C. albicans utilizes various pathogenicity mechanisms to cause infection in humans. These include polymorphism between yeast and hyphal forms, production of adhesins and invasins to adhere to and invade host cells, biofilm formation, secretion of hydrolytic enzymes, metabolic adaptation, and stress response mechanisms like heat shock protein production. Understanding these pathogenic factors provides opportunities for developing new antifungal therapies that specifically target virulence rather than cell viability.
A brief overview of Candida albicans by Zehraa Cheaib, Ammara Majeed, Adam Windle, Alex Edmonds, Eve Collinson & Alex Hutton at the University of Manchester School of Pharmacy. Spring of 2017.
A brief overview of Candida albicans by Zehraa Cheaib, Ammara Majeed, Adam Windle, Alex Edmonds, Eve Collinson & Alex Hutton at the University of Manchester School of Pharmacy. Spring of 2017.
Probiotics will act to beat your Candida overgrowth in three ways. They boost your immune system, they help create the right acidity for your stomach, and they crowd out the Candida yeast.
Este trabajo fue elaborado por uno de los grupos del 3° F de secundaria del Liceo Naval Montero sobre candidiasis,infección de mucha incidencia en las mujeres. Invito a verlo,puede resultar interesante para quien desee saber sobre el tema. Los autores de este archivo :
Brillith, CABRAL
Juan, DAGNINO
Adriana, ESTRADA
Lynn, GONZALO
Bryan, GUERRERO V.
Carmen, PORRAS
www.yolandaflores.net
What Are The Symptoms of Candida Yeast InfectionShoalman Jr.
Yeast infection or candidiasis is caused by candida fungus. It brings irritation, intense itching, and inflammation. By understanding Candida yeast infection and its symptoms helps you avoid conditions that can cause it. Adapted from Blog post http://getyourbesthealth.com/symptoms-candida-yeast-infection/
Candidia Species Commonly (Opportunistic human Pathogens)
C.albicans
C.glabata
C.guilliermandii
C.krusei
C.lusitaniae
C.parapsilosis
C.tropicalis
Candiia Species Uncommonly: 18 species
This is a simple description of vaginal candidiasis (moniliasis), which is one of the most common opportunistic yeast gynecological ailment that affects mostly the debilitated and immunosuppressive patients like the pregnant mothers, cancerous patients, stem cell transplantation recipients etc.
Dr Ajith Karawita, President of the Sri Lanka College of Venereologists. World Hepatitis Day was organized by the Sri Lanka College of Venereologists on world hepatitis day on 28 July 2015 at BMICH
Staphylococcus aureus,a bunch of grapes
commonly found on the skin or in the nose of even healthy individuals
cause skin infections but can cause pneumonia, heart valve infections, and bone infections.
Helicobacter Pylori infect more than 50% of worlds population.HP causes gastritis,PUD,gastric cancer and MALT lymphoma.Variable invasive and noninvasive diagnostic modilities are available.Eradication of H.Pylori is possible with proper therapy.
The presentation provide in depth knowledge about two of the most affecting bacteria to human health. They are Neisseria ( causing gonorrhea and Meningitis) and Shigella ( Diarrhea)
The rhinovirus is the most common viral infectious agent in humans and is the predominant cause of the common cold. HRVs can replicate in the lower airways and do appear to play a critical role in causing exacerbations of asthma and other chronic lung diseases.
DERIVATION OF MODIFIED BERNOULLI EQUATION WITH VISCOUS EFFECTS AND TERMINAL V...Wasswaderrick3
In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
2. CONTENTS: • Introduction
• Risk factors
• Pathogenicity Mechanisms
I. Polymorphism
II. Adhesins and invasins
III. Biofilm formation
IV. Contact sensing and thigmotrophism
V. Secreted Hydrolases
VI. pH sensing and regulation
VII. Metabolic adaptation
VIII. Environmental stress response
IX. Heat shock proteins
X. Metal acquisition
• Conclusion
3. INTRODUCTION
• There are 611,000 species of fungi . Of all these species, only around 600 species
are human pathogens.
• This relatively small group encompasses fungi that cause
• relatively mild infections of the skin (e.g., dermatophytes and Malassezia species).
