High Yield Exam 2

Basic Fungal Morphological Types (with examples) (Nash)

Morphological Type	Description	Species Examples
Yeast	Single-celled, spherical; reproduce by budding	Candida, Cryptococcus
Pseudohyphae	Elongated yeast cells that look like hyphae; grow by budding	Candida
Hyphae	Filamentous structures; grow by apical extension	Aspergillus (septate), Mucor (non-septate)
Spherule	Sac filled with endospores formed in host	Coccidioides
Dimorphic fungi	Can exist as yeast or hyphae depending on environment (important for disease)	Histoplasma, Blastomyces, Coccidioides, Candida, Cryptococcus

Dimorphism is important for disease — e.g., invasive Candida = hyphal form, mucosal candidiasis = yeast form

Three Basic Patterns of Diseases Caused by Fungi (Nash)

Fungal diseases are classified based on depth of infection:

Disease Type	Location	Examples	Notes
Superficial	Outer dead skin layer (stratum corneum), hair, nails	Tinea pedis, onychomycosis	Not life-threatening
Cutaneous / Mucosal	Skin below stratum corneum or mucosal surfaces	Chromoblastomycosis, oral thrush (Candida)	Can cause disfigurement
Systemic	Deep tissues / sterile body sites	Endemic: Coccidioides, Histoplasma, Blastomyces; Opportunistic: Aspergillus, Candida, Cryptococcus	Can be life-threatening

• Endemic systemic infections can occur in healthy people.

• Opportunistic infections occur when host defenses are compromised.

Conditions That Predispose to Opportunistic Fungal Infections (Nash)

Predisposing Condition	Why It Increases Risk
Immunodeficiency (AIDS, SCID, transplant immunosuppression)	Reduced immune response
Bone marrow suppression / cancer therapy	Reduced immune cells
Organ dysfunction	Reduced fungal clearance
Chronic lung disease (COPD, CF)	Impaired clearance of spores
Diabetes mellitus	Impaired immune function
Broad-spectrum antibiotics	Loss of competing microbiota
Age (neonates, elderly)	Weak immune defenses
Skin trauma / burns / surgery	Loss of barrier

Opportunistic fungi take advantage of breakdown of normal host defenses.

General Properties That Enable Fungi to Cause Disease (Nash)

Fungal pathogenicity depends on several properties:

Property	Description	Examples
1. Survival at body temperature	Many fungi cannot grow at 37°C → limits infection	Pathogenic fungi can grow at body temperature
2. Attachment & invasion	Adhesion molecules bind host proteins	Candida Int1p binds fibronectin/C3b; ALS proteins bind epithelial/endothelial cells
3. Survival in tissues / inside cells	Resist killing by phagocytes	Histoplasma survives in phagocytes; Cryptococcus capsule; melanin & catalase protect from oxidative burst
4. Invasion & dissemination	Tissue penetration and spread	Hyphal form of Candida; degradative enzymes
5. Enzyme production	Tissue destruction	Aspergillus secretes elastases, proteases, lipases

Release of degradative enzymes is one of the most important mechanisms for tissue invasion and destruction.

Role of Innate Immunity Defense Against Fungi (Nash)

First-line defenses:

• Skin and mucosal barriers

• Secretions (mucus, lysozyme)

• Normal microbiota (microbial antagonism)

Innate immune responses:

Component	Function
Epithelium & endothelium	Recognize fungi and release cytokines
Complement, defensins	Opsonization and killing
Macrophages & neutrophils	Phagocytose and kill fungi
NK cells, γδ T cells	Early immune response
Dendritic cells	Present antigen → activate adaptive immunity

Phagocytes:

• Kill spores, yeasts, hyphae

• Deplete nutrients (e.g., IDO depletes tryptophan)

Role of Adaptive Immunity Defense Against Fungi (Nash)

Response Type	Effect
TH1 (pro-inflammatory)	Activates phagocytes, CD8 T cells, memory response
TH2 / TReg (anti-inflammatory)	Reduces phagocyte activity, reduces inflammation, promotes antibody production
Granuloma formation	Indicates T-cell mediated immunity (e.g., endemic fungi like Coccidioides)
Type IV hypersensitivity	Seen with fungal skin tests

Antibodies do NOT provide strong protection against fungal reinfection.

