scholarly journals Survival Strategies of Pathogenic Candida Species in Human Blood Show Independent and Specific Adaptations

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Philipp Kämmer ◽  
Sylvie McNamara ◽  
Thomas Wolf ◽  
Theresia Conrad ◽  
Stefanie Allert ◽  
...  
Keyword(s):  
Whole Blood ◽  
Immune Cell ◽  
Fungal Infections ◽  
Fungal Species ◽  
Infection Model ◽  
Transcriptional Level ◽  
Content Type ◽  
Human Whole Blood ◽  
Common Causes ◽  
Individual Strategies

ABSTRACT Only four species, Candida albicans, C. glabrata, C. parapsilosis, and C. tropicalis, together account for about 90% of all Candida bloodstream infections and are among the most common causes of invasive fungal infections of humans. However, virulence potential varies among these species, and the phylogenetic tree reveals that their pathogenicity may have emerged several times independently during evolution. We therefore tested these four species in a human whole-blood infection model to determine, via comprehensive dual-species RNA-sequencing analyses, which fungal infection strategies are conserved and which are recent evolutionary developments. The ex vivo infection progressed from initial immune cell interactions to nearly complete killing of all fungal cells. During the course of infection, we characterized important parameters of pathogen-host interactions, such as fungal survival, types of interacting immune cells, and cytokine release. On the transcriptional level, we obtained a predominantly uniform and species-independent human response governed by a strong upregulation of proinflammatory processes, which was downregulated at later time points after most of the fungal cells were killed. In stark contrast, we observed that the different fungal species pursued predominantly individual strategies and showed significantly different global transcriptome patterns. Among other findings, our functional analyses revealed that the fungal species relied on different metabolic pathways and virulence factors to survive the host-imposed stress. These data show that adaptation of Candida species as a response to the host is not a phylogenetic trait, but rather has likely evolved independently as a prerequisite to cause human infections. IMPORTANCE To ensure their survival, pathogens have to adapt immediately to new environments in their hosts, for example, during the transition from the gut to the bloodstream. Here, we investigated the basis of this adaptation in a group of fungal species which are among the most common causes of hospital-acquired infections, the Candida species. On the basis of a human whole-blood infection model, we studied which genes and processes are active over the course of an infection in both the host and four different Candida pathogens. Remarkably, we found that, while the human host response during the early phase of infection is predominantly uniform, the pathogens pursue largely individual strategies and each one regulates genes involved in largely disparate processes in the blood. Our results reveal that C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis all have developed individual strategies for survival in the host. This indicates that their pathogenicity in humans has evolved several times independently and that genes which are central for survival in the host for one species may be irrelevant in another.

scholarly journals The Streptococcus iniae Transcriptional Regulator CpsY Is Required for Protection from Neutrophil-Mediated Killing and Proper GrowthInVitro

2011 ◽  
Vol 79 (11) ◽  
pp. 4638-4648 ◽  
Author(s):  
Jonathan P. Allen ◽  
Melody N. Neely
Keyword(s):  
Whole Blood ◽  
Local Environment ◽  
Growth Defect ◽  
Infection Model ◽  
Streptococcus Iniae ◽  
Virulence Determinants ◽  
Wild Type ◽  
Content Type ◽  
Proteose Peptone ◽  
Lysr Family

ABSTRACTThe ability of a pathogen to metabolically adapt to the local environment for optimal expression of virulence determinants is a continued area of research. Orthologs of theStreptococcus iniaeLysR family regulator CpsY have been shown to regulate methionine biosynthesis and uptake pathways but appear to influence expression of several virulence genes as well. AnS. iniaemutant with an in-frame deletion ofcpsY(ΔcpsYmutant) is highly attenuated in a zebrafish infection model. The ΔcpsYmutant displays a methionine-independent growth defect in serum, which differs from the methionine-dependent defect observed for orthologous mutants ofStreptococcus mutansandStreptococcus agalactiae. On the contrary, the ΔcpsYmutant can grow in excess of the wild type (WT) when supplemented with proteose peptone, suggesting an inability to properly regulate growth. CpsY is critical for protection ofS. iniaefrom clearance by neutrophils in whole blood but is dispensable for intracellular survival in macrophages. Susceptibility of the ΔcpsYmutant to killing in whole blood is not due to a growth defect, because inhibition of neutrophil phagocytosis rescues the mutant to WT levels. Thus, CpsY appears to have a pleiotropic regulatory role forS. iniae, integrating metabolism and virulence. Furthermore,S. iniaeprovides a unique model to investigate the paradigm of CpsY-dependent regulation during systemic streptococcal infection.

