Members of the normal microbiota may also cause disease when a shift in the environment of the body leads to overgrowth of a particular microorganism.
For example, the yeast Candida is part of the normal microbiota of the skin, mouth, intestine, and vagina, but its population is kept in check by other organisms of the microbiota.
If an individual is taking antibacterial medications, however, bacteria that would normally inhibit the growth of Candida can be killed off, leading to a sudden growth in the population of Candida , which is not affected by antibacterial medications because it is a fungus. An overgrowth of Candida can manifest as oral thrush growth on mouth, throat, and tongue , a vaginal yeast infection , or cutaneous candidiasis. Other scenarios can also provide opportunities for Candida infections. Untreated diabetes can result in a high concentration of glucose in the saliva, which provides an optimal environment for the growth of Candida, resulting in thrush.
Vaginal yeast infections can result from decreases in estrogen levels during the menstruation or menopause. The amount of glycogen available to lactobacilli in the vagina is controlled by levels of estrogen; when estrogen levels are low, lactobacilli produce less lactic acid. The resultant increase in vaginal pH allows overgrowth of Candida in the vagina. To cause disease, a pathogen must successfully achieve four steps or stages of pathogenesis : exposure contact , adhesion colonization , invasion, and infection.
In many cases, the cycle is completed when the pathogen exits the host and is transmitted to a new host. An encounter with a potential pathogen is known as exposure or contact. The food we eat and the objects we handle are all ways that we can come into contact with potential pathogens.
Yet, not all contacts result in infection and disease. For a pathogen to cause disease, it needs to be able to gain access into host tissue. An anatomic site through which pathogens can pass into host tissue is called a portal of entry. These are locations where the host cells are in direct contact with the external environment. Major portals of entry are identified in Figure 3 and include the skin, mucous membranes, and parenteral routes. Figure 3. Shown are different portals of entry where pathogens can gain access into the body.
With the exception of the placenta, many of these locations are directly exposed to the external environment. Mucosal surfaces are the most important portals of entry for microbes; these include the mucous membranes of the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Although most mucosal surfaces are in the interior of the body, some are contiguous with the external skin at various body openings, including the eyes, nose, mouth, urethra, and anus.
Most pathogens are suited to a particular portal of entry. The respiratory and gastrointestinal tracts are particularly vulnerable portals of entry because particles that include microorganisms are constantly inhaled or ingested, respectively.
Pathogens can also enter through a breach in the protective barriers of the skin and mucous membranes. Pathogens that enter the body in this way are said to enter by the parenteral route. For example, the skin is a good natural barrier to pathogens, but breaks in the skin e. In pregnant women, the placenta normally prevents microorganisms from passing from the mother to the fetus. However, a few pathogens are capable of crossing the blood-placental barrier.
The gram-positive bacterium Listeria monocytogenes , which causes the foodborne disease listeriosis, is one example that poses a serious risk to the fetus and can sometimes lead to spontaneous abortion.
Other pathogens that can pass the placental barrier to infect the fetus are known collectively by the acronym TORCH Table 3. Transmission of infectious diseases from mother to baby is also a concern at the time of birth when the baby passes through the birth canal. Babies whose mothers have active chlamydia or gonorrhea infections may be exposed to the causative pathogens in the vagina, which can result in eye infections that lead to blindness.
Fifth disease erythema infectiosum Treponema pallidum bacterium. Upon learning that Pankaj became sick the day after the party, the physician orders a blood test to check for pathogens associated with foodborne diseases.
There he is to receive additional intravenous antibiotic therapy and fluids. Following the initial exposure, the pathogen adheres at the portal of entry. The term adhesion refers to the capability of pathogenic microbes to attach to the cells of the body using adhesion factors , and different pathogens use various mechanisms to adhere to the cells of host tissues.
Figure 4. Glycocalyx produced by bacteria in a biofilm allows the cells to adhere to host tissues and to medical devices such as the catheter surface shown here. Molecules either proteins or carbohydrates called adhesins are found on the surface of certain pathogens and bind to specific receptors glycoproteins on host cells.
Adhesins are present on the fimbriae and flagella of bacteria, the cilia of protozoa, and the capsids or membranes of viruses. Protozoans can also use hooks and barbs for adhesion; spike proteins on viruses also enhance viral adhesion.
