Prof. Khaled H. Abu-Elteen

Prof. Khaled H. Abu-Elteen
Medical Mycology Prof. Khaled H. Abu-Elteen Zarqa Private UniversityBiology 4223 – The Fungi

Zarqa Private UniversityBiology 4223 – The Fungi
Fungal Diseases Mycosis- fungal infection < 100 cause human disease Not highly contagious Humans acquire from nature Groups based on degree on tissue involvement and mode of entry Cutaneous mycoses-dermatophytes Epidermis, hair & nails Contagious-direct or indirect contact Secrete keratinase that degrades keratin Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Mycoses Tinea( worm) capitis –blisters with scaly ring Ringworm of the scalp Spreads circularly forming bald spots Spread by contact with fomites , cats and dogs Tinea cruris- ringworm of groin Tinea pedis - athlete's foot Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycoses Dimorphic fungi Yeast form is invasive Can spread throughout body Usually caused by fungi in soil Inhalation of spores Begins in lungs and spread to rest of body Not contagious person to person Zarqa Private UniversityBiology 4223 – The Fungi

Introduction Obligate Parasitic Fungi (dermatophytes): evolved to attack the outer surface of humans Facultative soil fungi: thermal dimorphic saprobes, adaptations to human body Opportunistic saprobes: attack people with compromised immune systems Zarqa Private UniversityBiology 4223 – The Fungi

Introduction Fungal Infections Superficial infections: involve outermost layers of skin and its appendages [ nails or hair] ( Dermatophytosis) Cutaneous infections: involve deeper layers of skin causing allergic or inflammatory response Subcutaneous infections: fungi with low virulence, localized infection, or spread by mycelial growth Zarqa Private UniversityBiology 4223 – The Fungi

Introduction Systemic infections: caused by true pathogenic fungi or opportunistic saprobes Zarqa Private UniversityBiology 4223 – The Fungi

Mycoses: diseases cause by fungi
Superficial Cutaneous Subcutaneous Systemic Opportunistic Zarqa Private UniversityBiology 4223 – The Fungi 8

The Situation Frequency - most common fungal pathogen worldwide - 4th leading causes of nosocomial infections, 40% mortality - significant mortality and morbidity in low birth-weight infants - affects 75% women, 45% experience recurrence > 10 million visits/year - classified as a STD by CDC Immunocompromised - cancer and HIV-AIDs patientsC - most commonly manifested in patients with leukemia or HIV-AIDs infections. Oral candidiasis is often a clue to acute primary infectionC Public Concerns - increasing resistance to drug therapies due to antibiotics and antifungals Alarmingly, the statistics show how serious infections by C. albicans can be. The CDC has ranked it as the 4th leading pathogen in causing nosocomial bloodstream infections (Naglik et. Al., 2003). Surgical and neonatal intensive care units are dense sources of spread of Candida infections (Roilides et. Al., 2004). Moreover, 75% of women will suffer from a yeast infection at least once in her life (Owen et. Al., 2004). In the U.S., vaginitis accounts for 10 million visits to the physician each year. C. albicans is also considered a sexually transmissable pathogen for one’s ability to contract it though sexual intercourse (Prescott et. Al., 2002). Many environmental factors from taking steroids to being a patient in a hospital can predispose a person to diseases that are caused by C. albicans. These factors will be highlighted later in this discussion. Zarqa Private UniversityBiology 4223 – The Fungi

FUNGAL DISEASES Mycosis: Any fungal disease. Tend to be chronic because fungi grow slowly. Mycoses are classified into the following categories: I. Systemic mycoses: Fungal infections deep within the body. Can affect a number if tissues and organs. Usually caused by fungi that live in the soil and are inhaled. Not contagious. Examples: Histoplasmosis (Histoplasma capsulatum): Initial infection in lungs. Later spreads through blood to most organs. Coccidiomycosis (Coccidioides immites): Resembles tuberculosis. Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycosis: Histoplasmosis
Disseminated Histoplasma capsulatum, lung infection. Zarqa Private UniversityBiology 4223 – The Fungi

FUNGAL DISEASES (Continued) II. Cutaneous mycoses: Fungal infections of the skin, hair, and nails. Secrete keratinase, an enzyme that degrades keratin. Infection is transmitted by direct contact or contact with infected hair (hair salon) or cells (nail files, shower floors). Examples: Ringworm (Tinea capitis and T. corporis) Athlete’s foot (Tinea pedis) Jock itch (Tinea cruris) Zarqa Private UniversityBiology 4223 – The Fungi