How Fungal Binding to Different Receptors Causes Pro- vs Anti-Inflammatory Responses

Fungal PAMPs (immunogens)

• β-glucans

• Mannose polymers (GXM)

• Phospholipomannan (PLM)

Host PRRs

PRR	Type
TLR-2	Pattern recognition receptor
TLR-4	Pattern recognition receptor
TLR-9	Pattern recognition receptor
Dectin-1	β-glucan receptor
Mannose receptor (MR)	PRR
DC-SIGN	PRR
CR3	Complement receptor
Fc receptor	Antibody receptor

Pro- vs Anti-Inflammatory Signaling

Receptor Interaction	Response
TLR-2 + TLR-4	Pro-inflammatory
TLR-2 + Dectin-1	Pro-inflammatory
MR + CR3 or FcR	Pro-inflammatory
TLR-2 alone	Anti-inflammatory
MR alone	Anti-inflammatory
FcR ± CR3	Anti-inflammatory
Single PRR binding	Weak response → fungus survives

Location matters — Candida interaction with DC → pro-inflammatory, but in Peyer’s patches → anti-inflammatory.

Mechanisms by Which Fungi Block Pro-Inflammatory Responses (Nash)

Mechanism	Example
Shedding PAMP molecules to saturate PRRs	Pneumocystis sheds gpA → saturates PRRs
Inducing PRR shedding from host cells	gpA causes PRR shedding
Capsule shedding → anti-inflammatory signaling	Cryptococcus sheds GXM
Partial activation of TLR pathways	GXM only partially activates TLR4 → immunosuppressive

Shedding fungal molecules prevents multi-receptor activation → blocks pro-inflammatory response.

What are the basic fungal morphological types and how do they grow + Examples of each + Dimorphism importance? (Nash)

• Yeast – single-celled; reproduce by budding, Ex: Candida, Cryptococcus

• Pseudohyphae – elongated yeast; grow by budding but resemble hyphae, Ex: Candida

• Hyphae – filamentous; grow by apical extension (division only at tip), Ex: Aspergillus, Mucor

• Spherule – sac filled with endospores (formed in host), Ex: Coccidioides immitis

• Dimorphic fungi – exist as yeast or hyphae depending on environment; dimorphism often important for disease, Ex: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis

Different morphological forms are associated with different disease types:

• Candida yeast form → mucosal disease (thrush)

• Candida hyphal form → invasive candidiasis

What are the three basic patterns of fungal disease + Examples? (Nash)

1. Superficial – outer dead skin, hair, nails

2. Cutaneous/mucosal – skin below stratum corneum or mucosal surfaces

3. Systemic – deep tissue infections in sterile body sites

Type	Location	Examples
Superficial	Stratum corneum, nails, hair	Tinea pedis (athletes foot), onychomycosis
Cutaneous	Sub-epidermal tissue	Chromoblastomycosis
Mucosal	Mouth, GI tract, vagina	Oral candidiasis (Candida albicans)

• Systemic mycoses = deep tissue infections

• Endemic fungi infect healthy people (usually lung infection after inhalation):

  • Coccidioides immitis

  • Histoplasma capsulatum

  • Blastomyces dermatitidis

• Opportunistic fungi infect immunocompromised:

  • Aspergillus fumigatus

  • Candida albicans

  • Cryptococcus neoformans

How do fungi establish infection in host tissues? (Nash)

Survival and growth at body temperature

• Many fungi cannot grow at 37°C → limited to superficial infections

Attachment and invasion

• Adhesion molecules:

  • Candida Int1p binds fibronectin and C3b

  • ALS proteins (Als1p, Als3p) bind endothelial and epithelial cells

How do fungi survive in tissues or inside host cells? Give examples. (Nash)

• Some fungi survive and replicate inside phagocytes:

  • Histoplasma capsulatum survives in macrophages

• Some resist killing:

  • Cryptococcus neoformans → thick capsule

  • Many fungi produce melanin and catalase → protect from oxidative burst

How do fungi invade and disseminate through tissues? (Nash)

• Hyphal growth → invasion (e.g., Candida hyphae)

• Chemotropism → growth toward damaged tissue

• Thigmotropism → growth along surfaces

• Release of degradative enzymes → major mechanism of tissue destruction

  • Example: Aspergillus secretes elastases, proteases, lipases

What are the first-line innate defenses against fungi? (Nash)

• Skin and mucosal barriers

• Secretions (mucus, lysozyme)

