15. Microbial Infections I

What are the steps in microbial disease?

A
F
C
S

• acquire access to a portal of entry

• find a target

• colonize

• spread

Where do microbes encounter their targets?

mucosa, mucocutaneous junctions, or skin such as epithelial cells, tissue-associated leukocytes, or tissue-associated substances such as mucus

Why do microbes colonize their targets? What are a common target? What else is also possible?

to sustain and or amplify the encounter or cross the barrier system to gain access to targets located locally; leukocytes; entry into neurons

Where can microbes spread?

L
E
R
S

• locally

• enter regional blood and or lymphatic vessels and travel as cell-confined microbes inside lymphocytes, macrophages, or dendritic cells or as cell-free microbes

• regional lymph nodes

• systemically within lymphatic vessels and or to the blood vascular system

True or false: Microbes encounter, colonize, and invade new populations of target cells that are unique to a specific organ system and cause dysfunction and or lysis of target cells and disease.

true

molecules produced by microbes that enable them to replicate and cause disease

virulence factors

What do virulence factors include?

G
G
O

• glycoproteins

• glycolipids

• other types of molecules that are present in the structure of microbes

Some of these virulence factors are ________ to the ________ ________ of microbes. Other factors are ________ by microbes using the ________ ________ of the target cell as needed to ________.

integral; biologic structure; synthesized; metabolic processes; replicate

What are the functions of virulence factors?

C
I
E
S
A

• colonize target substances, cells, and or tissues

• invade target substances, cells, and or tissues

• evade barrier systems and defense mechanisms

• suppress innate and adaptive immune responses

• acquire nutrition from target substances, cells, and or tissues

What virulence factor allows for colonization?

adhesions

What virulence factor allows for invasion?

invasins

What virulence factor allows for evasion?

enzymes, toxic molecules

What virulence factor allows for suppression?

enzymes, toxic molecules

What virulence factor allows for acquisition?

siderophores

What are the portals of entry for microbes?

A
R
U
I
E
E

• alimentary system

• respiratory system

• urogenital system

• integumentary system

• ear

• eye

How do the microbes then gain access to broader expanses of mucosa?

via normal physiologic processes

What concept is central to pathogeneses of infectious diseases?

ability of microbes to reach a site in the body that has target cells or substances suitable for their growth and replication

True or false: Within each portal of entry, numerous sites contain potential target cells for microbes.

true

The alimentary system has diseases that occur where? Why is this significant?

O
T
E
S
S
C
L

• oral cavity

• tonsils

• esophagus

• stomach

• small intestine

• cecum

• large intestine

some microbes must travel within the alimentary system, often for a great distance, to rach their initial encounter target cells

When microbes initially encounter cells and tissues at portals of entry, what is colonization (infection) dependent on?

creating an initial nidus to establish, sustain, amplify, and, if needed, spread the microbe

Where do microbes reach? Then what happens?

basal side of epithelial cells; encounter other mucosal, mucocutaneous and cutaneous cells and tissues, where they may again replicate to sustain, amplify, and or spread the microbe

From where are microbes able to spread locally (submucosa and dermis and associated lymphoid tissues), regionally (lymph nodes), and or systemically (organ systems) to other target cells and cause disease?

these initial sites

general term used to categorize lymphoid nodules composed of lymphocytes, macrophages, and dendritic cells that are located in mucosa and submucosa of many organ systems and each of these cell types can serve as target cells

mucosa-associated lymphoid tissues (MALT)

modified epithelial cells of intestinal crypts

microfold cells (M cells)

In GALT, what are the nodules covered by?

microfold cells (M cells)

What is the function of M cells?

transfer luminal antigens across the mucosa to dendritic cells and immune cells (macrophaes and lymphocytes) in the nodule

How do microbes enter the alimentary system?

through ingestion

Once ingested, where are microbes trapped? What must they do?

in the mucus layer; must penetrate this layer to reach target cells

What is mucus in the alimentary system produced by? What is its purpose?

goblet cells; covers and protects microvilli

What is a favorable habitat for beneficial and competitive enteric microflora?

mucus layer

What else is the purpose of the mucus layer?

