Human Pathogens and Antifungal drugs Flashcards
What are some immune evasion virulence factors?
Masking of PAMPs using capsules or pigments
Escape from immune cells
What are some robustness/stress resistance virulence factors?
Cell wall
Detoxification
What are some morphological transition virulence factors?
Yeast to hypha
Spore to yeast
Spore to hypha
What are some growth in host virulence factors?
37 degrees
Host derived nutrients
Adaptation to niches
What are some adhesion/invasion virulence factors?
Biofilm formation
Translocation
What are some damage virulence factors?
Physical forces
Secreted enzymes
Toxins
What are the prerequisites for life in or on humans?
The ability to grow well at 37 degrees
The ability to utilize many different carbon and nitrogen sources, and to scavenge for limiting elements
The ability to recognize and adapt to the conditions within the human host, which are very different from those outside
What happened after the asteroid hit Earth?
Fungi took over, need to decompose all of that dead matter
What do superficial/cutaneous mycoses affect?
Affects skin, hair, and nails
What do subcutaneous mycoses affect?
Affects muscle and connective tissue immediately below the skin; mainly tropical
What do systemic (invasive) mycoses affect?
Involves internal organs
Primary vs. opportunistic
What do allergic mycoses affect?
Affects lungs or sinuses
Patients may develop chronic conditions
What is a Malassezia infection?
Superficial/cutaneous
Can induce skin inflammation
Is the cause of dandruff
Obligate lipophile: colonizers around sebaceous glands
When does the maximum density of Malassezia occur?
Between the late teens and early middle age
Where do species utilizing keratin colonize and what do they cause?
Colonize hair, nails, and skin
Cause tinea (ringworm), tinea pedis (athlete’s foot), and toenail infection
Where do dermatophytes derive from?
Ascomycetes, specifically the order Onygenales in the class Eurotiomycetes
Candida is found in what percent of people?
Found in 40-60% of healthy adults and is one of the most common human-associated fungi
What is a candida infection?
Superficial/cutaneous
An ascomycete of the class Saccharomycetes
Infections are formed mostly by the yeast stage
Is the primary cause of candidiasis and thrush
What can cause serious Candida infections?
Antibiotic therapy and immunodeficiency
What do subcutaneous infections include and what fungi primarily cause them?
Include a variety of mycoses that develop in muscle and connective tissue
Mostly ascomycetes
What is Sporthrix?
A fungi that causes the subcutaneous infection sporotrichosis that is mostly acquired by traumatic injury
What other fungi can cause subcutaneous infections?
Zygomycetes
Dark hyphal fungi
Onygenales
What is a primary, systemic infection?
True fungal pathogens that can overcome the physiological and cellular defenses of the normal human host by changing their morphological form
Tend to be geographically restricted
Primary systemic fungal infections are mostly what?
Dimorphic
Who can primary systemic fungi infect?
Healthy individuals; cultures represent a severe biohazard to laboratory personnel and must be handled with extreme caution in an appropriate pathogen-handling cabinet
What is the primary site of infection of a primary systemic fungi?
Usually pulmonary, following the inhalation of conidia
Which two genera may require up to containment level 3?
Cryptococcus
Histoplasma
What is histoplasmosis?
Systemic infection
Derived from bat or bird excrement
Symptoms may mimic those of TB
Symptoms are similar to blastomycosis
What is blastomycosis?
Systemic infection
May originate from soil
Begins as asymptomatic pulmonary lesions and spreads to skin and bones
Can infect pets, jumps from pets to human
Common in subsistence communities in which hunting and fishing are daily activities
Where is the blastomycosis incidence high?
In the Kenora region
What is coccidiomycosis?
Systemic infection
Infects human lungs in dust storms
Forms large spherules which form endospores that spread the fungus further in the lungs and tissue
Can spread to the adrenal glands, bones, CNS, joints, lymph nodes and skin, and can be fatal
What are the two phases of the coccidioides life cycle?
Parasitic and saprobic
What is paracoccidioidomycosis?
Systemic infection
Infection through inhalation; widespread asymptomatic exposure but rare form can be lethal in juveniles
Most cases are men between 30-50 years old
Dimorphic switch from mycelium/conidium to yeast inhibited by physiological concentrations of the female sex hormone estradiol
Contains a high-affinity binding protein with similar properties to mammalian receptor proteins responding to steroid hormones
What are the differences between yeast and hyphal cell wall in paracoccidioides?
hyphae = beta 1-3-glycan is the major component
yeast = alpha 1-3-glucan is the major component
Blastomycosis and paracoccidioidomycosis are what type of disease?
Granulomatous diseases that can lead to extreme deformation of skin and facial features
What are opportunistic systemic infections?
Infections of the body which occur almost exclusively in debilitated patients whose normal defense mechanisms are impaired
Caused by cosmopolitan fungi which have a very low inherent virulence
What is aspergillosis?