• Fungi that cause severe cutaneous infections (e.g., Sporotrix schenkii)
• Fungi that have the potential to cause life-threatening systemic infections (e.g., Aspergillus
fumigatus, Cryptococcus neoformans, Histoplasma capsulatum, and Candida albicans).
• Candida spp are the fourth most common cause of hospital-acquired systemic
infections in the United States with crude mortality rates of up to 50%.
• C. albicans and other Candida species are present in the oral cavity of up to 75% of
the population.
4. CANDIDIA INFECTION:
• C. albicans can cause two major types of infections in humans:
I. superficial infections, such as oral or vaginal candidiasis
II. life-threatening systemic infections
• These oral infections with Candida species are termed “oral candidiasis” (OC) and
can affect the oropharynx and/or the esophagus of persons with dysfunctions of the
adaptive immune system.
• However, mildly immunocompromised individuals can frequently suffer from
recalcitrant infections of the oral cavity.
• It is estimated that approximately 75% of all women suffer at least once in their
lifetime from vulvovaginal candidiasis (VVC).
5. RISK FACTORS:
• HIV is a major risk factor for developing OC.
• Further risk factors for developing OC include the wearing of dentures and extremes
of age.
• Predisposing factors for VVC are less well defined than for OC and include diabetes
mellitus, use of antibiotics, oral contraception, pregnancy and hormone therapy
• Both neutropenia and damage of the gastrointestinal mucosa are risk factors for the
development of systemic (disseminated) candidiasis.
• Further risk factors include
• Central venous catheters, which allow direct access of the fungus to the bloodstream,
• The application of broad-spectrum anti-bacterials, which enable fungal overgrowth.
• Trauma or gastrointestinal surgery, which disrupts mucosal barriers.
7. POLYMORPHISM:
• C. albicans is a polymorphic fungus
• Can grow either as ovoid-shaped budding yeast.
• As elongated ellipsoid cells with constrictions at the septa (pseudohyphae) or as parallel-walled true hyphae.
• Further morphologies include white and opaque cells, formed during switching, and chlamydospores, which are thick-walled
spore-like structures.
• A range of environmental cues affect C. albicans morphology.
For example, at low pH (< 6) C. albicans cells predominantly grow in the yeast
form, while at a high pH (> 7) hyphal growth is induced.
• A number of conditions, including starvation, the presence of
serum or N-acetyl-glucosamine, physiological temperature and CO2
promote the formation of hyphae.
8. PHENOTYPIC SWITCHING:
• The transition between yeast and hyphal growth forms is termed as phenotypic switching and it has been proposed that both
growth forms are important for pathogenicity.
• The hyphal form has been shown to be more invasive than the yeast form. On the other hand the smaller yeast form is believed to
represent the form primarily involved in dissemination.
• Such hypha-associated proteins
include the hyphal wall protein
Hwp1, the agglutinin-like sequence
protein Als3, the secreted aspartic
proteases Sap4, Sap5 and Sap6 and
the hypha-associated proteins Ece1
and Hyr1.
10. ADHESINS AND INVASIONS.
• C. albicans has a specialized set of proteins (adhesins) which mediate adherence
• to other C. albicans cells to other microorganisms, to abiotic surfaces and to host cells.
• The best studied C. albicans adhesins are the agglutinin-like sequence (ALS) proteins which form a family consisting of
eight members (Als1–7 and Als9). The ALS genes encode glycosyl phosphatidylinositol (GPI)-linked cell surface
glycoproteins.
• Of the eight Als proteins, the hypha-associated adhesin Als3 is especially important for adhesion.
• Another important adhesin of C. albicans is Hwp1, which is a hypha-associated GPI-linked protein.
• Hwp1 serves as a substrate for mammalian trans-glutaminases and this reaction may covalently link C. albicans hyphae to
host cells.
• Hwp1 and Als3 were also demonstrated to contribute to biofilm formation by acting as complementary adhesins.
11. INVASION:
• C. albicans is a remarkable pathogen as it can utilize two different mechanisms to
invade into host cells:
• Induced endocytosis
• Active penetration
12. INDUCED ENDOSYTOSIS
• In this process the fungus expresses specialized proteins on the cell surface
(invasins) that mediate binding to host ligands (such as E-cadherin on epithelial
cells and N-cadherin on endothelial cells)
• That triggers engulfment of the fungal cell into the host cell.