Opportunistic Infection by Candida albicans in an AIDS Patient
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Severe nail infection with Trichophyton rubrum in a 37-year-old male AIDS patient. Zarqa Private UniversityBiology 4223 – The Fungi

Disseminated Histoplasma capsulatum, skin infection. Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Mycosis Ringworm skin infection: Tinea corporis Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Mycosis Candida albicans infection of the nails. Zarqa Private UniversityBiology 4223 – The Fungi

FUNGAL DISEASES (Continued) III. Subcutaneous mycoses: Fungal infections beneath the skin. Caused by saprophytic fungi that live in soil or on vegetation. Infection occurs by implantation of spores or mycelial fragments into a skin wound. Can spread to lymph vessels. IV. Superficial mycoses: Infections of hair shafts and superficial epidermal cells. Prevalent in tropical climates. Zarqa Private UniversityBiology 4223 – The Fungi

FUNGAL DISEASES (Continued) Opportunistic mycoses: Caused by organisms that are generally harmless unless individual has weakened defenses: AIDS and cancer patients Individuals treated with broad spectrum antibiotics Very old or very young individuals (newborns). Examples: Aspergillosis: Inhalation of Aspergillus spores. Yeast Infections or Candidiasis: Caused mainly by Candida albicans. Part of normal mouth, esophagus, and vaginal flora. Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Infections Dermatophytic hyphomycetes 40 species Epidermophyton (2 species) Microsporum (17 species) Trichophyton (24 species) 50% of dermatophytes human specific Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Infections Cause common tinea (ringworm) Grow only on humans Reservoir not in soil or animals Reservoir in carpets and upholstery for up to two years Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Infections Trichophyton rubrum Chronic infections of the toe nails Zarqa Private UniversityBiology 4223 – The Fungi

Tinea corporis Subcutaneous mycoses Subcutaneous infections - over 35 species produce chronic inflammatory disease of subcutaneous tissues and lymphatics. e.g. sporotrichosis - ulcerated lesions at site of inoculation followed by multiple nodules - caused by a dimorphic fungus: Sporotrix schenckii. Zarqa Private UniversityBiology 4223 – The Fungi 23

Cutaneous Infections Microsporum canis Reservoir in cat May move to humans or dogs Dies out after one or two person-person transfers Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Infections Disease process Fungus stimulates epithelial cells of skin to divide more frequently Makes more keratin available to fungus Some species race specific in humans Some species body location specific Zarqa Private UniversityBiology 4223 – The Fungi

Cutaneous Infections Candida albicans – candidiasis Normal component of gut mycota Excessive wetness  overgrowth on skin Vaginal candidiasis common in pregnant women Zarqa Private UniversityBiology 4223 – The Fungi