The production of glycocalyces slime layers and capsules Figure 4 , with their high sugar and protein content, can also allow certain bacterial pathogens to attach to cells. Biofilm growth can also act as an adhesion factor. A biofilm is a community of bacteria that produce a glycocalyx, known as extrapolymeric substance EPS , that allows the biofilm to attach to a surface. Persistent Pseudomonas aeruginosa infections are common in patients suffering from cystic fibrosis, burn wounds, and middle-ear infections otitis media because P.
The EPS allows the bacteria to adhere to the host cells and makes it harder for the host to physically remove the pathogen. The EPS not only allows for attachment but provides protection against the immune system and antibiotic treatments, preventing antibiotics from reaching the bacterial cells within the biofilm.
In addition, not all bacteria in a biofilm are rapidly growing; some are in stationary phase. Since antibiotics are most effective against rapidly growing bacteria, portions of bacteria in a biofilm are protected against antibiotics.
Once adhesion is successful, invasion can proceed. Invasion involves the dissemination of a pathogen throughout local tissues or the body. Pathogens may produce exoenzymes or toxins, which serve as virulence factors that allow them to colonize and damage host tissues as they spread deeper into the body. Pathogens may also produce virulence factors that protect them against immune system defenses. Figure 5 shows the invasion of H. Figure 5. Some are obligate intracellular pathogens meaning they can only reproduce inside of host cells and others are facultative intracellular pathogens meaning they can reproduce either inside or outside of host cells.
By entering the host cells, intracellular pathogens are able to evade some mechanisms of the immune system while also exploiting the nutrients in the host cell. Entry to a cell can occur by endocytosis. For most kinds of host cells, pathogens use one of two different mechanisms for endocytosis and entry.
One mechanism relies on effector proteins secreted by the pathogen; these effector proteins trigger entry into the host cell. This is the method that Salmonella and Shigella use when invading intestinal epithelial cells. When these pathogens come in contact with epithelial cells in the intestine, they secrete effector molecules that cause protrusions of membrane ruffles that bring the bacterial cell in. This process is called membrane ruffling. The second mechanism relies on surface proteins expressed on the pathogen that bind to receptors on the host cell, resulting in entry.
For example, Yersinia pseudotuberculosis produces a surface protein known as invasin that binds to beta-1 integrins expressed on the surface of host cells. Some host cells, such as white blood cells and other phagocytes of the immune system, actively endocytose pathogens in a process called phagocytosis. Although phagocytosis allows the pathogen to gain entry to the host cell, in most cases, the host cell kills and degrades the pathogen by using digestive enzymes.
Normally, when a pathogen is ingested by a phagocyte, it is enclosed within a phagosome in the cytoplasm; the phagosome fuses with a lysosome to form a phagolysosome, where digestive enzymes kill the pathogen see Pathogen Recognition and Phagocytosis.
However, some intracellular pathogens have the ability to survive and multiply within phagocytes. Often, these phenotypic variations have their origin in different modifications and organization of nuclear DNA-protein complexes commonly known as chromatin. For instance, changes in the chromosomal organization of genes cause variability of surface proteins in Trypanosoma brucei and allow this pathogenic parasite to evade recognition by the immune system of the host.
However, the very small size of the nucleus and the limited amount of genetic material present in unicellular organisms such as trypanosomes or other protozoan parasites have so far hindered the use of single-cell technologies to probe the underlying mechanisms that cause changes in chromatin organization. To overcome these barriers, Cell2Cell has brought together experts from different research areas to enable the transfer of a broad set of methodologies from chromatin biology, parasitology, bioinformatics and high-throughput microscopy.
In addition, besides investigating the pathogenic parasites Trypanosoma brucei and Plasmodium falciparum responsible for sleeping sickness and malaria, respectively , Cell2Cell will exploit the vast knowledge and technical advances established in various yeast model systems. Toxins related to the direct attack to the host organism. A diffusible, heat-stable substance, with a mass of less than 14 kDa, can be rapidly extracted from the surface of the conidium.
This diffusible substance has been shown to affect competent macrophages, inhibiting the respiratory burst, phagocytosis and the release of cytokines by macrophages, 30, and its effect is reversible. This component has still not been identified, but may allow the fungus to remain in the lungs and express its pathogenic effects.