• Normal microbiota (microbial antagonism – e.g., lactobacilli produce acids that inhibit fungi)

What innate immune responses occur after fungal invasion? (Nash)

• Epithelium and endothelium recognize fungi → cytokine release

• Complement, collectins, defensins → opsonization and killing

• Recruitment of:

  • Macrophages

  • Neutrophils

  • NK cells

  • γδ T cells

• Dendritic cells → bridge to adaptive immunity

Fungal PAMPs: β-glucans, mannose polymers (GXM), phospholipomannan (PLM)
Host PRRs: TLR-2, TLR-4, TLR-9, Dectin-1, MR, DC-SIGN, CR3, FcR

What is the role of adaptive immunity in fungal infections? (Nash)

• TH1 responses (pro-inflammatory):

  • Activate phagocytes

  • Activate CD8 T cells

  • Produce memory response

  • Granuloma formation

  • Type IV hypersensitivity

• TH2/TReg responses (anti-inflammatory):

  • Reduce phagocyte activity

  • Reduce leukocyte migration

  • Promote antibody production

• Antibodies help opsonization but do not provide strong protection against reinfection

How do PRR interactions trigger pro-inflammatory responses to fungi (Candida example)? How do PRR interactions trigger anti-inflammatory responses? (Nash)

Pro-inflammatory responses occur when multiple PRRs are activated, especially:

• TLR-2 + TLR-4 → MYD88 pathway → pro-inflammatory

• TLR-2 + Dectin-1 → β-glucan recognition → pro-inflammatory

• MR + CR3 or FcR → pro-inflammatory

Anti-inflammatory responses occur when only one PRR is activated:

• TLR-2 alone → anti-inflammatory

• MR alone → anti-inflammatory

• FcR ± CR3 → anti-inflammatory

• Example: Candida binding only to CR3 → organism survives phagocytosis

Mechanisms fungi use to block pro-inflammatory responses (Nash)

Shedding fungal PAMP molecules → saturate PRRs → prevent multiple receptor activation

• Example: Pneumocystis jirovecii sheds gpA protein

Induce PRR shedding from host cells

• Pneumocystis gpA can cause PRRs to be shed from host cell surface

Capsule shedding → anti-inflammatory signaling

• Cryptococcus sheds GXM capsule material → anti-inflammatory response

During fungal infection, what are the main fungal immunogens and host receptors involved? (Nash)

Fungal Immunogen (PAMP)	Host Receptor
β-glucans	TLR-2, Dectin-1
Mannose polymers (GXM)	TLR-4, MR
Phospholipomannan (PLM)	TLRs
Opsonized fungi	CR3, FcR

What immune cells and cytokine responses are involved in pro- vs anti-inflammatory responses? (Nash)

Response	Cells	Cytokine/Effect
Pro-inflammatory	Macrophages, neutrophils, DC, NK, TH1	Activate phagocytes, inflammation, granulomas
Anti-inflammatory	TReg, TH2	Reduce phagocyte activity, inhibit leukocyte migration, antibody production

General Clinical Features of Malaria (Nash)

Major Clinical Features

Feature	Cause
Cyclic spiking fevers (every 1–3 days)	RBC infection → RBC rupture → merozoite release
Fever	TNF-α and IL-1 released by macrophages in response to merozoite release
Headache	Systemic inflammatory response
Chills	Cytokine release
Vomiting	Systemic illness

Timing: Symptoms begin 10–15 days after mosquito bite.

Severe Malaria Disease Manifestations (Nash)

Severe Manifestation	Mechanism
Anemia	RBC destruction + suppression of erythropoiesis
Ischemic injury	Infected RBCs adhere to endothelium → block small vessels
Organ damage	Brain, kidney, lung, GI tract
Cerebral malaria	Most severe → caused by P. falciparum
Death	Almost all deaths from P. falciparum

RBC aggregation → blocked blood vessels → tissue hypoxia.

Four Most Common Plasmodium Species

Species	Fever Pattern	Notes
P. vivax	Every 2 days (tertian fever)	Common
P. ovale	Every 2 days (tertian fever)	Similar to vivax
P. malariae	Every 3 days (quartan fever)	Chronic infection
P. falciparum	Every 3–4 days or continuous	Most severe, cerebral malaria

Microbiologic Features of Plasmodium (Nash)

Feature	Description
Organism type	Eukaryotic unicellular parasite
Genome	Haploid for most of lifecycle
Chromosomes	14
Lifestyle	Obligate parasite
Morphology	Polymorphic (different forms in lifecycle)
Hosts	Mosquito (primary host), human (intermediate host)

Polymorphic = different morphology at different lifecycle stages.