P
B

• physical barrier

• biologic barrier protecting the intestine

Serving as a biologic barrier, how does the mucus layer protect the intestine against microbes?

T
B
S
A

• thickness and viscosity

• binding to bacterial adhesins

• serving as a reservoir for immunoglobulin A (IgA) and lysozyme

• acting as a free radical scavenger

Generally, what part of the alimentary system are there more goblet cells in?

more in the large intestine than in the small intestine, and more in the ileum than in the jejunum or duodenum

What does not cover M cells? Why is this significant?

a mucus layer; microbes can readily interact with their cell membranes

True or false: Once entrapped in the mucus layer, microbes must then penetrate it to gain access to target cells for infection. Additionally, microbes also encounter mucosal fluids (gastric acid and mucins), secretions (lysozyme), and humoral mediators (immunoglobulins), and must also compete with normal microflora for resources and for receptors expressed on target cells.

true

interface between materials in the lumen of intestinal crypts and the lymphoid nodules

M cells

What is the function of M cells?

transfer luminal antigens across the mucosa to dendritic cells and immune cells (macrophages and lymphocytes) in the nodule

tissue that has afferent lymphatic vessels that drain to regional mesenteric lymph nodes

peyer’s patches (GALT)

How do microbes enter the respiratory system? How are they deposited on mucosa?

inhaled through the nostrils; based on physical properties of the agent such as size, shape, weight, and electrostatic charge

Rank these microbes from smallest to largest: fungi, protozoa, prions, viruses, and bacteria.

prions < viruses < bacteria < fungi < protozoa

In a normal functioning respiratory system, only fomites of what size can be inhaled into bronchioles, alveolar ducts, and alveoli? What is the function of these structures?

~ 1 um or less (viruses and some bacteria); oxygen-carbon dioxide (O2-CO2) exchange portion of the respiratory system

When fomites are inhaled, what do they first encounter? What happens once this occurs?

nasal turbinates; movement of air through the turbinates causes centrifugal turbulence, which forces then against mucosa where they are trapped in the overlying mucus layer for removal by the mucociliary apparatus

If the size of the fomites allows them to pass through the turbinates, ________ ________ pushes fomites against ________ ________, where they are trapped in the ________ ________ for removal.

inertial turbulence; airway mucosal; mucus layer

True or false: Depending on the species, airways can branch 23 times en route from the trachea to the alveoli.

true

What is the outcome of these turbulence mechanisms?

trap fomites in the mucus layer overlying ciliated mucosal epithelial cells

When fomites are trapped in the mucus layer, what do they encounter? How are they removed?

the innate immune system; mucociliary apparatus

What is the mucociliary apparatus composed of? What is its purpose?

the mucus layer and ciliated mucosal epithelial cells; important defensive mechanism in the respiratory system

How is the mucus layer described? What does it consist of?

biphasic; consists of a luminal viscoelastic or gel layer used to trap fomites and a serous inner layer in which the cilia of ciliated mucosal epithelial cells beat

Where do the tips of the cilia slightly enter? What is the purpose of their beating?

the gel layer; moves the gel and fomites

What is the directionality of the mucus flow determined by?

the rhythmic unidirectional beating pattern of the cilia

In the nasal cavity and sinuses, what way do cilia move the mucus and debris?

caudally toward the pharynx for swallowing

In the conducive portion of the respiratory system, what way do cilia move mucus and debris?

cranially toward the pharynx for swallowing

What happens if the mucus layer and or the mucociliary apparatus are dysfunctional? What is based on this mechanism?

gravity influences the deposition of fomites; pathogenesis of many bronchopneumonias

Mucosa of the conducive portion of the respiratory system contain ________ cells and ________ and ________ ________ that commonly migrate through the mucosa and the mucus layer during their normal patterns of leukocyte trafficking. These cells serve as a ________ defense mechanism against infections.

dendritic; alveolar; tissue macrophages; primary

Microbes have ________ ________ that allow them to evade killing by phagocytes and use them like a “Trojan horse” to ________ the agent and ________ other cells and tissues.

virulence factors; spread; infect

What cells are common targets for microbes and along with mucosal epithelia, serve as the initial nidus of infection before microbes spread locally?

dendritic cells and alveolar and tissue macrophages

What does the skin consist of?

E
D
A
S

• epidermis

• dermis

• adnexa (hair follicles, sebaceous glands, sweat glands)

• subcutis

The skin serves as what type of barrier? How does it protect the body against microbes?

D
S
N

• dryness and acidity

• sebum (oils)

• normal bacterial flora

How do microbes enter through the skin? What does this allow for it to gain access to?

penetration; muscle, blood, lymphatic vessels, and ECM and connective tissue

What is another way that microbes may also be deposited directly in the blood vascular system?

penetration of a capillary, venule, or lymphatic vessel by an insect proboscis

Microbes commonly colonize and injure specific populations of cells called “________ ________".”

target cells

The specific cells and substances used as targets are often based on what?

ligand-receptor interactions in which proteins (ligands) expressed on the surface of microbes bind to receptors on membranes of target cells

Receptors expressed on target cells are usually what?

those involved in normal function of cells

How does colonization of the surface of these target cells or the invasion of cells occur?

through endocytosis/phagocytosis

Once colonization occurs, the microbe then ________ ________ of the normal metabolic systems of these cells and uses them or their resources to replicate in and or spread to other cells and or organ systems. The outcome of this process is usually ________ and or ________ of infection cells and inflammation, which leads to ________ ________.

establishes control; dysfunction; lysis; clinical disease

What are the functional groups that target cells can be placed in once exploited by microbes?

I
U
L

• initially encountered at the portals of entry

• used to spread microbes locally, regionally, or systemically

• located systemically within other organ systems

True or false: Microbes may use cells in one, some, or all of these groups to successfully complete their life cycles.

true

As a general rule, what do target cells initially encountered at portals of entry tend to be?

epithelial cells and mucosa-associated macrophages (monocytes), lymphocytes, dendritic cells, and nerve endings

Target cells that are used to spread microbes locally, regionally, or systemically tend to be what? What do they do? What is this called?

macrophages (monocytes), lymphocytes, or dendritic cells; migrate through the body and encounter other organ systems; leukocyte trafficking

From local sites, how do infected lymphocytes and macrophages spread? What occurs? What then happens?

via lymphatic vessels to regional lymph nodes; additional cells are infected and then spread via lymphatic vessels to the thoracic duct and the circulatory system; infected cells spread systemically to other organ systems in which the specific target cells are infected

True or false: Microbes can use nerve endings and fibers to spread within the nervous system and or systemically.

true

What is an important step in the pathways of spread?

crossing a mucosal (or cutaneous) barrier system

What are the distinct mechanisms a microbe may use to spread?

1. E

2. I

3. E

4. M

5. M

6. M

7. T

1. endosomes and transcytosis via M cells

2. intercellular direct entry

3. endosomes and transcytosis via other types of epithelial cells (ciliated, microvillous border)

4. mucosa-associated dendritic cells

5. migrating mucosa-associated leukocytes

6. mucosa-associated nerve endings

7. transcytosis and endosomes (microvesicles)

For some microbes, the mechanisms and pathways of colonization, replication, and spread occur at ________ location. For others, the processes involve ________ locations, including mucosa or skin at the site of the initial encounter, as well as tissues and cells located locally, regionally, and systemically.

one; multiple

How can some motile microbes enter mucosa?

by moving directly through epithelial cells or between them through intracellular junctional complexes to spread to subadjacent MALTs

What are the mechanisms used to cross mucosa at portals of entry?

M
T
I
C
D
L
N

• M cell entry

• transcytosis and endocytosis/exocytosis

• intercellular direct entry (motility)

• cell polarity

• dendritic cell entry

• leukocyte “trojan horse” entry

• nerve ending entry

What are the mechanisms used to spread systemically?

P
L

• passive manner by dispersal of cell free microbes in lymph via the lymphatic system or in plasma via the circulatory system to randomly encounter appropriate target cell

• leukocyte trafficking which occurs as cells migrate through all organ systems during their normal surveillance activities for the lymphoid system

prevent microbes from gaining access to target cells and tissues and examples are those formed by bone and meninges

structural barriers

What are microscopic structural barrier formed by?

mucosa, mucocutaneous junctions, and skin

How is skin protected from microbes?

P
K
S

• physical thickness anchored by junctional complexes

• keratinization, acidity, and oiliness (sebum) of the outer stratum corneum and stratum lucidum (antibacterial and antifungal properties)

• sloughing of keratinized cells into the environment

True or false: In contract, the physical (thickness) defensive attributes of mucosa are not as substantial as those of the skin. Skin ranges from 0.5 to 5.0 mm in thickness, whereas mucosa ranges from 10 to 100 um in thickness.

true

What do tissue-level functional barriers include?

peristalsis and mucociliary clearance

What do molecular level functional barriers include?

mucus and substances with bacteriostatic and bactericidal capabilities, such as lysozyme, defensins, surfactant, gastric acid, bile acids, and digestive enzymes

What is the function of substances and processes such as tears, cerumen, and desquamation of skin cells?

to flush microbes off mucosa and skin and out of the organ system

What is the function of mucus?

P
P

• provides nutrients for resident microflora that compete for resources needed by microbes

• provides a suitable environment for mucosa-associated leukocytes that phagocytize and kill microbes

Mucosa of the alimentary and respiratory systems are covered by what?

protective mucous gel composed predominantly of mucin glycoproteins synthesized and secreted by goblet cells

What are the functions of the mucus layer?

B
T
T
F
D

• block microbes from reaching target cells

• trap microbes so that they can be phagocytosed by mucosal macrophages and neutrophils

• trap microbes so that they can be exposed to bacteriostatic and bactericidal molecules sequestered in the mucin matrix

• facilitate phagocytosis of microbes via mucosa-associated macrophages, mucosal dendritic cells, and M cells

• deliver microbial antigens to local lymphoid tissues such as peyer’s patches or BALT and then to regional lymph nodes via afferent lymphatic drainage

What can change the function of goblet cells and the chemical composition of mucus, making mucosa more susceptible to infection?

stressors

What is the purpose of acute inflammation?

dilute and isolate microbes in edema fluid and fibrin, then phagocytose and kill them, before finally processing and presenting their antigens to effector cells of the adaptive immune response

True or false: With cell and tissue injury, the fluidic phase (vascular phase) of acute inflammation dilutes, walls off, and kills microbes via edema fluid, fibrin, and humoral factors of the complement and coagulation systems. Some of these factors, cytokines released by injured cells, and microbial debris are chemotactic and recruit neutrophils and macrophages to the site, cause vasodilation, and increase vascular permeability contributing to the fluidic phase.

true

What does the fluidic phase hinder?

colonization and spread of microbes from the portal of entry and isolates them so that they subsequently can be phagocytized and killed by neutrophils and macrophages during the cellular phase of the acute inflammatory response

Additionally, what else do phagocytes do?

present microbial antigens to cells of the adaptive immune system, such as macrophages, lymphocytes, and dendritic cells

What is the intended outcome of acute inflammation?

to slow and kill microbes and enable broad activation of an effective adaptive immune response

intracellular process used by phagocytes to kill microbes

phagosome-lysosome fusion

cellular organelles that contain an array of enzymes and toxic molecules

lysosomes

How do microbes enter phagocytic cells? Where are they found?

via phagocytosis and endocytosis; intracellular vesicles (phagosomes or endosomes)

What do these vesicles do? What does this release?

fuse with lysosomes; array of degradative enzymes and toxic molecules into the fused vesicle, now called a phagolysosome, that are designed to kill the microbe

Pathogenic microbes often have virulence factors that do what? What does this allow?

act to block phagosome-lysosome fusion, or if fusion occurs, to neutralize the effects of toxic molecules released from lysosomes; prevention of lysosomal killing then allows them to colonize the phagocytic cells

What are the mechanisms used to penetrate the mucus layer and gain access to target cells?

P
D
C

• penetrating motility

• digestion of mucus via enzymes

• consumption of mucus as an energy source

What are the pathogenic advantages that mucus provides to bacteria?

M
B
A

• mucin oligosaccharides represent a direct source of carbohydrates, peptides, and exogenous nutrients, including vitamins and minerals

• bacteria that colonize mucus avoid rapid expulsion out of the alimentary system by peristalsis

• adhesion to specific molecules within the mucin facilitates colonization of the mucus layer by microbes