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Fungal Pathogenesis

                                               Medical Mycology

Fungal Pathogenesis :                                            lecture-3

·        Pathogen: microbe has ability to causing infection, some microbes are highly pathogenic ,whereas others cause disease  rarely (low pathogenic).

·        Pathogenecity : it is referred to the ability of microbe to produce disease.

·        Infection, in general , is presence and multiplication of microbe within human body ,and cause disease. In other word ,the term infection has two meaning (i) presence of pathogenic organism in the body ,(ii) symptoms of disease .

·        People gets infection or not is determined by balance number and virulence of microbe and competency of that host defense. Highly virulent microbe requires fewer number of organism to cause disease than less virulent one. 

       The infectious disease equation:  

·        Most microbial infections are communicable capable of spreading from person to person , but some are not communicable . If a disease is highly communicable ,the term contagious is applied.

·        Many infectious disease are symptomatic , also many are asymptomatic ,the clinical features are not apparent(subclinical) because the host defense have eliminated the organism before it could multiply to sufficient number to cause the symptoms of disease.

·        Opportunistic pathogen : ability of some organisms to cause disease when defense of person is reduced such as immunocompromised patients.

·        Certain infections lead to chronic carrier state , in which organism continue to grow with or without producing symptoms in the host.

·        Some infections result in latent state , after which reactivation of growth of microorganism and recurrent of symptoms may occur .

·        The subsequent infection by same organism  in  same patient is called  re-infection.

·        The infection is occurring or acquired from hospital , called nosocomial infection.

·        Three epidemiological terms are used to describe infection :

Endemic infection, that occur at low level in certain geographic areas.

Epidemic ;occur at higher  rate than usual .

Pandemic the infection spread rapidly over large area of globe (worldwide distribution).

Sources of infection :

Most pathogenic fungi are exogenous ,their natural habitats being soil,  water and organic debris.  Some pathogenic are endogenous such as Candida ,which are part of normal flora.

     Main sources of infection are ;

1.     Soil; may serves as mother source for infection of many pathogenic organisms or spores, especially fungi.

2.     Man : is common source of infection from patients or carriers. The carrier is person recovered from disease but harboring pathogenic organism in his body. Fomites are inanimate objects of patients that serves as source of pathogenic organisms.

3.     Animals ; are important source of organisms that infect human , the  organisms can transmitted from infected animals to human .The animals can be service as either reservoir or made transmission of certain organisms.

4.     plant; infected plants are considered as important source for human infection.

5.     Water; many pathogenic may be found in water.

Transmission and portal of entry:

    Portals of entry(routes of infection) :

1.     Skin barrier.

2.     Respiratory tract.

3.     Elementary tract.

4.     genital tract

Nearly all fungal infections are derived from environment, their natural habitats being soil. Infective stage of fungi is spore. Human become accidental host for fungi by the following transmission routes;

1.     direct contact :The transmission may occur through skin contact with patient or contact with infected animal or exposure to contact with  infected plant , or the infection can be occurs by trauma .

2.     Inhalation : the fungi may be transmitted by inhalation of fungal spores  .

3.     Ingestion : the fungi can be transmitted by consumption of contaminated water or food , or ingestion of poisonous mushroom.

4.     sexual contact : some pathogenic fungi  can be transmitted from person to person and cause disease during sexual intercourse or during delivery.

Pathogenesis:

Mechanisms of fungal pathogenesis are poorly understood.

·        The ability of fungi to cause disease appears to be an accidental phenomenon. The two major physiologic barriers to fungal growth within the human body are temperature and redox potential. Most fungi are mesophilic and can not grow at 37C. Similarly, most fungi are saprophytic and their enzymatic pathways function more efficiently at the redox potential of non-living substrates than at the relatively more reduced state of living metabolizing tissue. In addition, the body has a highly efficient set of cellular defenses to combat fungal proliferation. Thus, the basic mechanism of fungal pathogenicity is its ability to adapt to the tissue environment and to withstand the lytic activity of the host s cellular defenses.

·        In general, the development of human mycoses is related primarily to the immunological status of the host and environmental exposure, rather than to the infecting organism. A small number of fungi have the ability to cause infections in normal healthy humans by:

         (i)  Having a unique enzymatic capacity,

(ii) Exhibiting thermal dimorphism , the change in shape when the shift from yeast(Y)form in animal body to mold(M) in environment is known as YM shift, or change from M( in environment) to Y( in body),  which known as MY shift.

         (iii) By having an ability to block the cell-mediated immune defenses of the host.

There are then many "opportunistic" fungi which cause infections almost exclusively in debilitated patients whose normal defense mechanisms are impaired. The organisms involved are cosmopolitan fungi which have a very low inherent virulence.

·        The pathogenic fungi don’t produce potent toxin or other potent virulence factors but have  some potent substances such as;

1.     Cell wall is composed largely of carbohydrate layer as well as have glycoprotein and lipids . During infection , the cell wall have important pathogenic properties.

·        The surface components of cell wall mediate attachment of fungus to host cells.

·        Polysaccharide of cell wall may activate the complement cascades and provoke an inflammatory reaction.

·        Cell wall release immunodominant antigens that elicit cellular immune responses.

2.     capsule of some fungi is composed of polysaccharides and proteins . The capsule has important role in pathogenesis ;

·        surface mannoproteins mediate adherence to target cell in some species of fungi.

·        capsular polysaccharides of some fungi act as antiphagocytic .

3.     some fungi have melanized cell wall importing a brown or black pigment , such fungi are dematiaceous (phaeoid) . The melanin has associated with virulence.

 In addition to mycotic infections , there are two other kinds of fungal diseases ;(i) mycotoxicoses (ii)allergies to fungal spores.

Fungal toxins:

     Many fungi produce poisonous substances called mycotoxins that can cause mycotoxicoses (intoxication) and damage . the mycotoxins ars secondary metabolites .

    Generally , main dangerous fungal toxins for human;

·        Aflatoxin : is produced by Aspergillus flavus . The toxin is powerful and resistant to high temperature . when the toxin is ingested with spoiled grains and peanuts , and metabolized by liver to epoxide which a potent carcinogen that induce tumor suppressor gene leading to loss of growth control that cause liver tumor (hepatic carcinoma) and damage.

·        Amanitin : is produced by Amanita mushroom,( while Agaricus mushroom is safe for eating), mycotoxicoses occur after eating the poisonous mushroom may cause mycetismus disease ,which characterized by severe damage to liver ,kidney or bone marrow. Amanitin is potent hepatotoxin, their toxicity is bases on its ability to inhibit RNA-polymerase which prevent RNA synthesis. Cooking has little effects on potent of the toxin.

·        Ergotis : is produced by Claviceps purpura , which infects grains and produces alkaloids that cause vascular and neurologic effects.

·         Ochratoxin : is produced by Aspergillus ochraceus

·        Patutin : is produced by Penicillium claviforme and other species

·        Zearalenone :is produced by Fusarium graminearum and other species

Hypersensitivity to fungal spores

Throughout life, the respiratory tract is exposed to air-borne conidia and spores of many fungi . these particles often possess potent surface antigens capable of stimulating and eliciting strong allergic reaction. Depending on the site of deposition of allergen, a patient may exhibit rhinitis, bronchial asthma, alveolitis or general pneumonitis.

Some infected persons may become hypersensitivity to products of dermatphytes called dermatophytid (id), usually vesicle on the body , especially on hands (fingers), the lesion do not contain hyphae                   (no fungus is present in lesion). the lesion is responses to circulating fungal antigens, the patient with this lesion often are atropic and elevated IgE. the patient with tinea infection show positive for trichophytin skin test.

    Allergies to spores of aspergillus are manifested by asthmatic reaction , bronchoconstriction mediated by IgE, esionophilia , and (wheal and flare) reaction.

Treatment and prevention :

     1. corticosteroids or attempts to desensitize patient.

     2. avoidance of affending allergen .