Malaria Primary vs Intermediate Host (Nash)

Host	Role
Mosquito	Primary (definitive) host → sexual reproduction
Human	Intermediate host → asexual reproduction

Malaria Extracellular vs Intracellular Stages in Humans (Nash)

Stage	Location	Extracellular or Intracellular
Sporozoite	Blood → liver	Extracellular (short time)
Liver stage	Hepatocytes	Intracellular
Merozoite	Blood	Extracellular (~10 min)
Trophozoite	RBC	Intracellular
Schizont	RBC	Intracellular
Gametocyte	RBC	Intracellular

Most of lifecycle is intracellular → immune evasion.

Which Stages Trigger Adaptive Immunity in Maria? Which Stage That Causes Fever Spikes? (Nash)

Likely stages:

• Sporozoites (extracellular)

• Merozoites (extracellular)

• Proteins on surface of infected RBCs

Because antibodies can only target extracellular stages or exposed antigens.

RBC rupture → merozoite release → macrophages release TNF-α & IL-1 → fever spike.
This occurs every time schizont ruptures RBC.

Innate Human Resistance to Malaria (Nash)

Most effective natural defense = inherent resistance due to:

• Missing receptor used by parasite

• RBCs that are poor host cells

Examples

Resistance Mechanism	Example
RBC receptor deficiency	Duffy antigen deficiency
RBC receptor abnormality	Glycophorin A abnormality
Abnormal RBCs	Sickle cell trait
Enzyme deficiency	G6PD deficiency
RBC disorders	Thalassemia

These make RBCs poor host cells for parasite.

Acquired Protective Immunity in Malaria (Nash)

Primary Mechanism

Antibodies:

• Against parasite

• Against proteins on infected RBC surface

• May block parasite entry into cells

• May prevent blood-stage infection

Why Immunity Develops Slowly

Reason	Explanation
Short extracellular stage	Merozoites extracellular ~10 min
Antigenic diversity	Many different parasite antigens
Antigen mutation	Parasite surface proteins mutate

Therefore immunity develops gradually over lifetime in endemic regions.

Challenges for Malaria Vaccine (Nash)

Challenge	Explanation
Different receptors used to enter cells	Hard to block all
Highly polymorphic surface antigens	Antigen variation
Short extracellular stage	Limited antibody exposure
Intracellular lifecycle	Hidden from immune system
Antigen mutation	Immune escape

Full Life Cycle Summary Plasmodium Lifecycle (Nash)

In Mosquito

1. Mosquito ingests gametocytes

2. Gametes fuse → zygote

3. Zygote → ookinete

4. Ookinete → oocyst

5. Oocyst releases sporozoites

6. Sporozoites migrate to salivary glands

In Human

1. Mosquito injects sporozoites

2. Sporozoites infect liver cells (hepatocytes)

3. Develop into merozoites

4. Merozoites infect RBCs

5. RBC stage: trophozoite → schizont → merozoites

6. RBC ruptures → merozoites infect new RBCs

7. Some become gametocytes → infect mosquito

Dormant liver stage: hypnozoite → causes relapse

How Humans Acquire Immunity to Malaria (Nash)

Mechanism	Description
Antibodies to parasite	Block infection
Antibodies to infected RBC surface proteins	Reduce severity
Gradual exposure	Immunity develops over time
Innate resistance	Genetic traits
Prophylactic drugs	Prevent infection

Immunity does not eliminate parasite, but reduces disease severity.

What type of bacterium is Mycobacterium tuberculosis? (Eoh)

Small (~2 µm), aerobic, non-motile, rod-shaped bacillus that is acid-fast, slow-growing, and uses humans as its only known host/reservoir.

Why is M. tuberculosis acid-fast?

Because its cell envelope contains mycolic acids, which are long, waxy lipids that retain carbol fuchsin dye during acid-fast staining.

What are the main layers of the M. tuberculosis cell envelope?

Plasma membrane → Peptidoglycan → Arabinogalactan → Mycolic acid layer → Glycolipids → Capsular layer

MAP= Mycolic acid – Arabinogalactan – Peptidoglycan