate Candida-host communication and is able to act as a virulence factor.

scholarly journals Yersinia pestis Subverts the Dermal Neutrophil Response in a Mouse Model of Bubonic Plague

mBio ◽  
2013 ◽  
Vol 4 (5) ◽  
Author(s):  
Jeffrey G. Shannon ◽  
Aaron M. Hasenkrug ◽  
David W. Dorward ◽  
Vinod Nair ◽  
Aaron B. Carmody ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Immune Cells ◽  
Innate Immune ◽  
Health Concern ◽  
Virulence Plasmid ◽  
Innate Immune Cells ◽  
Bubonic Plague ◽  
Content Type ◽  
Large Numbers ◽  
Neutrophil Response

ABSTRACTThe majority of humanYersinia pestisinfections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis,Y. pestiscan evade the host’s innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathognomonic bubo of bubonic plague. In this study, several cytometric and microscopic techniques were used to characterize the early host response to intradermal (i.d.)Y. pestisinfection. Mice were infected i.d. with fully virulent or attenuated strains of dsRed-expressingY. pestis, and tissues were analyzed by flow cytometry. By 4 h postinfection, there were large numbers of neutrophils in the infected dermis and the majority of cell-associated bacteria were associated with neutrophils. We observed a significant effect of the virulence plasmid (pCD1) on bacterial survival and neutrophil activation in the dermis. Intravital microscopy of i.d.Y. pestisinfection revealed dynamic interactions between recruited neutrophils and bacteria. In contrast, very few bacteria interacted with dendritic cells (DCs), indicating that this cell type may not play a major role early inY. pestisinfection. Experiments using neutrophil depletion and a CCR7 knockout mouse suggest that dissemination ofY. pestisfrom the dermis to the dLN is not dependent on neutrophils or DCs. Taken together, the results of this study show a very rapid, robust neutrophil response toY. pestisin the dermis and that the virulence plasmid pCD1 is important for the evasion of this response.IMPORTANCEYersinia pestisremains a public health concern today because of sporadic plague outbreaks that occur throughout the world and the potential for its illegitimate use as a bioterrorism weapon. Since bubonic plague pathogenesis is initiated by the introduction ofY. pestisinto the skin, we sought to characterize the response of the host’s innate immune cells to bacteria early after intradermal infection. We found that neutrophils, innate immune cells that engulf and destroy microbes, are rapidly recruited to the injection site, irrespective of strain virulence, indicating thatY. pestisis unable to subvert neutrophil recruitment to the site of infection. However, we saw a decreased activation of neutrophils that were associated withY. pestisstrains harboring the pCD1 plasmid, which is essential for virulence. These findings indicate a role for pCD1-encoded factors in suppressing the activation/stimulation of these cellsin vivo.

scholarly journals Conidial Melanin of the Human-Pathogenic Fungus Aspergillus fumigatus Disrupts Cell Autonomous Defenses in Amoebae

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Iuliia Ferling ◽  
Joe Dan Dunn ◽  
Alexander Ferling ◽  
Thierry Soldati ◽  
Falk Hillmann
Keyword(s):  
Aspergillus Fumigatus ◽  
Dictyostelium Discoideum ◽  
Immune Cells ◽  
Pathogenic Fungus ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Membrane Repair ◽  
Protective Function ◽  
Content Type ◽  
Human Pathogenic Fungus

ABSTRACT The human-pathogenic fungus Aspergillus fumigatus is a ubiquitous saprophyte that causes fatal lung infections in immunocompromised individuals. Following inhalation, conidia are ingested by innate immune cells and can arrest phagolysosome maturation. How this virulence trait could have been selected for in natural environments is unknown. Here, we found that surface exposure of the green pigment 1,8-dihydroxynaphthalene-(DHN)-melanin can protect conidia from phagocytic uptake and intracellular killing by the fungivorous amoeba Protostelium aurantium and delays its exocytosis from the nonfungivorous species Dictyostelium discoideum. To elucidate the antiphagocytic properties of the surface pigment, we followed the antagonistic interactions of A. fumigatus conidia with the amoebae in real time. For both amoebae, conidia covered with DHN-melanin were internalized at far lower rates than were seen with conidia lacking the pigment, despite high rates of initial attachment to nonkilling D. discoideum. When ingested by D. discoideum, the formation of nascent phagosomes was followed by transient acidification of phagolysosomes, their subsequent neutralization, and, finally, exocytosis of the conidia. While the cycle was completed in less than 1 h for unpigmented conidia, the process was significantly prolonged for conidia covered with DHN-melanin, leading to an extended intracellular residence time. At later stages of this cellular infection, pigmented conidia induced enhanced damage to phagolysosomes and infected amoebae failed to recruit the ESCRT (endosomal sorting complex required for transport) membrane repair machinery or the canonical autophagy pathway to defend against the pathogen, thus promoting prolonged intracellular persistence in the host cell and the establishment of a germination niche in this environmental phagocyte. IMPORTANCE Infections with Aspergillus fumigatus are usually acquired by an inhalation of spores from environmental sources. How spores of a saprophytic fungus have acquired abilities to withstand and escape the phagocytic attacks of innate immune cells is not understood. The fungal surface pigment dihydroxynaphtalene-melanin has been shown to be a crucial factor for the delay in phagosome maturation. Here, we show that this pigment also has a protective function against environmental phagocytes. Pigmented conidia escaped uptake and killing by the fungus-eating amoeba Protostelium aurantium. When ingested by the nonfungivorous phagocyte Dictyostelium discoideum, the pigment attenuated the launch of cell autonomous defenses against the fungal invader, such as membrane repair and autophagy, leading to prolonged intracellular retention. Membrane damage and cytoplasmic leakage may result in an influx of nutrients and thus may further promote intracellular germination of the fungus, indicating that A. fumigatus has acquired some of the basic properties of intracellular pathogens.