Biology of Candida albicans
Commensal Pathogen A thin-walled dimorphic fungus Morphogenesis Unicellular yeast (harmeless) Filamentous (pathogenic) Principal Cell Wall Polymers Gluccan Mannan Strict aerobe, favors moist surfaces Commensally found in gut, genitals, and lungs Body Temp 37º C, neutral pH The genus Candida includes approximately 154 species of which Candida albicans is the most frequently (50%) isolated in human fungal infections. C. albicans is also the most abundant and significant of all the Candida related species. Its natural habit is found mainly contained in animals and humans, and on average, colonizes 50% of healthy individuals (Henderson, 2005). However, C. albicans and related species are frequently recovered from hospitals, foods, counter tops, medical equipment and so on. It is part of the normal human microflora of mainly skin and mucosal membranes of gastrointestinal, genitourinary, and respiratory tracts (Hidalgo, 2005). A healthy host is typically extremely resistant to the potentially pathogenic effects of C. albicans. However, when slight alterations of the host’s environment occurs, a harmless commensal organism can turn into agents of severely inflicting illnesses (Naglik et. Al., 2003). A host may become highly susceptible to C. albicans when the following defense mechanisms are challenged: intact mucocutaneous barriers, phagocytic cells, polymorphonuclear leukocytes, monocytic cells, complement system, immunoglobulins, cell-mediated immunity, and mucocutaneous protective bacterial flora (Hidalgo, 2005). There are many risk factors that can stage the scene for susceptibility. These include granulocytopenia, bone-marrow transplation, organ transplanation, general and invasive surgical procedures, catheters, chemotherapy, radiation therapy, the use of corticosteroids, oral contraceptives, broad-spectrum antibiotics, prolonged hospitalization, trauma, pregnancy, sexual intercourse, and premature low-weight births (Hidalgo, 2005). Biological characteristics Candida albicans is a yeast-like fungus that has the capability to produce blastoconidia, pseudohyphae, and true hyphae (Hidalgo, 2003). Only Candida albicans and one other Candida species (C. dubliniensis) are capable of germ-tube production. Germ-tube production occurs at the beginning of true hyphae formation. In lab diagnostics, this feature is key to identifying a sample with strains of C. albicans (Larone, 1995). C. albicans can also be recognized for its production of a typical asexual spore called a chlamydoconidium (Larone, 1995). Exhibiting structural dimorphism is a key biological feature of C. albicans. That is why C. albicans considered “yeast-like” because it can take on the form of yeast, reproducing by budding, or mould, reproducing by hyphal elongation (Gow, 2002). Its ability to morphogenosize into various forms enables its survival in the host as a colonizer (Calderone, 2002). Substances such as biotin, cysteine, serum transferrin, and zinc stimulate dimorphism (Baron, 1996). Bud yeast formation is also favored in environments where pH and temperature are low (Baron, 2002). For instance, C. albicans is a harmless commensal in the vagina where the pH is low and exists as yeast. In its normal environment of the mucosal membranes of humans and animals, C. albicans grows as yeast. When the environment is perturbed however, C. albicans demonstrates hyphal growth (Kwon-Chung & Bennett, 1992). This is seen when the number of beneficial bacteria in the vagina declines. Beneficial bacteria, including species of Lactobacilli, abundantly populate the vagina and secrete lactic acid, which keeps the pH low. When these are wiped out, the pH level is elevated and changes the environment to an ideal environment for C. albicans to grow and multiply (Kwon-Chung & Bennett, 1992). The cell wall is significant for protection, and it also represents the primary way that C. albicans is able to interact with its host. A number of cell-wall proteins are necessary to ensure the proper binding and adherence of the organism to its host, which is a significant factor of virulence. Carbohydrates make up about 80-90% of the cell wall of C. albicans, and the majority of these carbohydrates are glucan and mannan polymers (Chauhan et. Al., 2002). It has been determined that mannan is a major antigen of Candida species, and the different serological concentrations aid as a tool in identifying certain ones (Suzuki, 2002). C. albicans, in particular, contains around 20% of mannan in its cell wall (Baron, 1996) % of the carbohydrates are glucans, which have been suggested to impede the antifungal amphotericin B from gaining access to the organism plasma membrane (Baron, 1996). The cell wall matrix is layered, which seems to serve a functional role in providing the cell with a rigid structure against osmotic and environmental threats (Chauhan et. Al., 2002). Figure 1. Yeast in Oral Scraping A sample of an oral scraping contains yeast cells and pseudohyphae ( Zarqa Private UniversityBiology 4223 – The Fungi Rapid Multiplication & Spread

Diseases by C. albicans Thrush Esophagitis Cutaneous Candidiasis Genital Yeast Infections Deep Candidiasis The common diseases that C. albicans can cause are oropharyngeal candidiasis, which includes thrush and esophagitis, cutaneous candidiasis, genital yeast infections, and deep candidiasis. As an overview, thrush and esophagitis are infections concering the mouth and throat. Patients infected with HIV or who have cancer have these types being the most frequent manifestations of mucotaneous lesions (Ruhnke, 2002). Cutaneous candidiasis is infection of the skin, scalp, and nails by C. albicans. An example is diaper rash that often occurs in newborn infants. Genital yeast infections, especially those women, are extremely frequent, but can affect men, too. Several lifestyle factors can predispose a man or woman to a genital yeast infection. Deep candidiasis is also known as invasive candidiasis and afflicts mainly people who are severely immunocompromised. Colonies of C. albicans invade the bloodstream and can spread to many areas of the body destroying tissue and leading to organ failure. It is one type of sepsis that carries a significant mortality and morbidity rate particularly in intensive care units where nosocomial infections are rampant (Marr, 2004). Recall that C. albicans is the fourth leading cause of nosocomial infections in the United States (Marr, 2004). Zarqa Private UniversityBiology 4223 – The Fungi