Caused mostly by A. fumigatus
Abundant in compost, hay, and straw
Would lead to respiratory infections in people working with hay in confined spaces
Now it is one of the most frequently acquired nosocomial infections following immunosuppressive therapy
What is allergic bronchopulmonary aspergillosis?
Leads to asthmatic reactions in asthma and cystic fibrosis patients
What is pulmonary aspergilloma?
Forms balls of hyphae with host cells in the lungs
What is invasive aspergillosis?
Spreads from the respiratory tract through blood vessels into other organs, especially the brain
What is opportunistic candidiasis?
Same as the cutaneous form, but in immunocompromised patients it can enter the bloodstream
4th most common nosocomial infection
High mortality rate
What are some Candida virulence factors?
Ability to adhere to host tissue
Produces adhesins that bind to a range of host proteins
Possesses an arsenal of extracellular enzymes that break down host proteins, including antibodies, lipases, and phospholipase
Ability to switch between yeast, hyphae, and pseudohyphae
Can form diploids and triploids
What is cryptococcosis?
Opportunistic systemic infection
Through the inhalation of spores
Mostly latent or harmless, but in immunocompromised patients it can enter the bloodstream and cause meningoencephalitis
Melanin and the thick, acidic, mucopolysaccharide capsule of the yeast inhibits phagocytosis
What is pneumocystosis?
Opportunistic systemic infection
Passed from human to human in close proximity
Causes pneumonia in premature babies, malnourished infants, and immunocompromised patients
Contains cholesterol, not ergosterol, in the PM
Previously thought to be a protest
What is zygomycosis?
Opportunistic systemic infection
One of the most acute and destructive fungal infections known
Typically involves the rhino-facial-cranial area, lungs, GI tract, skin, or less commonly other organ systems
How can fungal allergic reactions be mediated?
IgE-mediated hypersensitivity
IgG-mediated hypersensitivity
Immune complex-mediated hypersensitivity
Cell-mediated hypersensitivity
What are 3 targets for antifungal therapy?
Plasma membrane = fungi mainly use ergosterol instead of cholesterol
DNA synthesis = some compounds may be selectively activated by fungi, arresting DNA synthesis
Cell wall = mammals do not have a polysaccharide-based cell wall
What are azole antifungals?
A large group of synthetic agents, which includes drugs used in bacterial and parasitic as well as fungal infections
The majority are used as a topical treatment
Widely used because of their broad therapeutic window, wide spectrum of activity, and low toxicity
Why are the Azoles a good line of defense?
They are good for most fungi and they are easily synthesized
How do azoles disrupt ergosterol synthesis?
In fungi, cytochrome P450 enzyme lanosterol 14-alpha demethylase is responsible for the conversion of lanosterol to ergosterol
Azoles bind to Erg11 inhibiting the production of ergosterol
How do Azoles act?
Through an unhindered nitrogen, which binds to the iron atom of the heme, preventing the activation of oxygen which is necessary of the demethylation of lanosterol
How do Azoles work?
They inhibit the fungal P450 enzymes reponsible for the synthesis of ergosterol
The resulting depletion of ergosterol alters the fluidity of the membrane and this interferes with the action of the membrane-associated enzymes
What is the overall effect of Azoles?
Inhibition of growth
How do polyene antibiotics disrupt existing ergosterol?
Binds sterols in fungal plasma membrane
Binding interferes with permeability and transport functions, forms a pore in the membrane
Repercussion = loss of intracellular K, Mg, sugars, and metabolites and then cell death due to electrolyte leakage
Which fungi are polyene antibiotics active against?
Most except for Aspergillus terreus and Scedosporium
What are some issues with Amphotericin B?
The metabolic fate is unknown, only 2-5% appear in the urine
Children tolerate it better than adults
What does flucytosine do to fungi?
It interferes with RNA and DNA synthesis by introducing a fluorouracil precursor to uridine triphosphate
It is introduced via a fungal-specific uptake mechanism so it doesn’t cross-react with mammalian RNA
What is the first reaction with flucytosine?
5-FC to 5-FU via cytosine deaminase
What is the second reaction with flucytosine?
Inhibition of thymidylate synthase = no dTMP, no DNA
Fluorine inhibits the synthesis of dTMP = no T in DNA
Incorporation into RNA, but F inhibits translation
What is flucytosine active against?
A limited range of fungal infections, mainly candida and cryptococcus
What is an issue with flucytosine?
Rapid resistance when it is used alone due to decreased permease (uptake) activity and altered 5-FC metabolism
What is flucytosine often used with?
AmB
What are echinocandins?
Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by inhibition of beta 1-3 D-glucan synthase
Glucan synthases are absent from mammalian tissues
Loss of cell wall glucan results in osmotic fragility
What do echinocandins contribute to?
Cell lysis at growing tips
What is echinocandin’s activity spectrum?
Candida
Pneumocystis
Aspergillus, but no fusarium
Not cryptococcus neoformans