scholarly journals Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells

2020 ◽  
Vol 6 (2) ◽  
pp. 57 ◽  
Author(s):  
Manuela Gómez-Gaviria ◽  
Nancy E. Lozoya-Pérez ◽  
Monika Staniszewska ◽  
Bernardo Franco ◽  
Gustavo A. Niño-Vega ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune Cells ◽  
Secretory Pathway ◽  
Mononuclear Cells ◽  
Cell Wall Composition ◽  
Innate Immune ◽  
Protein Glycosylation ◽  
Innate Immune Cells ◽  
Neutral Locus

The secretory pathway in Candida albicans involves the protein translocation into the lumen of the endoplasmic reticulum and transport to the Golgi complex, where proteins undergo posttranslational modifications, including glycosylation and proteolysis. The Golgi-resident Kex2 protease is involved in such processing and disruption of its encoding gene affected virulence and dimorphism. These previous studies were performed using cells without URA3 or with URA3 ectopically placed into the KEX2 locus. Since these conditions are known to affect the cellular fitness and the host–fungus interaction, here we generated a kex2Δ null mutant strain with URA3 placed into the neutral locus RPS1. The characterization of this strain showed defects in the cell wall composition, with a reduction in the N-linked mannan content, and the increment in the levels of O-linked mannans, chitin, and β-glucans. The defects in the mannan content are likely linked to changes in Golgi-resident enzymes, as the α-1,2-mannosyltransferase and α-1,6-mannosyltransferase activities were incremented and reduced, respectively. The mutant cells also showed reduced ability to stimulate cytokine production and phagocytosis by human mononuclear cells and macrophages, respectively. Collectively, these data showed that loss of Kex2 affected the cell wall composition, the protein glycosylation pathways, and interaction with innate immune cells.

scholarly journals Immune Sensing of Candida albicans

2021 ◽  
Vol 7 (2) ◽  
pp. 119 ◽  
Author(s):  
Ebrima Bojang ◽  
Harlene Ghuman ◽  
Pizga Kumwenda ◽  
Rebecca A. Hall
Keyword(s):  
Candida Albicans ◽  
Immune Responses ◽  
Immune Cells ◽  
Oral Candidiasis ◽  
Innate Immune ◽  
Vaginal Mucosa ◽  
Innate Immune Cells ◽  
Innate Immune Responses ◽  
Immune Sensing ◽  
Infection Types

Candida albicans infections range from superficial to systemic and are one of the leading causes of fungus-associated nosocomial infections. The innate immune responses during these various infection types differ, suggesting that the host environment plays a key role in modulating the host–pathogen interaction. In addition, C. albicans is able to remodel its cell wall in response to environmental conditions to evade host clearance mechanisms and establish infection in niches, such as the oral and vaginal mucosa. Phagocytes play a key role in clearing C. albicans, which is primarily mediated by Pathogen Associated Molecular Pattern (PAMP)–Pattern Recognition Receptor (PRR) interactions. PRRs such as Dectin-1, DC-SIGN, and TLR2 and TLR4 interact with PAMPs such as β-glucans, N-mannan and O-mannan, respectively, to trigger the activation of innate immune cells. Innate immune cells exhibit distinct yet overlapping repertoires of PAMPs, resulting in the preferential recognition of particular Candida morphotypes by them. The role of phagocytes in the context of individual infection types also differs, with neutrophils playing a prominent role in kidney infections, and dendritic cells playing a prominent role in skin infections. In this review, we provide an overview of the key receptors involved in the detection of C. albicans and discuss the differential innate immune responses to C. albicans seen in different infection types such as vulvovaginal candidiasis (VVC) and oral candidiasis.

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