• Even killed hyphae are taken up, indicating that induced endocytosis is a passive
process that does not require the activities of viable fungal cells.
• Two invasins have been identified so far, namely Als3 (which also functions as an
adhesin) and Ssa1. Ssa1 is a cell-surface expressed member of the heat shock protein
70 (Hsp70) family.
• Als3 and Ssa1 bind to host E-cadherin and likely induce endocytosis by a clathrin-
dependent mechanism;
14. ACTIVE PENETRATION:
• In contrast, active penetration is a fungal-driven process and requires viable C.
albicans hyphae.
• It is still unclear exactly which factors mediate this second route of invasion into
host cells. Fungal adhesion and physical forces are believed to be crucial.
• Secreted aspartic proteases (Saps) have also been proposed to contribute to active
penetration.
15. BIOFILM FORMATION
• A further important virulence factor of C. albicans is its capacity to form biofilms on
abiotic or biotic surfaces. Catheters, dentures (abiotic) and mucosal cell surfaces
(biotic) are the most common substrate
• Mature biofilms provide resistance to antimicrobial agents and host immune factors
in comparison to planktonic cells.
• The factors responsible for heightened resistance include the complex architecture
of biofilms, the biofilm matrix, increased expression of drug efflux pumps and
metabolic plasticity.
• Dispersion of yeast cells from the mature biofilm has been shown to directly
contribute to virulence, as dispersed cells were more virulent in a mouse model of
disseminated infection.
• The major heat shock protein Hsp90 was recently identified as a key regulator of
dispersion in C. albicans biofilms. In addition, Hsp90 was also required for biofilm
antifungal drug resistance.
16. Figure 2. Schematic model indicating biofilm formation and development of Candida infections.
J.M. ten Cate et al. J DENT RES 2009;88:105-115
17. CONTACT SENSING AND THIGMOTROPISM
• An important environmental cue that triggers hypha and biofilm formation in C.
albicans is contact sensing. Upon contact with a surface, yeast cells switch to hyphal
growth.
• On mucosal surfaces, these hyphae can then invade into the tissue.
• Contact to solid surfaces also induces the formation of biofilms.
• On surfaces with particular topologies (such as the presence of ridges) directional
hyphal growth (thigmotropism) may occur.
• Brand et al. demonstrated that thigmotropism of C. albicans hyphae is regulated by
extracellular calcium uptake through the calcium channels .
18. SECRETED HYDROLASES.
• Following adhesion to host cell surfaces and hyphal growth, C. albicans hyphae can secrete hydrolases, which have been proposed
to facilitate active penetration into these cells.
• In addition, secreted hydrolases are thought to enhance the efficiency of extracellular nutrient acquisition.
• Three different classes of secreted hydrolases are expressed by C. albicans:
• Proteases,
• Phospholipases
• Lipases.
PROTEASES:
• The family of secreted aspartic proteases (Saps) comprises ten members, Sap1–10.
• Sap1–8 are secreted and released to the surrounding medium, whereas Sap9 and Sap10 remain bound to the cell surface.
• Sap1–3 have been shown to be required for damage of reconstituted human epithelium (RHE) in vitro, and for virulence in a mouse
model of systemic infection.
19. PHOSPHOLIPASES:
• The family of phospholipases consists of four
different classes (A, B, C and D).
• Only the five members of class B (PLB1–5)
are extracellular and may contribute to
pathogenicity via disruption of host
membranes.
• Both plb1Δ/Δ and plb5Δ/Δ mutants have
been shown to be attenuated in virulence in a
mouse model of systemic infection.
LIPASES:
• The third family of secreted hydrolases, the
lipases,
• It consists of 10 members (LIP1–10).
• A lip8Δ/Δ mutant had reduced virulence in a
mouse model of systemic infection, supporting
a role for these extracellular hydrolases in C.
albicans pathogenicity
20. PH-SENSING AND REGULATION
• C. albicans senses pH via the Rim101
signal transduction pathway.
• In this pathway, environmental pH is
measured by the plasma membrane
receptors Dfg16 and Rim21.
• Activation of these receptors leads to
induction of a signaling cascade.
• Finally leading to activation of the major
pH-responsive transcription factor
Rim101 via its proteolytic cleavage.