scholarly journals Intravital Imaging of Candida albicans Identifies Differential In Vitro and In Vivo Filamentation Phenotypes for Transcription Factor Deletion Mutants

mSphere ◽  
2021 ◽  
Author(s):  
Rohan S. Wakade ◽  
Manning Huang ◽  
Aaron P. Mitchell ◽  
Melanie Wellington ◽  
Damian J. Krysan
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Deletion Mutants ◽  
Filamentous Form ◽  
Content Type ◽  
Yeast Form ◽  
Common Causes ◽  
Do So

Candida albicans is one of the most common causes of fungal infections in humans. C. albicans undergoes a transition from a round yeast form to a filamentous form during infection, which is critical for its ability to cause disease. Although this transition has been studied in the laboratory for years, methods to do so in an animal model of infection have been limited.

scholarly journals Role of Fungal Infections in Carcinogenesis and Cancer Development; A Literature Review

2021 ◽  
Author(s):  
Kamran Hosseini ◽  
Hossein Ahangari ◽  
Florence Chapeland-leclerc ◽  
Gwenael Ruprich-Robert ◽  
Vahideh Tarhriz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Fungal Infections ◽  
The Elderly ◽  
Fungal Species ◽  
Clinical Findings ◽  
Cancer Development ◽  
Microbial Infection ◽  
Common Causes ◽  
Acquired Immunodeficiency ◽  
Comprehensive Framework

Cancer is a serious debilitating disease and one of the most common causes of death. In recent decades the high risk of various cancers enforced scientists to discover novel prevention and treatment methods to diminish the mortality of this terrifying disease. Accordingly, its prevention can be possible in near future. Based on epidemiological evidence, there is a clear link between pathogenic fungal infections and cancer development. This association is often seen in people with weakened immune systems such as the elderly and people with acquired immunodeficiency (AIDS). Carcinoma in these people is first seen chronically and then acutely. Although the different genetic and environmental risk factors are involved in carcinogenesis, one of the most important risk factors is fungal species and infections associating with cancers etiology. Now it is known that microbial infection is responsible for initiating 2.2 million new cancer cases. In this way, many recent studies have focused on investigating the role and mechanism of fungal infections in diverse cancers occurrence. This review provides a comprehensive framework of the latest clinical findings and the association of fungal infections with versatile cancers including esophageal, gastric, colorectal, lung, cervical, skin, and ovarian cancer.

scholarly journals P-MAPA, a Fungi-Derived Immunomodulatory Compound, Induces a Proinflammatory Response in a Human Whole Blood Model

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Mariana Torrente Gonçalves ◽  
Carla Cristina Squaiella-Baptistão ◽  
Giselle Pidde ◽  
Priscila Hess Lopes ◽  
Iseu da Silva Nunes ◽  
...  
Keyword(s):  
Animal Models ◽  
Complement Activation ◽  
Whole Blood ◽  
Cell Activation ◽  
Immune Cell ◽  
Ex Vivo ◽  
Proinflammatory Response ◽  
Human Whole Blood ◽  
Human Leukocytes ◽  
Immunomodulatory Properties