Oropharyngeal Thrush * Pseudomembranous * Atrophic * Angular chelitis Symptoms Risk Factors HIV Treatment: topical antifungals Figure 1. Angular chelitis In 400 B.C., Hippocrates described oral thrush as oral ulcers. It was not until 1839 when Langenbeck detected fungi in the oral cavity. Then in 1846, Berg connected that the fungi caused oral thrush. To demonstrate, he infected healthy infants with samples he had taken from the oral lesions and saw the manifestation of thrush (Ruhnke, 2002). Although that would be considered an unethical approach to studying science in today’s society, it was a common practice to understand pathogenecity that lasted until the middle of the 20th century (Ruhnke, 2002). Thrush is the common name for an oral infection that is caused by Candida albicans. The areas of the mouth that are affected are the moist surfaces around the lips, inside the cheeks, and on the tongue and palate. Thrush in patients with cancer and AIDS is frequently observed. Other patients who are at-risk for developing thrush are elderly people, people who have diabetes, or those who have irritation from wearing dentures. There are three types of oral thrush that are clinically classified: pseudomembranous, atrophic, and angular chelitis (Samaranayake et. al., 1990). White, thick plaques that spot the sites of the buccal, mucosa, tongue, palata, and uvula characterize pseudomembraneous candidiasis. When these plaques are removed, they leave an erythematous bleeding surface. Symptoms include burning, pain, and changes in taste. In atrophic candidiasis, there is diffuse erythema that affects mainly the palate and the tongue and result in soreness. Oftentimes, this is denture-induced. Finally, in angular chelitis, the corners of the mouth show signs of cracking and inflammation and associated with the feeling of pain, burning, and soreness (Samarnayake et. al., 1990). When Candida infections spread to the esophagus, a condition known as esophagitis occurs. Symptoms related to this disease may be dysphagia, odynophagia, chest pain, and possible fever (Mildvan, 1995). Candidal esophagitis is the most frequent candidal disease in patients with HIV-AIDS and with oral candidiasis, contributes to an incident rate as high as 50-90% (Ruhnke, 2002). In many clinical cases, esophagitis is a marker that the HIV-infected patient is becoming significantly immunocompromised and is developing AIDs (HSTAT, 2005). Treatment for most oropharyngeal candidiasis typically involves topical antifungal agents (nystatin and clotrimazole) for thrush (Intelihealth). For more severe cases including esophagitis, treatment would require the administration of ketoconazoles or fluconazoles, which can be taken orally (Intelihealth). Flucanzole has proven to be the most effective medication in patients with HIV/AIDS (Intelihealth). Figure 2. Oral Thrush, atrophic Figure 3. Oral Thrush, pseudomembranous Zarqa Private UniversityBiology 4223 – The Fungi