• Rim101 then enters the nucleus and
mediates pH-dependent responses
22. METABOLIC ADAPTATION
• Metabolic adaptability and flexibility mediates the effective assimilation of alternative
nutrients in dynamic environment and infection in different host niches.
• Glycolysis, gluconeogenesis and starvation responses are all thought to contribute to host
colonization and pathogenesis.
• In healthy individuals C. albicans is predominantly found as part of the gastrointestinal
microbiome.
• Although the concentration of nutrients in this environment can be naturally high, growth of
the fungus is believed to be controlled through competition with other members of the
intestinal microbial flora.
• During disseminated candidiasis in susceptible individuals, C. albicans gains access to the
bloodstream. Blood is relatively rich in glucose (6–8 mM), the preferred nutrient source of
most fungi.
23. ENVIRONMENTAL STRESS RESPONSE
• C. albicans robust stress responses contributes to its survival and virulence by
facilitating the adaptation to changing conditions and protecting it against host-
derived stresses.
• Phagocytic cells of the immune system produce oxidative and nitrosative stresses.
pH stress occurs, for example, in the gastrointestinal and urogenital tract.
• Stress-responsive regulatory pathways, were shown to be essential not only for
efficient stress adaptation, but also for full virulence of the fungus
• Cellular responses to stresses include heat shock-, osmotic-, oxidative- and
nitrosative-stress responses
24. THE HEAT SHOCK RESPONSE
• The heat shock response is mediated
by heat shock proteins which act as
molecular chaperones to prevent
deleterious protein unfolding and
aggregation.
• Additionally, thermal stress leads to
trehalose accumulation in C. albicans,
which is thought to act as a “chemical
chaperone” by stabilizing proteins
prone to unfolding.
OSMOTIC STRESS RESPONSE
• The osmotic stress response results in
intracellular accumulation of the
compatible solute glycerol to
counteract loss of water due to the
outward-directed chemical gradient.
• Glycerol biosynthesis is mediated by
the glycerol 3-phosphatase Gpp1 and
the glycerol 3-phosphate
dehydrogenase Gpd2.
25. OXIDATIVE STRESS RESPONSE:
• Reactive oxygen species (ROS), such as peroxide, superoxide anions, and hydroxyl
radicals, induce an.
• Catalase Cta1 and superoxide dis-mutase, Sod1 and Sod5, are crucial for efficient
detoxification of ROS in C. albicans,
• Neutrophils also produce reactive nitrogen species (RNS), which induce a nitrosative
stress response in phagocytosed C. albicans cells.
• The major protein implicated in detoxification of RNS is the flavohemoglobin-related
protein Yhb1.
• Deletion of Yhb1 renders C. albicans cells sensitive to RNS and attenuates virulence
in a mouse model of systemic candidiasis.
27. HEAT SHOCK RESPONSE
• The heat shock response is a conserved reaction of living organisms to stressful
conditions such as high temperature, starvation and oxidative stress.
• Such stresses can induce protein unfolding and nonspecific protein aggregation,
ultimately leading to cell death.
• These specialized proteins act as chaperones and prevent protein unfolding and
aggregation by binding to their clients and stabilizing them
• Six major Hsps have been identified in C. albicans:
• Hsp104, Hsp90, Hsp78, two Hsp70 proteins (Ssa1 and Ssa2) and Hsp60.
28. Heat shock proteins Functions
HSP104 biofilm formation,
Hsp90 regulates drug resistance,
morphogenesis, biofilm formation and
virulence.
HSP78 transcriptionally up-regulated in
response to phagocytosis by
macrophages.
HSP60 Have a role in thermo-tolerance
Ssa1 and Ssa2 (stress-70 subfamily A) function as receptors for antimicrobial
peptides
29. SMALL HEAT SHOCK PROTEINS
• In addition to the above mentioned heat shock proteins, six small Hsps (sHsps) have also
been identified in C. albicans.
• sHsps are low-molecular-mass chaperones that prevent protein aggregation. Upon heat, or
other forms of stress, bind aggregated proteins.
• In these chaperone-aggregate complexes, client proteins are held ready for disaggregation
and refolding by other major Hsps, such as Hsp104.