P-MAPA is a complex compound, derived from Aspergillus oryzae cultures, that has shown immunomodulatory properties in infection and cancer animal models. Despite promising results in these models, the mechanisms of cellular activation by P-MAPA, suggested to be Toll-like receptor- (TLR-) dependent, and its effect on human immune cells, remain unclear. Using an ex vivo model of human whole blood, the effects of P-MAPA on complement system activation, production of cytokines, and the expression of complement receptors (CD11b, C5aR, and C3aR), TLR2, TLR4, and the coreceptor CD14 were analyzed in neutrophils and monocytes. P-MAPA induced complement activation in human blood, detected by increased levels of C3a, C5a, and SC5b-9 in plasma. As a consequence, CD11b expression increased and C5aR decreased upon activation, while C3aR expression remained unchanged in leukocytes. TLR2 and TLR4 expressions were not modulated by P-MAPA treatment on neutrophils, but TLR4 expression was reduced in monocytes, while CD14 expression increased in both cell types. P-MAPA also induced the production of TNF-α, IL-8, and IL-12 and oxidative burst, measured by peroxynitrite levels, in human leukocytes. Complement inhibition with compstatin showed that P-MAPA-induced complement activation drives modulation of C5aR, but not of CD11b, suggesting that P-MAPA acts through both complement-dependent and complement-independent mechanisms. Compstatin also significantly reduced the peroxynitrite generation. Altogether, our results show that P-MAPA induced proinflammatory response in human leukocytes, which is partially mediated by complement activation. Our data contribute to elucidate the complement-dependent and complement-independent mechanisms of P-MAPA, which ultimately result in immune cell activation and in its immunomodulatory properties in infection and cancer animal models.

scholarly journals Novel Role for theyceGHTellurite Resistance Genes in the Pathogenesis of Bacillus anthracis

2013 ◽  
Vol 82 (3) ◽  
pp. 1132-1140 ◽  
Author(s):  
Sarah E. Franks ◽  
Celia Ebrahimi ◽  
Andrew Hollands ◽  
Cheryl Y. Okumura ◽  
Raffi V. Aroian ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Resistance Genes ◽  
Immune Defense ◽  
Infection Model ◽  
Oxygen Species ◽  
Host Defenses ◽  
Content Type ◽  
Human Whole Blood ◽  
Transposon Mutants

ABSTRACTBacillus anthracis, the causative agent of anthrax, relies on multiple virulence factors to subvert the host immune defense. UsingCaenorhabditis elegansas an infection model, we screened approximately 5,000 transposon mutants ofB. anthracisSterne for decreased virulence. One of the attenuated mutants resulted in loss of expression ofyceGandyceH, the last two genes in a six-gene cluster of tellurite resistance genes. We generated an analogous insertional mutant to confirm the phenotype and characterize the role ofyceGHin resistance to host defenses. Loss ofyceGHrendered the mutants more sensitive to tellurite toxicity as well as to host defenses such as reactive oxygen species and the cathelicidin family of antimicrobial peptides. Additionally, we see decreased survival in mammalian models of infection, including human whole blood and in mice. We identify a novel role for theyceGHgenes inB. anthracisSterne virulence and suggest thatC. elegans is a useful infection model to study anthrax pathogenesis.

scholarly journals In Vitro Activities of Ravuconazole and Isavuconazole against Dematiaceous Fungi

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Hailin Zheng ◽  
Nana Song ◽  
Huan Mei ◽  
Jiacheng Dong ◽  
Dongmei Li ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Fungal Species ◽  
The Other ◽  
Dematiaceous Fungi ◽  
Content Type ◽  
Bipolaris Spicifera

ABSTRACT The in vitro activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as Bipolaris spicifera and Veronaea botryosa, remain more susceptible to other triazoles or to echinocandins.

scholarly journals Mycobacterium tuberculosisRequires Regulation of ESX-5 Secretion for Virulence in Irgm1-Deficient Mice

2018 ◽  
Vol 87 (2) ◽  
Author(s):  
Sarah R. Elliott ◽  
Dylan W. White ◽  
Anna D. Tischler
Keyword(s):  
Binding Site ◽  
Response Regulator ◽  
Phosphate Limitation ◽  
Infection Model ◽  
Transcriptional Level ◽  
Mobility Shift ◽  
Content Type ◽  
Constitutive Activation ◽  
Type Vii Secretion ◽  
Mouse Infection Model