In particular, it has been associated with the pathogenicity level of A. Ergot alkaloids are a complex family of indole-derived mycotoxins that affect the nervous and reproductive systems of exposed individuals through interactions with monoamine receptors. This gene encodes a dimethylallyl tryptophan synthase that appears to control a determinant step in ergot alkaloid biosynthesis, as when dmaW was knocked out all known ergot alkaloids were eliminated from A.
However, none of these genes have yet been tested for virulence. Gliotoxin is the major and the most potent toxin produced by A. This toxin is related to the allergic process, since it is one of the immunodominant antigens of allergic aspergillosis. This immunomodulator effect could be helping the immune evasion of A.
This molecule has hemolytic activity on rabbit and sheep erythrocytes, cytotoxic effects on macrophages and endothelial cells in vitro , and can be detected during infection in vivo It is worth mentioning that in a recent study the levels of expression of certain of the genes discussed above gliP , aspHS , asp f 1 , and dmaW were determined by real-time RT-PCR analysis, and higher expression was observed in vivo than in vitro.
Other toxins produced by A. Helvolic acid is part of a small family of steroidal antibiotics known as fusidanes. At high concentrations it can affect the oxidative burst of macrophages, the metabolism of low density lipoproteins and in vivo it induces ciliostasis and rupture of epithelial cells.
It has also been reported that fumitremorgin A fumitremorgin B , and fumitremorgin C 77 , neurotropic toxins that cause tremors, seizures, and abnormal behavior in mice, are produced in a dose-dependent manner. Another toxin described to be produced by A. Mammalian organisms present a broad variety of microenvironments in which A.
Table 5 shows the major molecules and genes related to virulence covered in this section. Genes and molecules related with nutrient uptake in invasive growth. As indicated above, one of the host antimicrobial mechanisms is nutrient deprivation, and the amount of secreted hydrolases encoded on the genome , may allow A.
Various researchers have demonstrated a clear link between elastase activity of A. Other metalloproteases have been identified in A. Two aspergillopepsins have been identified, a secreted aspergillopepsin Pep which matches the known Asp f 10 allergen, and another one associated to the cell wall Pep2.
These enzymes can bind to collagen, and even to hormones and cytokines, and degrade them. Their role in T cell activation has also been described. Finally A. This could be explained by the secretion of other phospholipases by A. Different proteases may play unique or overlapping roles during pathogenesis, and is difficult to obtain evidence of them as individual virulence factors. It is worth noting that there are at least 99 putative secreted proteases for the A. Recently, the biosynthesis of trehalose has been linked to virulence in pathogenic fungi.
Trehalose is a non-reducing disaccharide the expression of which increases during the life cycle of A. Its concentration also increases after heat shock but not in response to other types of stress and in this fungus it is related with reduction in pathogenicity. The double mutation was required to block the trehalose accumulation, and this double mutant was hypervirulent in murine model of IA and was also associated with alterations in the cell wall and resistance to macrophage phagocytosis.
The uptake of certain components is essential for most organisms and the ability to acquire these components in limiting environments, such as in the human host, is a necessary requirement for virulence of human pathogens.
One of these limiting components in the human host is iron. As humans do not produce siderophores, most of these genes, and particulary sidA and sidC , could be good targets for new antifungal therapies. Zinc is another essential element for fungal growth. It has recently been described that the zrfC gene encodes a transporter devoted to obtaining zinc from alkaline zinc-limiting media.
In alkaline and extreme zinc-limiting conditions, the transcriptional regulators ZafA and PacC induce the simultaneous transcription of zrfC and asp f 2 genes. Specifically, ZafA upregulates the expression of zrfC and Asp f 2 under zinc-limiting conditions regardless of the environmental pH, whereas PacC represses the expression of these genes under acidic growth conditions.
However, the deletion of the transcriptional regulator zafA gene impairs the germination and growth capacity of A. Nitrogen metabolism has also been related to A. Several sources of nitrogen may be used by A. The proteins that are involved in nitrate transport and processing are transcriptionally regulated by the areA gene.
However, this mutant strain presented a delayed-growth phenotype in the lung tissue. It has been proposed that this system regulates the A. The degradation of amino acids could be important in A. The fungus metabolizes propionyl-CoA via the methylcitrate cycle. This mutant strain displayed attenuated virulence in a murine model of IA, so that this activity does provide a suitable target for new antifungals.