• C. albicans is predicted to encode six sHsps: Hsp31, Hsp30, Hsp21, two Hsp12 proteins and
Hsp10.
• As yet only Hsp12 and Hsp21 have been investigated.
Hsp12 is expressed in response to different stresses, including heat shock and oxidative stress.
sHsp 21 is crucial for regulation of intracellular levels of trehalose.
30. METAL ACQUISITION
• Among the most important metals are iron, zinc, manganese and copper, required by the
fungus.
• Pathogenic microorganisms, as well as their respective hosts, have evolved elaborate
mechanisms to acquire or restrict access to these metals.
• To date, the most widely investigated transition metal with regard to pathogenesis is iron.
• C. albicans acquires this metal by different strategies including
I. A reductive system,
II. A siderophore uptake system
III. A heme-iron uptake system.
• One mechanism of zinc acquisition by C. albicans is that it secretes the zinc-binding protein
Pra1 (pH-regulated antigen 1), which, analogous to siderophore-mediated iron acquisition,
acts as a zincophore by binding extracellular zinc and re-associating with the fungal cell. Re-
association of Pra1 is mediated by the zinc transporter Zrt1
35. CONCLUSIONS:
• Understanding the pathogenicity mechanisms that C. albicans uses during infection is crucial for the
development of new antifungal therapies and diagnostics.
• Classically, antifungal drugs were designed to exert fungicidal activities, Recently however, specifically
targeting virulence factors has been proposed as a new and promising antifungal strategy.
• Several virulence factors, such as dimorphism, the secretion of proteases and the expression of adhesins
and invasins, have been suggested as attractive targets.
• Another avenue of research is the interplay between host nutritional immunity and fungal nutrient
acquisition systems. In particular, interfering with the iron, zinc, manganese or copper homeostasis
mechanisms of pathogenic microorganisms may represent promising therapeutic strategies.
• As our detailed understanding of fungal pathogenicity mechanisms improves, the potential for
developing novel therapeutic and diagnostic strategies expands.
TLR-mediated signals as escape mechanisms from host defence. Recent literature suggests that certain microorganisms are recognized by TLRs for the activation of host defence but also activate alternative TLR pathways with inhibitory effects on innate immunity. Thus, whereas interaction of Candida mannan with TLR4 induces release of chemokines, leukocyte recruitment, and protection, interaction of Candida glucans and phospholipomannan with TLR2 primarily mediates release of the anti-inflammatory cytokine IL-10, resulting in inhibition of the host defence and increased susceptibility to infection. Similar mechanisms have been suggested for other microorganisms such as Y. enterocolitica and A. fumigatus. TICAM-1, TIR-containing adapter molecule-1.
Loss of TLR4-mediated signals during yeast-to-hypha transition
of C. albicans. Recognition of C. albicans blastoconidia involves
both TLR2 and TLR4. The yeast-to-hypha transition results in the loss
of proinflammatory TLR4-mediated signals and a TLR2-mediated
anti-inflammatory cytokine profile, used by C. albicans as an escape
mechanism from the host defense.
Schematic model indicating multi-species biofilm formation and development of Candida infections.
Figure 1. An overview of selected C. albicans pathogenicity mechanisms. Yeast cells adhere to host cell surfaces by the expression of adhesins.
Contact to host cells triggers the yeast-to-hypha transition and directed growth via thigmotropism. The expression of invasins mediates uptake of the fungus by the host cell through induced endocytosis. Adhesion, physical forces and secretion of fungal hydrolases has been proposed to facilitate the second mechanism of invasion, i.e., fungal-driven active penetration into host cells by breaking down barriers. The attachment of yeast cells to abiotic (e.g., catheters) or biotic (host cells) surfaces can give rise to the formation of biofilms with yeast cells in the lower part and hyphal cells in the upper part of the biofilm. Phenotypic plasticity (switching) has been proposed to influence antigenicity and biofilm formation of C. albicans. in addition to these virulence factors, several fitness traits influence fungal pathogenicity. They include a robust stress response mediated by heat shock proteins (Hsps); auto-induction of hyphal formation through uptake of amino acids, excretion of ammonia (NH3) and concomitant extracellular alkalinization; metabolic flexibility and uptake of different compounds as carbon (C) and nitrogen (N) sources; and uptake of essential trace metals, e.g., iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn).