I. INTRODUCTION

After adherence to the mucous membranes, many pathogenic bacteria and viruses multiply on (or in ) the epithelial surface causing localized disease. Others have specialized virulence factors and strategies that allow them to invade across the epithelial cell surface (local invasion), or invade across the epthelial cell surface and spread systemically through the body.

II. VIRAL INFECTIONS

A. Review of viral entry into cells.

1. Direct penetration

2. Fusion with the cell membrane

3. Receptor mediated endocytosis

B Viral infections localized to the epithelial cell surfaces

1. Localized infections of the mucous membranes- “The HIT AND RUN” Infection Strategy

2. Warts – a localized viral infection of the skin

III. BASIC PRINCIPLES: HOW MICROBES SPREAD SYSTEMICALLY THROUGH THE BODY

A. What's under the epithelial cell surface?

1. The basement membrane

2. If the microbe reaches the subepithelial tissues it is exposed to 3 important host defenses:

a. Tissue fluids

b. The Lymphatic System

c. Phagocytic Cells

INFLAMMATION

B. Methods of systemic spread:

1. Direct Spread

2. Via the Lymphatics

a. Lymphatic vessels

b. Lymph nodes

c. Thoracic Duct ------Blood

3. Via the Blood

a. By directly entering a subepithelial vessel

b. By entering via the lymphatics and the lymph nodes

c. Microbes localize in the organs of the Reticuloendothelial (RES) System. What happens to pathogens that pass in the blood through the RES?

1. They many not be phagocytosed.

2. They are taken up and killed.

3. They are taken up and grow in the macrophages and/or the endothelial cells (cells that line the blood vessels)

4. There is transfer of the microbes from the macrophages to the neighboring tissue cells. (If into the hepatic cells – hepatitis)

d. What forms are microbes carried in the blood?

1. Free in plasma

2. Associated with white cells

3. Associated with red cells

4. Associated with platelets

4. Other routes of systemic spread:

a. Invasion of the CSF:

1. By the bloodstream (hematogenous spread)

2. By peripheral nerve fibers (neuronal spread)

b. Spread from organ to organ in the pleural or peritoneal cavities

C. SYSTEMIC VIRAL INFECTIONS (Steps in the Process):

1. Entry into the Body and Infection of the mucous membranes

Why do some pathogens invade and others don't?????

a. Temperature

b. The site of budding (for viruses)

c. Microbes must reach susceptible target tissues

i. Sometimes a different target tissue from where they started

ii. Sometimes they end up back where they started from

d. Infections may be confined because they are kept in check by host defenses.

2. Viruses reach the blood via a subepithelial vessel or the lymphatics

a. Primary viremia: May be short and silent for viruses

b. Growth of the viruses in primary target tissue

c. Reseeding of viruses into the blood

d. Multiplication in secondary target tissues

e. There may or may not be exit from the body

IV. Examples of systemic viral infections: measels, polio and mousepox

V. RASHES: There may be entry into the skin from above or below:

A. Through the epidermis:

1. A variety of skin and soft tissue infections

2. Formation of papillomas – warts

B. Through the dermis (caused by infections or toxins):

1. Macule

2. Papule

3. Vesicle

C. Ulcer

VI. Bacterial invasion and spread

A. One way of categorizing bacterial pathogens is whether they are primarily extracellular or intracellular pathogens. These two terms have broad and narrow meanings:

1. Extracellular pathogen – a bacterial pathogen that can grow and reproduce freely, and may move extensively within the tissues of the body.

(A more narrow meaning and one that we will use in this class- to describe the relationship between a pathogenic bacterium and the professional phagocytic cells (the neutrophils, monocytes and macrophages). In this context, an extracellular pathogen is one that cannot survive inside the phagocyte once it has been ingested.

2. Intracellular pathogens –pathogens that can live inside of host cells, especially phagocytes.

(Extracellular phases of intracellular pathogens: Note that no organism can be wholly intracellular all the time. If it is to replicate successfully (whether it is a viral or bacterial pathogen), there must be transmission between the host's cells and some exposure to the extracellular environment)

(A more narrow meaning with regards to the interaction of bacterial pathogens and the phagocytic cells. An intracellular pathogen is one that is able to survive and grow inside the professional phagocyte.)

a. Obligate intracellular pathogens - viruses,the rickettsiae, and the Chlamydiae, and includes some bacterial pathogens such as M. tubercuclosis, M. leprae, Legionella pneumophila, and Listeria monocytogenes.

b. Facultative intracellular pathogens – can survive and multiply inside or outside of professional phagocytes.

B. PATTERNS IN BACTERIAL PATHOGENESIS

1. Colonization of the mucosal surfaces with:

a. Local destruction of the microvilli – enteropathogenic E. coli

b. Production of an exotoxin that acts:

i. Locally – V. cholerae and cholera toxin (acts on the gut mucosa producing diarrhea)

ii. Systemically – C. diptheriae and diptheria toxin (C. diptheriae colonizes the bloodstream and acts on remote organs in the body especially the heart)

2. Initial colonization of the mucosal surface followed by invasion across the mucous membranes:

(Remember: The ability of bacterial pathogens to cross the mucous membranes either intracellularly or intercellularly) and reach the deeper tissues of the host is associated with specific virulence factors. Passive carriage can be accomplished without virulence factors – opportunistic pathogens.

1. Bacterial pathogens invade intercellularly with the help of enzymes:

a. hylauronidase - allow the bacteria to invade intercellularly by destroying the tight junctions.

b. collagenase – (formed by clostridia that cause gas gangrene) causes the breakdown of collagen, which is the ground substance of bone, skin, and cartilage. Helps with spread from the initial site of infection.

c. protease

Other enzymes and toxins associated with invasion once the microbes have breached the mucous membranes:

d. coagulase – produced by staphylococci; causes the coagulation of plasma, which produces a fibrin clot.

e. streptokinase – activates the proteolytic enzyme plasmin – which causes the dissolution of blood clots and, thus, allows the spread of streptococci. There is an essentially identical substance produced by the staphylococci that is called staphylokinase.

f. DNAses

g. hemolysins – damage RBC membranes releasing iron (a needed nutrient for microbial growth)

h. leukocidins – kill white blood cells

2. Bacteria invade directly into the epithelial cells with the help of a bacterial cell surface protein – invasin.

3. Bacteria invade by entering through the M cell