That is the case, for example, of four putative inorganic phosphate transporters and six secreted acid phosphatases. The environmental conditions found by pathogenic fungi in the colonization and infection of the host are different to those found in their normal environmental niche.
The signals must be detected and transmitted through mechanisms of gene regulation and metabolism, enabling the fungus to adapt to them. Several regulatory mechanisms have been studied in A. Molecules and genes involved in signaling, metabolic regulation and response to stress conditions. Mitogen activated protein kinase MAP kinase.
Fungi, like other eukaryotes, can regulate their cellular physiology in response to environmental changes via MAPK pathways. These environmental changes include conditions of stress increased osmolarity, heat shock, high concentrations of heavy metals, and reactive oxygen species , nutrient limitation, disruption of cell wall integrity, and mating pheromones.
The three MAPKKs are Ste7 like, Pbs2 like, and Mkk2 like, suggesting their possible roles in mating, osmotic regulation, and cell wall integrity, respectively. This gene is necessary for the osmotic stress response, it negatively regulates conidial germination in response to less-preferred nitrogen sources; and is activated upon either carbon or nitrogen starvation during vegetative growth.
However, although the deletion of this gene in A. Many signal transduction pathways are activated by heterotrimeric G-proteins whose activation is frequently coupled to cell surface receptors. In fungi, G-proteins play integral roles in germination, vegetative growth, cell cycle control, mating, cell—cell fusion, morphogenesis, chemotaxis, pathogenicity, and secondary metabolism.
Furthermore, compared with the wild type, the sensitivity of the mutant strains towards reactive oxygen intermediates was greater, and the mutants displayed attenuated virulence in a murine infection model. These authors concluded that the receptors are involved in integrating and processing stress signals via modulation of the calcineurin pathway.
Ras proteins are monomeric GTPases which act as molecular switches that transduce signals from the outside of the cell to signaling cascades inside the cell. The first, RasA, appears to have a crucial role in hyphal growth and asexual development, and its function is linked to cell wall integrity, 88 while deletion of the A.
In fungi, two-component histidine kinases are involved in response mechanisms to extracellular changes in osmolarity, resistance to dicarboximide fungicides, and cell-wall assembly. Steinbach et al. In agreement with these results, Da Silva Ferreira et al. A recent study has also suggested that calcineurin is involved in septum formation and conidiophore development.
Soriani et al. Thus, crzA is an attractive fungus-specific antifungal target for the treatment of IA. A conserved signal transduction cascade linking environmental stress to amino acid homeostasis is the CPC system that acts via phosphorylation of the translation initiation factor eIF2 by a sensor kinase.
The transcription factor Ace2 influences virulence in other fungi. It is known that A. MedA is a development regulated protein that governs adherence, host interactions, and virulence in A. This mutant also exhibited reduced virulence in both invertebrate and mammalian models of IA. These results suggest that MedA downstream targets mediate virulence and might provide novel therapeutic targets for IA.
The presence of A. It is known that levels of oxygen are significantly lower at sites of inflammation. The mechanisms of hypoxic adaptation of the aerobic A. Willger et al. These authors have demonstrated that the srbA gene plays a critical role in ergosterol biosynthesis, azole resistance, and the maintenance of cell polarity in A.
Data concerning all known A. Only 23 molecules currently hold an official name of allergen, and have names in the range Asp f 1—Asp f One of these, Asp f 15, has been proposed to be removed from the list due to it having been demonstrated that it is identical to Asp f 13, and the Asp f 6 allergen has shown a high degree of homology with Asp f 9.
However, the sequence of Asp f 56 kDa is not predicted to be encoded in any of the sequenced Aspergillus genomes. However, other allergenic components do not have virulence activities except as allergens.
Among these, Asp f 6 Mn-Sod , Asp f 8 P2 acidic ribosomal protein , Asp f 11 and Asp f 27 cyclophilins , and Asp f 28 and Asp f 29 thioredoxins have been shown to belong to families of cross-reactive pan-allergens. Allergens of A. Allergenic behaviour of the aforementioned molecules, due to their presence on conidia, their release by the destruction of the conidia by pulmonary phagocytes, or their production during the growth of fungus is unclear in IA. We were able to identify two different situations, namely, the infections caused by Aspergillus in immunocompetent or immunocompromised patients.
