WEEK 3: INFECTIOUS DISEASES

Infection

Entry and multiplication of a microorganism within a host

Disease

Microbial factors + Host factors → Tissue injury → Clinical manifestations

Infectious dose, Route of entry, Virulence, Microbial tropism, Host immune status, Genetic susceptibility

Important determinants

Pathogen

→ Adherence

→ Colonization

→ Invasion

→ Evasion of host defenses

→ Replication

→ Tissue injury

Host

→ Innate immunity

→ Adaptive immunity

→ Inflammation

→ Tissue repair

Microorganism

must overcome physical barriers and immune defenses to establish infection

Host response

can eliminate the organism but can also contribute substantially to tissue damage

Respiratory tract, Gastrointestinal tract, Genitourinary tract, Skin, Mucous membranes, Blood, Placenta

Major portals of entry

Common mechanisms of transmission

Respiratory droplets/aerosols, Fecal–oral transmission, Direct contact, Sezual transmission, Arthropod vectors, Contaminated food/water, Vertical transmission

Route of entry

often determines which organs are initially affected and can influence the type of disease produced

Mechanisms of microbial injury

Direct cellular damage, Toxins, Enzymes, Nutrient depletion, Induction of inflammation, Immune-mediated tissue injury, Alteration of cellular growth

Immune response

may cause as much or more tissue damage than the organism itself

Microbial Virulence factors

•Adhere to host cells

•Invade tissues

•Avoid phagocytosis

•Resist complement

•Survive intracellularly

•Obtain nutrients

•Produce toxins

Capsules

inhibit phagocytosis

Adhesins

promote attachment

Protein A

interferes with antibody function

Coagulase

promotes fibrin formation

Endotoxins

triggers systemic inflammation

Innate immune response

•Skin and mucosal barriers

•Antimicrobial peptides

•Complement

•Neutrophils

•Macrophages

•Natural killer cells

•Pattern-recognition receptors

Innate immunity

responds rapidly to conserved microbial structures. Pattern-recognition receptors detect pathogen-associated molecular patterns.

Adaptive Immune Response

Humoral immunity

Cell-mediated immunity

Humoral Immunity

•B cells → antibodies

Important against:

•Extracellular bacteria

•Toxins

•Some viruses

Cell-mediated immunity

T cells → macrophage activation and cytotoxicity

Important against:

Intracellular organisms

Viruses

Mycobacteria

Some fungi

Different pathogens

require different immune mechanisms. Defects in particular immune pathways therefore predispose patients to characteristic infections.

Suppurative

Neutrophils, pus, abscess

Mononuclear

Lymphocytes, macrophages

Granulomatous

Activated macrophages, giant cells

Cythopathic

Cellular enlargement, inclusions

Necrotizing

Extensive tissue destruction

Tissue response

can provide clues about the infectious agent

Suppurative Inflammation

Characteristic findings:

•Neutrophil accumulation

•Liquefactive tissue destruction

•Pus formation

•Abscess formation

Commonly associated with:

•Staphylococcus

•Streptococcus

•Other pyogenic bacteria

Abscess

Central necrotic material

↓

Surrounded by neutrophils

↓

Granulation tissue

↓

Fibrous capsule in chronic lesions

Abscesses

represent localized collections of inflammatory cells and necrotic debris. They are especially characteristic of pyogenic bacterial infections.

Granuloma

organized collection of activated macrophages

Granulomatous Inflammation

Components:

Epithelioid macrophages

Multinucleated giant cells

Surrounding lymphocytes

Causes include:

•Mycobacterium tuberculosis

•Certain fungi

•Some parasites

•Foreign materials

Caseating granuloma

TB classically produces?

Extracellular bacteria

•→ Toxins

•→ Enzymes

•→ Inflammation

•→ Tissue destruction

Intracellular bacteria

•→ Survival inside macrophages

•→ Cell-mediated immunity

•→ Granulomatous inflammation

Bacterial Infections

extracellular and intracellular

Exotoxins, endotoxin

Bacterial toxins

Mainly bacteria

source of exotoxin

Gram-negative bacteria

source of endotoxin

Protein

nature of exotoxin

LPS

nature of endotoxin

Highly specific

specificity of exotoxin

Broad systemic effects

specificity of endotoxin

Very high

potency of exotoxin

Low

potency of endotoxin

Neurologic, GI, Cytoxic

effects of exotoxin

Fever, inflammation, shock

effects of endotoxin

Possible

exotoxin toxoid vaccines

No

endotoxin toxoid vaccines

Viral Infections

•Attach to host-cell receptors

•Enter cells

•Replicate

•Assemble

•Exit the cell

Mechanisms of injury

•Direct cytolysis

•Apoptosis

•Altered cellular function

•Immune-mediated injury

Histologic clues

•Nuclear inclusions

•Cytoplasmic inclusions

•Multinucleated giant cells

•Cellular enlargement

Viral Cytopathic effects

•Cell swelling

•Cell lysis

•Syncytium formation

•Inclusion bodies

•Chromatin margination

•Apoptosis

Fungal Infections

•Yeasts

•Molds

Dimorphic fungi

Clinical Categories

•Superficial

•Cutaneous

•Subcutaneous

•Systemic

•Opportunistic

Important organisms

•Candida

•Aspergillus

•Cryptococcus

•Histoplasma

Coccidioides

Opportunistic fungal infections

particularly important in patients with impaired cellular immunity or neutrophil dysfunction

Protozoa, Helminths

parasitic infections

Protozoa

unicellular organism

Helminths

multicellular worms

Common tissue response

•Eosinophilic inflammation

•Granuloma formation

•Fibrosis

•Mechanical obstruction

•Nutritional depletion

Eosinophil-rich inflammation

Tissue-invasive helminths commonly provoke

Mycobacterium tuberculosis

Tuberculosis

Pathogenesis

Inhalation

↓

Alveolar macrophage uptake

↓

Intracellular survival

↓

T-cell activation

↓

Macrophage activation

↓

Granuloma formation

Classic lesion

Caseating granuloma

•

•Central caseous necrosis

•Epithelioid macrophages

•Langhans-type giant cells

•Peripheral lymphocytes

HIV/ AIDS

•CD4⁺ T lymphocytes

•Macrophages

•Dendritic cells

Progressive immune dysfunction

HIV infection

↓

CD4⁺ T-cell loss

↓

Impaired cellular immunity

↓

Opportunistic infections + malignancies

Major complications of aids

•Opportunistic infections

•Kaposi sarcoma

•Certain lymphomas

•Neurologic disease

•Wasting

Pneumocystis jirovecii

Pneumonia

Cryptococcus

Meningitis

Candida

mucosal/ systemic infection

CMV

Retinitis, GI Disease

Toxoplasma

brain lesions

Microbes

cause injury directly and indirectly through immune responses.

Histopathologic patterns

help identify the class of pathogen

Bacteria

commonly produce suppurative or necrotizing inflammation

Viruses

produce characteristic cytopathic changes

Granulomatous inflammation

fungi and mycobacteria frequently produce?

Immunodeficiency

dramatically changes the spectrum and severity of infection.