Genital Yeast Candidiasis Symptoms Risk Factors - disruption of normal microbiota Treatment - direct genital administration - tablets, suppositories, creams Figure 1. Vaginal Yeast Culture In 400 B.C., Hippocrates described oral thrush as oral ulcers. It was not until 1839 when Langenbeck detected fungi in the oral cavity. Then in 1846, Berg connected that the fungi caused oral thrush. To demonstrate, he infected healthy infants with samples he had taken from the oral lesions and saw the manifestation of thrush (Ruhnke, 2002). Although that would be considered an unethical approach to studying science in today’s society, it was a common practice to understand pathogenecity that lasted until the middle of the 20th century (Ruhnke, 2002). Thrush is the common name for an oral infection that is caused by Candida albicans. The areas of the mouth that are affected are the moist surfaces around the lips, inside the cheeks, and on the tongue and palate. Thrush in patients with cancer and AIDS is frequently observed. Other patients who are at-risk for developing thrush are elderly people, people who have diabetes, or those who have irritation from wearing dentures. There are three types of oral thrush that are clinically classified: pseudomembranous, atrophic, and angular chelitis (Samaranayake et. al., 1990). White, thick plaques that spot the sites of the buccal, mucosa, tongue, palata, and uvula characterize pseudomembraneous candidiasis. When these plaques are removed, they leave an erythematous bleeding surface. Symptoms include burning, pain, and changes in taste. In atrophic candidiasis, there is diffuse erythema that affects mainly the palate and the tongue and result in soreness. Oftentimes, this is denture-induced. Finally, in angular chelitis, the corners of the mouth show signs of cracking and inflammation and associated with the feeling of pain, burning, and soreness (Samarnayake et. al., 1990). When Candida infections spread to the esophagus, a condition known as esophagitis occurs. Symptoms related to this disease may be dysphagia, odynophagia, chest pain, and possible fever (Mildvan, 1995). Candidal esophagitis is the most frequent candidal disease in patients with HIV-AIDS and with oral candidiasis, contributes to an incident rate as high as 50-90% (Ruhnke, 2002). In many clinical cases, esophagitis is a marker that the HIV-infected patient is becoming significantly immunocompromised and is developing AIDs (HSTAT, 2005). Treatment for most oropharyngeal candidiasis typically involves topical antifungal agents (nystatin and clotrimazole) for thrush (Intelihealth). For more severe cases including esophagitis, treatment would require the administration of ketoconazoles or fluconazoles, which can be taken orally (Intelihealth). Flucanzole has proven to be the most effective medication in patients with HIV/AIDS (Intelihealth). Most genital yeast infections are caused by Candida albicans. Vaginal yeast infections are most common and affect nearly 75% of women during a lifetime. 45% of women have recurrence rates of two or more yeast infections. Symptoms include intense vaginal itch and/or soreness, secretion of a thick cheeslike discharge, burning, pain, and severe discomfort. Conditions that predispose a woman to an infection are pregnancy, diabetes, frequent douching, the use of birth control pills and antibiotics, and HIV-infection (Owen et. Al., 2004). These are factors that may tempt the virulence capabilities of C. albicans alter the normal vaginal flora (Ruhnke, 2002). For instance, members of Lactobacilli, are beneficial, normal habitants of the vagina that suppress the growth of C. albicans (Mayo Clinic. 2003). These bacteria secrete lactic acid that helps keep the pH of the vagina low, which prevents the growth of many microbes that could only survive at a neutral pH (Prescott, 2002). When these members are eliminated in cases of antibiotic treatment, however, the environment of the vagina becomes favorable for candidal growth. This explains some studies that suggest the consumption of yogurt, which contains lactobacilli cultures, is helpful during yeast infections or urinary tract infections to replenish the environment with the beneficial microbiota (Mayo Clinic, 2003). Figure 1 shows an image of C. albicans in a vaginal yeast sample. Growth is noted by the presence of hyphae. C. albicans also affects men in a manifestation called balanitis. The glans of the penis is inflamed and the symptoms include discharge, redness, and sometimes itchiness. Balanitis is often clinically diagnosed in men who have not had their foreskin circumcised. The domain under the foreskin is warm and moist and thus, ideal for the growth of C. albicans. Figure 2 shows an infiltrate of plasma cells lining in the dermis of a male’s glans that has affected by balanitis. The inflammation that arises from balanitis is a reactive immunological process, which explains the presence of the plasma cells. Also present are numerous capillaries, and extravasated red cells and macrophages may be seen (Ramani, webpathology.com). Figure 2. Plasma cell balanitis. A band-like infiltrate of plasma cells is in the dermis of the male penis. Zarqa Private UniversityBiology 4223 – The Fungi

Deep Candidiasis According to a survey conducted by the CDC, 8 in every 100,000 persons have candidemia each year (CDC). In deep candidiasis, C. albicans infects the bloodstream and spreads throughout the circulatory system and causes severe infection. Newborns, especially those who have low birth weights, severely immunocompromised patients, or those who have severe medical problems are vulnerable to this type of an infections. The fungi may gain access to the bloodstream through catheters, tracheotomies, ventilation, and deep surgical wounds (Intelihealth). It is for this reason that many hospitals need to reevaluate their protocol in treating patients to prevent high rates of nosocomial infections. It is also possible to get infected by C. albicans through intravenous drug abuse, severe burns, and traumatic wounds (Intelihealth). The symptoms include fevers and chills that are not usually alleviated after antibiotic treatment and symptoms associated with different affected organ sites. Death due to organ failure is inevitable if the sepsis is not treated. The treatment for deep candidiasis usually calls for the intravenous administration of amphotericin B. Invasive candiadis is involved in four over-lapping forms that typically begins as an episode of candidemia and leads to various clinical subtypes. These subtypes are catheter-related, acute disseminated, chronic disseminated, and deep organ candidiasis. Catheter-related candidemia is noted as the most common form of candidiasis, which puts C. albicans as the 4th most commonly isolated nosocomial pathogen. Infections of this type are mainly local. A direct contamination of the catheter makes it potentially potent to the patient as the organism can gain entry into the bloodstream and spread to other places in the body. Figure 1. Four forms of invasive candidiasis ( Zarqa Private UniversityBiology 4223 – The Fungi

Pathogenesis Host Recognition Adhesins Enzymes Hydrolases: Phosphoplipases, Lipases, Proteinases Morphogenesis Yeast form to Filamentous hyphae/pseudohyphae Phenotypic Switching Without its virulence factors, Candida albicans would not survive in the human body. The major mechanisms of its pathogenesis come in the form of host recognition, the production of enzymes, the ability to assume different morphologies, and the capacity to switch phenotypically (Calderone & Gow, 2002). Host Recognition Host recognition involves key players called adhesins (Calderone & Gow, 2002), which also contribute to colonization. In studies where genes that encoded for adhesions were deleted, C. albicans demonstrated the inability to adhere onto the host and as a result, infection did not proceed (Calderon & Gow, 2002). Thus, adhesion is a major virulence determinant of C. albicans. What prompted these studies of adherence factors were investigations led by King et. al. in the 1980s. An assay was developed to measure the adherence of several species in Candida by using radiolabeled Candida species that were added to human buccal or vaginal exfoliated cells in a suspension. Filters removed non-adhering yeasts and adherence was measured by the amount of radiolabeled yeast cells left. The studies revealed that C. albicans adhered most significantly and to the greatest extent (Calderone & Gow, 2002). Adhesins are either polysaccharide or glycoprotein, but are more abundant as glycoproteins (Calderone & Gow, 2002). Types of adhesins include MP66 whose ligand is Asialoglcospingolipid, MP-hemed whose ligand is fibronectin, and Ala1p whose ligand is also fibronectin (Cormack et. al., 1999). Not only do adhesins allow C. albicans to bind to human epithelial cells, but also to human proteins and internal tissues (Calderone & Gow, 2002). The adherence onto plastic surfaces by C. albicans is yet another growing problem that exacerbates the spread of candidiasis in hospital settings. The contamination of indwelling catheters in patient pools often initiates systemic candidiasis (Jarvis, 1995). Plastics also have the great capacity to collect biofilms, which promotes the adherence of C. albicans. In studies that focused on the adherence of C. albicans to different medical catheters, it was found that polyvinyl catheters supported the most for biofilm formation and polyurethane supported it the least (Hawser & Douglas, 1994). Of all the species of Candida that were tested, C. albicans contributed to the most biofilm mass (Hawser & Douglas, 1994). This nature is an important one for experimental investigation because it could correlate with organisms that are embedded in biofilms have more resistance to antifungal drugs. Recent studies have shown that there is an increased resistance to amphotericin B for organisms that are in a biofilm (Baillie and Douglas, 1999). Enzyme Hydrolases Gaining entry into the host is an important strategy for C. albicans and many other pathogenic organisms. To aid in doing so, C. albicans produces hydrolytic digestive enzymes such as the secreted aspartyl proteinases (SAPs) and phospholipase B (PLB) (Calderone & Gow, 2002). Hydrolytic enzymes play a central role in the pathogenesis of C. albicans, just as they do in many other pathogenic fungi, bacteria, and protozoa (Naglik et. Al., 2003). In contrast to bacteria, C. albicans tends to produce hydrolytic enzymes that are broad-spectrum rather than highly-substrate specific (Hube and Naglik, 2002). Hydrolytic enzymes serve multiple purposes from the digestion of molecules for nutrient absorption to host tissue invasion by the destruction of cell membranes (Hube and Naglik, 2002). Three major categories of hydrolytic enzymes are known to be involved with C. albicans’ virulence (Hube and Naglik, 2002). These enzymes are proteinases, phospholipases, and lipases (Naglik et. al., 2003). Proteinases