In immunocompetent patients Aspergillus can produce several hypersensitivity diseases due to these allergens, such as ABPA, allergic rhinosinusitis, asthma, and aspergilloma. Inhalation of fungal spores, often considered the traditional route of exposure, has been associated with the induction or exacerbation of these respiratory diseases.
Large numbers of inhaled fungal spores are removed from the lungs prior to germination, but a few conidia could escape phagocytosis and may begin to germinate. Dormant or nonviable A. Specific structures, factors secreted by fungi or released by killed conidia, can play an important role in allergic sensitization, but the environmental and patient-specific factors such as the personal history of previous contact in early life immune development are also critical to acquire tolerance or allergic sensitization in immunocompetent individuals.
All Aspergillus allergens appear to activate a Type I hypersensitivity response in sensitized patients with production of high affinity IgG and IgE antibodies. During the last years only a few studies have investigated A. Gravelat et al. This study revealed that in established infections, A. The acquisition of competence is referred to the shift of hyphae from a state in which they cannot undergo asexual reproduction to one in which they can.
In contrast, mRNA of genes expressed specifically by conidia and precompetent hyphae was not detected. Many genes required for mycotoxin synthesis, including aspHS , gliP , mitF , and metAP , were expressed at significantly higher levels during invasive infection than in vitro.
On the other hand, the expression of gliP mRNA in vitro was found to be highly dependent on culture conditions. Furthermore, this expression was found to be dependent on the transcription factor StuA both in vitro and in vivo. These results highlight the importance of the evaluation of putative virulence factors expressed by competent hyphae and the analysis of gene expression levels during invasive infection rather than in vitro alone.
Gene expression assays have also been developed to analyse the function of various proteins, comparing the gene expression profiles of the mutant against those of the reference strain. For example, Soriani et al. Similarly, Twumasi-Boateng et al. Using transcriptomic analysis, other authors have investigated the exit from dormancy of A.
Finally, DNA microarray-based studies have also been used for the detection and identification of fungal pathogens, including A. The most recent progress in research has revealed how components of the immune system are able to eliminate the fungus and that the weakness of immune system has a role in the development of aspergillosis. Likewise, some of the mechanisms that the fungus uses to evade immune responses, to obtain nutrients and to cause damage to the host and thus generate an IA, have been identified.
If we consider only the classical definitions of virulence factors, i. In fact, that would exclude, for example, normal or adaptive mechanisms of the fungi to grow in different environmental niches, which are extensively used during the colonization of a human host. As detailed in this review, a large number of genes and molecules have been identified and investigated in some depth as potential virulence factors.
However, none of them have proven to be sufficiently important to fully explain the virulence of A. The pleiotropic effect of certain genes, the function of various genes associated with the virulence in the normal growth of A.
On the other hand, virulence studies use animal models with high levels of immunosuppression, which can also lead to failure to detect the effect on the virulence of the mutant strains.
Likewise, the animal immunosuppression used, focusing mainly on causing neutropenia, only simulates the situation in neutropenic patients without providing any data for the other types of patients with aspergillosis. From all this data, the idea has emerged that the pathogenesis of diseases caused by this fungus in immunocompromised patients is very complex. As shown in Fig. We begin to understand the intricacies of its metabolism but much remains to be learned concerning the activity of this fungus in vivo.
Furthermore, understanding changes in the host microenvironment, including hypoxia, pH, available nutrients, and immune responses, and how these signals are processed by the fungus, could be useful to determine the efficacy and effectiveness of particular antimicrobial strategies. The data so far have helped to improve diagnosis and identify new targets for antifungal development, which in combination with currently available therapies can improve the prognosis for IA patients.
Expression studies using DNA microarrays of A. In particular, these expression studies using DNA microarrays are being applied to different stress conditions such as heat shock and antifungal activity. Summary of genes and molecules associated with the virulence of Aspergillus fumigatus contained in this review. Genes and molecules invo ISSN: What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Descargar PDF. Autor para correspondencia.
Table 1. Table 2. Table 6. Table 7. The most recent gene expression studies using DNA-microarrays may be help us to understand this complex virulence, and to detect targets to develop rapid diagnostic methods and new antifungal agents.
Aspergillus fumigatus. Palabras clave:. Texto completo. Virulence assayed in animal model. New antifungal target? Table 3. DHN-melanin: melanin-1,8 dihydroxynaphthalene. Allergic bronchopulmonary aspergillosis.
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