ABSTRACTTheMycobacterium tuberculosistype VII secretion system ESX-5, which has been implicated in virulence, is activated at the transcriptional level by the phosphate starvation-responsive Pst/SenX3-RegX3 signal transduction system. Deletion ofpstA1, which encodes a Pst phosphate transporter component, causes constitutive activation of the response regulator RegX3, hypersecretion of ESX-5 substrates and attenuation in the mouse infection model. We hypothesized that constitutive activation of ESX-5 secretion causes attenuation of the ΔpstA1mutant. To test this, we uncoupled ESX-5 from regulation by RegX3. Using electrophoretic mobility shift assays, we defined a RegX3 binding site in theesx-5locus. Deletion or mutation of the RegX3 binding site reversed hypersecretion of the ESX-5 substrate EsxN by the ΔpstA1mutant and abrogated induction of EsxN secretion in response to phosphate limitation by wild-typeM. tuberculosis. Theesx-5RegX3 binding site deletion (ΔBS) also suppressed attenuation of the ΔpstA1mutant in Irgm1−/−mice. These data suggest that constitutive ESX-5 secretion sensitizesM. tuberculosisto an immune response that still occurs in Irgm1−/−mice. However, the ΔpstA1ΔBSmutant remained attenuated in both NOS2−/−and C57BL/6 mice, suggesting that factors other than ESX-5 secretion also contribute to attenuation of the ΔpstA1mutant. In addition, a ΔpstA1ΔesxNmutant lacking the hypersecreted ESX-5 substrate EsxN remained attenuated in Irgm1−/−mice, suggesting that ESX-5 substrates other than EsxN cause increased susceptibility to host immunity. Our data indicate that whileM. tuberculosisrequires ESX-5 for virulence, it tightly controls secretion of ESX-5 substrates to avoid elimination by host immune responses.

scholarly journals Genome-Wide Assessment of Streptococcus agalactiae Genes Required for Survival in Human Whole Blood and Plasma

2020 ◽  
Vol 88 (10) ◽  
Author(s):  
Luchang Zhu ◽  
Prasanti Yerramilli ◽  
Layne Pruitt ◽  
Matthew Ojeda Saavedra ◽  
Concepcion C. Cantu ◽  
...  
Keyword(s):  
Streptococcus Agalactiae ◽  
Whole Blood ◽  
Molecular Mechanisms ◽  
Insertion Site ◽  
Shikimate Pathway ◽  
Bacterial Survival ◽  
Content Type ◽  
Human Whole Blood ◽  
Pathway Gene ◽  
Genome Wide

ABSTRACT Streptococcus agalactiae (group B streptococcus, or GBS) is a common cause of bacteremia and sepsis in newborns, pregnant women, and immunocompromised patients. The molecular mechanisms used by GBS to survive and proliferate in blood are not well understood. Here, using a highly virulent GBS strain and transposon-directed insertion site sequencing (TraDIS), we performed genome-wide screens to discover novel GBS genes required for bacterial survival in human whole blood and plasma. The screen identified 85 and 41 genes that are required for GBS growth in whole blood and plasma, respectively. A common set of 29 genes was required in both whole blood and plasma. Targeted gene deletion confirmed that (i) genes encoding methionine transporter (metP) and manganese transporter (mtsA) are crucial for GBS survival in whole blood and plasma, (ii) gene W903_1820, encoding a small multidrug export family protein, contributes significantly to GBS survival in whole blood, (iii) the shikimate pathway gene aroA is essential for GBS growth in whole blood and plasma, and (iv) deletion of srr1, encoding a fibrinogen-binding adhesin, increases GBS survival in whole blood. Our findings provide new insight into the GBS-host interactions in human blood.

scholarly journals Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to Candida Species

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Paige E. Negoro ◽  
Shuying Xu ◽  
Zeina Dagher ◽  
Alex Hopke ◽  
Jennifer L. Reedy ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Essential Role ◽  
Immune Cell ◽  
Fungal Infections ◽  
Lectin Binding ◽  
Invasive Fungal Infections ◽  
Solid Organ ◽  
Spleen Tyrosine Kinase ◽  
Cellular Activation ◽  
Content Type