hydrolyze peptide bonds, phospholipases hydrolyzes phospholipids, and lipases hydrolyze lipids. More specifically, C. albicans secrete aspartyl proteinases, PLB2, PLB2, and PLD-type phospholipases, and Lip1 through Lip10 lipases (Ghannoum, 2000). It has been purported that the phospholipases enhance virulence by mediating the adhesion and lyssis of host cell membranes during an infection (Ghannoum, 2000). While evidence implicates these findings, more research is needed to determine the actual relationship and mechanism (Ghannoum, 2000). Further study on lipases is also necessary to understand their involvement in the organism’s pathogenesis. However, it has been implicated that the broad lipolytic activity may contribute to its persistence and virulence (Hube and Naglik, 2002). The secreted aspartyl proteinases are encoded by a family of ten SAP genes and are concluded to be key virulence determinants of Candida albicans (Felk et. al., 2000). Studies have shown their involvement in hyphal formation, adhesion, and phenotypic switching (Naglik et. al., 2002). The correlation between SAP and Candida virulence has been determined by isolating C. albicans from various candidal diseases and noting the SAP activity. For instance, increased SAP activity occurred in C. albicans strains that were isolated form HIV-positive patients with oral candidiasis compared with HIV-negative C. albicans strains carriers (De Bernardis et. al., 19992). The same effect was found in isolates from patients with oropharyngeal candidiasis and vaginal candidiasis. In animal models, the strains with more SAP production led to higher levels of tissue colonization in the liver, kidneys, and spleen (Abu-Elteen et. al., 2001). Ten different kinds of SAP have been identified that range in size from 35 to 50 kDA. SAP1 to SAP3 execute high activity at a low pH while SAP4 to SAP6 execute high activity at a high pH (Naglik et. al., 2003). The different optimal pH levels for each SAP may be an evolutionary advantage for proteinases to adapt to varying kinds of environment. For instance, the pH of the oral cavity is different than the pH of the gastrointestinal tract, and C. albicans would have to demonstrate the ability to survive in each one. SAP is also significant for facilitating the adherence of C. albicans onto host cells and tissues followed by the degradation of host proteins (Naglik et. al., 2003). It is also found to play some role in hyphal formation and in the regulation of phenotypic switching, which enhances C. albicans’ virulence (Naglik et. al., 2003). The molecular mechanisms are unclear, however, and more research is necessary. Morphogenesis The characteristic that C. albicans is dimorphic and can convert from yeast buds to filamentous hyphae/pseudohyphae under varying conditions indicates another virulent property. One study of an isolated C. albicans strain that was regulated for suppressed hyphal growth was found to be avirulent in an animal mouse model compared to its wild type (Calderone & Gow, 2002). Moreover, the normal environment of the vagina is a classic example to illustrate the non-pathogenic and pathogenic nature of C. albicans. In normal healthy individuals, C. albicans exists as yeast whose growth is mainly suppressed by beneficial bacteria that reside in the vagina. When C. albicans turns virulent, however, its morphology changes into filamentous hyphae (Brown, 2002). Phenotypic Switching The ability for C. albicans to undergo phenotypic switching is a postulated mechanism of virulence. Switching could changes in the expression of cell-surface antigens, tissue affinities of the organism, enzyme production, and drug sensitivity (Calderone & Gow, 2002). Switching also had profound effects on the susceptiblity to antifungal drugs, producing strains that are resistant (Vargas et. al., 2000). Zarqa Private UniversityBiology 4223 – The Fungi

Virulence assay of different C. albicans strains using the skin equivalent (AST 2000) Figure 1. skin equivalent before infection Figure 2. Infection with pathogenic clinical isolate of C. albicans. After 48 h the yeast penetrates the skin equivalent and destroys the tissue This slide illustrates the responses to different C. albicans strains using a skin sample. In Figure 1, there is no infection, and the skin sample is healthy. In Figure 2, the skin has been infected with a pathogenic strain of C. albicans. The skin equivalent is penetrated and tissue is destroyed. In Figure 3, non-pathogenic strains of C. albicans have infected the skin equivalent, but not change is observed. (Fraunhofer, 2002) Hence, the virulence factors that were mentioned in the previous slide must be significant in the success of infection of C. albicans. Figure 3. Infection with non-pathogenic C. albicans. This strain is not able to penetrate into the tissue and thus behaves as avirulent as shown in the mouse model of systemic infection. Zarqa Private UniversityBiology 4223 – The Fungi (Fraunhofer, 2002)

MORPHOGENESIS Figure 1. Morphogenesis. Morphogenesis in C. albicans is a pivotal virulence factor that allows rapid multiplication and subsequent dissemination in host tissue. ( This slide shows the different routes of morphology that C. albicans may take according to the environment it is in. Figure 2. Morphogenic forms of Candida albicans Zarqa Private UniversityBiology 4223 – The Fungi

Subcutaneous Infections
Fungal Activity Fungi normally saprobic Introduced through wounds Adapt to the human animal by changes in morphology physiology Zarqa Private UniversityBiology 4223 – The Fungi

Chromoblastosis Common among barefoot peoples of the tropics Soil hyphomycete species Enters human by thorns or wood slivers Fungus grows  host cells respond by rapid cell division  wart-like growths on feet or legs Zarqa Private UniversityBiology 4223 – The Fungi

Mycotic Mycetoma Disease of barefoot tropical people Entry: wound on foot Attacks various tissues Stimulates formation of tumor Compact fungal colonies form within tumor Zarqa Private UniversityBiology 4223 – The Fungi

Skin ruptures and some colonies extrude Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycoses Introduction Caused by . . . Specialized pathogens Dimorphic One form outside the host Another form inside the host Opportunistic saprobes Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycoses Dimorphic Pathogen Mycoses Histoplasmosis Histoplasma capsulatum Grows on bird droppings, chicken manure, bat guano Conidia inhaled  primary lung infection  almost always fatal until recently Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycoses Histoplasma capsulatum Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycoses Coddidioidomycosis Coccidioides immitis Dry, saline soils Endemic to SW deserts of North America Valley fever Until recently – almost always fatal Zarqa Private UniversityBiology 4223 – The Fungi

Systemic Mycoses Infection, disease process, and clinical symptoms similar to histoplasmosis Can be effectively treated with fluconazole Zarqa Private UniversityBiology 4223 – The Fungi

Opportunistic Pathogens/Disease
General Pathogens all grow well at 37C None cause disease in well individuals Require breakdown in resistance system Complication of diabetes, AIDS, advanced cancer, sequel to steroid or antibiotic treatments Zarqa Private UniversityBiology 4223 – The Fungi

Zygomycosis Species of Zygomycota Rhizopus, Mucor, Rhizomucor Rhinocerebral mycosis Spores enter through sinuses Grows rapidly outward to the eyes and inward towards the brain Zarqa Private UniversityBiology 4223 – The Fungi

Aspergillosis Aspergillus sp. Bronchiopulmonary aspergillosis Mucus within the bronchi  severe allergic reaction Aspergilloma Forms a mycelia ball in lung cavity formed from earlier TB Zarqa Private UniversityBiology 4223 – The Fungi

Surgical intervention often required Invasive aspergillosis Severely debilitated Immunosuppressed (AIDS) Almost always fatal until recently Zarqa Private UniversityBiology 4223 – The Fungi

AIDS and Mycoses Aspergillosis Candidiases (Candidiasis seen in 2/3 of AIDS patients Cryptococcosis Zygomycosis Esophogeal candidiasis and cryptococcosis are strong indicators of AIDS Zarqa Private UniversityBiology 4223 – The Fungi

PRIMARY ANTI-FUNGAL AGENTS
Polyene derivatives Amphotericin B Nystatin Azoles Ketoconazole Fluconazole Itraconazole Voriconazole Zarqa Private UniversityBiology 4223 – The Fungi

Azoles There are a few rare serious side effects from Itraconazole and Fluconazole Zarqa Private UniversityBiology 4223 – The Fungi

5-fluorocytosine (5-FC)
Interferes With RNA Synthesis Zarqa Private UniversityBiology 4223 – The Fungi

MECHANISMS OF ACTION Polyenes Azoles Griseofulvin 5 - FC Ergosterol in cell membrane Interfere with ergosterol synthesis Forms a barrier to fungal growth Inhibits RNA synthesis Zarqa Private UniversityBiology 4223 – The Fungi

Prof. Khaled H. Abu-Elteen

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Prof. Khaled H. Abu-Elteen

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