ABSTRACT Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-organ or bone marrow transplantation. In addition, inhibitors of spleen tyrosine kinase (Syk) have been recently developed for the treatment of patients with refractory autoimmune and hematologic indications. Neutrophils are the initial innate cellular responders to many types of pathogens, including invasive fungi. A central process governing neutrophil recognition of fungi is through lectin binding receptors, many of which rely on Syk for cellular activation. We previously demonstrated that Syk activation is essential for cellular activation, phagosomal maturation, and elimination of phagocytosed fungal pathogens in macrophages. Here, we used combined genetic and chemical inhibitor approaches to evaluate the importance of Syk in the response of neutrophils to Candida species. We took advantage of a Cas9-expressing neutrophil progenitor cell line to generate isogenic wild-type and Syk-deficient neutrophils. Syk-deficient neutrophils are unable to control the human pathogens Candida albicans, Candida glabrata, and Candida auris. Neutrophil responses to Candida species, including the production of reactive oxygen species and of cytokines such as tumor necrosis factor alpha (TNF-α), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to Candida species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics. IMPORTANCE Neutrophils are recognized to represent significant immune cell mediators for the clearance and elimination of the human-pathogenic fungal pathogen Candida. The sensing of fungi by innate cells is performed, in part, through lectin receptor recognition of cell wall components and downstream cellular activation by signaling components, including spleen tyrosine kinase (Syk). While the essential role of Syk in macrophages and dendritic cells is clear, there remains uncertainty with respect to its contribution in neutrophils. In this study, we demonstrated that Syk is critical for multiple cellular functions in neutrophils responding to major human-pathogenic Candida species. These data not only demonstrate the vital nature of Syk with respect to the control of fungi by neutrophils but also warn of the potential infectious complications arising from the recent clinical development of novel Syk inhibitors for hematologic and autoimmune disorders.

scholarly journals Comparison of Performance Characteristics of Aspergillus PCR in Testing a Range of Blood-Based Samples in Accordance with International Methodological Recommendations

2016 ◽  
Vol 54 (3) ◽  
pp. 705-711 ◽  
Author(s):  
Jan Springer ◽  
P. Lewis White ◽  
Shanna Hamilton ◽  
Denise Michel ◽  
Rosemary A. Barnes ◽  
...  
Keyword(s):  
Whole Blood ◽  
Clinical Performance ◽  
Fungal Infections ◽  
Plasma Samples ◽  
Serum Samples ◽  
European Organization ◽  
Content Type ◽  
Extraction Processes ◽  
Automated Dna Extraction ◽  
Control Study

Standardized methodologies for the molecular detection of invasive aspergillosis (IA) have been established by the EuropeanAspergillusPCR Initiative for the testing of whole blood, serum, and plasma. While some comparison of the performance ofAspergillusPCR when testing these different sample types has been performed, no single study has evaluated all three using the recommended protocols. StandardizedAspergillusPCR was performed on 423 whole-blood pellets (WBP), 583 plasma samples, and 419 serum samples obtained from hematology patients according to the recommendations. This analysis formed a bicenter retrospective anonymous case-control study, with diagnosis according to the revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus definitions (11 probable cases and 36 controls). Values for clinical performance using individual and combined samples were calculated. For all samples, PCR positivity was significantly associated with cases of IA (for plasma,P= 0.0019; for serum,P= 0.0049; and for WBP,P= 0.0089). Plasma PCR generated the highest sensitivity (91%); the sensitivities for serum and WBP PCR were 80% and 55%, respectively. The highest specificity was achieved when testing WBP (96%), which was significantly superior to the specificities achieved when testing serum (69%,P= 0.0238) and plasma (53%,P= 0.0002). No cases were PCR negative in all specimen types, and no controls were PCR positive in all specimens. This study confirms thatAspergillusPCR testing of plasma provides robust performance while utilizing commercial automated DNA extraction processes. Combining PCR testing of different blood fractions allows IA to be both confidently diagnosed and excluded. A requirement for multiple PCR-positive plasma samples provides similar diagnostic utility and is technically less demanding. Time to diagnosis may be enhanced by testing multiple contemporaneously obtained sample types.

Sign in / Sign up

Export Citation Format

Share Document