Microbial Infections

Lecture 15, 16

What are the steps of microbial diseases?

1. acquire access to a portal of entry

2. find a target

3. colonize

4. spread

Where are encounter “targets”?

• mucosa

• mucocutaneous junctions

• skin: epithelial cells, tissue associated leukocytes, mucus

Microbial disease colonize target and/or amplify the ancounter or cross the barrier system to gain access to largets located?

locally

What are common local targets?

leukocytes, although entry into neurons also possible

Microbial diseases spread locally and enter what?

regional blood and/or lymphatic vessels

Microbial diseases travel as what and inside what cells when they enter regional blood and/or lymphatic vessels?

“cell confined microbes” inside lymphocytes, macropahges, or dendritic cells or as “cell free” microbes

Cell confined microbes travel inside which cells?

• lymphocytes

• macrophages

• dendritic cells

Once microbes/microbial diseases spread locally and enter the regional blood and/or lymphatic vessels, how do they spread?

spread to regional lymph nodes then spread systemically within lymphatic vessels and/or to blood vascular system

Once microbial diseases spread systemically, they encounter, colonize, and invade new populations of target cells that are unique to a specific organ system and cause what?

dysfunction and/or lysis of target cells and disease

What are virulence factors?

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

What are examples of virulence factors?

• glycoproteins

• glycolipids

• other molecules present in microbe structure

Some virulence factors are integral to the ______ of microbes; other factors are ______ by microbes using the metabolic process of the _____ as needed to replicate.

• biologic structure

• synthesized

• target cell

What do virulence factors do?

• colonize

• invade

• evade

• suppress

• acquire

How do viruenlce factors colonize?

using adhesins

How do virulence factors invade?

using invasins

How do virulence factors evade barrier systems and defense mechanisms?

• enzymes

• toxic molecules

How do virulence molecules suppress innate and adaptive immune responses?

• enzymes

• toxic molecules

How do virulence factors acquire nutrition from targets?

siderophores

What are the portal of entry for microbes?

• alimentary / GI

• respiratory

• urogenital

• integumentary

• ear

• eye

Microbes gain access to broader expanses of mucosa via?

normal physiologic processes

The ability of microbes to reach a site in the body that has “target cell or substances” suitable for their growth and replication is a concept central to what?

pathogenesis

When microbes initially encounter cells and tissues at portals of entry, colonization depends on creating what?

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

From which sites do microbes spread?

initial sites

Match the route of exposure to target cell/tissue:

Inhalation

respiratory mucosa

Match the route of exposure to target cell/tissue:

direct contact

conjunctival mucosa

otic mucosa

skin and subcutis

Match the route of exposure to target cell/tissue:

ingestion

alimentary mucosa

Match the route of exposure to target cell/tissue:

penetration

endothelium / blood cells

Match the route of exposure to target cell/tissue:

ascending entry

urogenital mucosa

What is the 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?

MALT

What cells transfer luminal antigens across the mucosa to dendritic cells and immune cells in the nodule?

M cells

In GALT, nodules are covered by modified epithelial cells of intestinal crypts called what?

microfold cells (M cells)

Mucus in the alimentary system is produced by what?

goblet cells

Mucus covers and protects what in the alimentary system?

microvilli

The mucus layer is a favorable habitat for beneficial and competitive enteric microflora. It is also what?

• physical barrier

• biological barrier

How is the mucus layer of the alimentary system serving as a biological barrier. / what properties does it have that makes it a biological barrier?

• thickness and viscosity

• binds to bacterial adhesins

• serves as reservoid for IgA and lysozyme

• acts as free radical scavenger

Generally, there are more goblet cells in which part of the small intestine?

ileum

Are there more goblet cells in the large or small intestine?

large

A mucus layer does not cover what cells, which allows microbes to readily interact with cell membranes?

M cells

What cells are the interface between material in the lumen of intestinal crypts and the lymphoid nodules?

M cells

What has afferent lymphatic vessels that drain to regional mesenteric lymph nodes?

Peyers patches (GALT)

What is the smallest group of microbe?

prions

What is the largest group of microbes?

protozoa

In a normal functioning respiratory system, only fomites of what size in diameter can be inhaled into bronchioles, alveolar ducts, and alveoli?

1 micrometer or less

What are the oxygen-carbon dioxide exchange portion of the respiratory systems?

bronchioles, alveolar ducts, and alveoli

When fomites are inhaled, what do they encounter first?

nasal turbinates

The movement of air through the turbinates causes what?

centrifugal turbulence

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

the innate immune system

When fomites are trapped in the mucus layer, they encounter the innate immune system and are removed by what?

the mucociliary apparatus

What is composed of the mucus layer and ciliated mucosal epithelial cells and is an important defense mechanism in the respiratory system?

mucociliary apparatus

The mucus layer of the respiratory system is what?

biphasic

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

caudally toward the pharynx for swallowing

In the conductive portion of the respiratory system, cilia move mucus and debris what direction?

cranially toward the pharynx for swalloing

If the mucus layer and/or the mucociliary apparatus are dysfunction, what influences the deposition of fomites?

gravity

If the mucus layer and/or the mucociliary apparatus are dysfunction, gravity influences the deposition of fomites. The pathogenesis of what is based on this mechanism?

bronchopneumonias

What cells serve as a primary defense mechanism against infections in the repiratory system?

dedndritic cells

alveolar and tissue macrophages

The skin consists of what?

• epidermis

• dermis

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

• subcutis

The skin is a physical and biological barrier protecting the body against microbes via?

• its dryness and acidity

• sebum (oils)

• normal bacterial flora

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

ligand receptor interactions

Colonization on the surface of target cells or invasion of teh cells is often through what process?

endocytosis/phagocytosis

What are the three functional groups we can place target cells into?

• those initially encountered at the portals of entry

• those used to spread microbes locally, regionally, or systemically

• those located systemically within other organ systems

What is leukocyte trafficking?

migration of mucosal and tissue macrophages, dendritic cells, or lymphocytes

What are the 7 distinct mechanisms by which microbes cross mucosa at portals of entry?

• M cell entry

• transcytosis and endocytosis/exocytosis

• intercellular direct injury

• cell polarity

• dendritic cell entry

• leukocyte trojan horse entry

• nerve ending entry

What are the mechanisms microbes use to spread systemically?

• passive manner by diperal of cell free microbes in lymph via lymphatic system or plasma via circulatory system

• via leukocyte trafficking

What are examples of structural barriers in the body?

• bone

• meninges

• microscopic ones formed by mucosa, mucocutaneous junctions, skin

How is skin protected from microbes?

• physical thickness anchored by junctional complexes

• keratinization, acidity, oiliness of outer stratum corneum and stratum lucidum

• sloughing of keratinized cells into environment

What are examples of tissue level functional barriers?

• peristalsis

• mucociliary clearance

What are examples of molecular level functional barriers?

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

What is the function of the mucus layer in the alimentary and respiratory systems?

• block microbes from reaching target cells

• trap microbes for phagocytsosis by macrophages and neutrophils

• trap microbes for exposure to bacteriostatic and bactericidal molecules

• facilitate phagcytosis via mucosa associated macrophages, mucosal dendriic cells, and M cells

• delivr microbial antigens to local lymphoid tissues and then to regional lymph node

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

stress

What has the purpose of diluting and isolating microbes in edema fluid and fibrin, then phagocytose and killing of microbes, before finalyl processing and presenting antigens to effector cells of adaptive immune response?

acute inflammation

What phase of the acute infalmmatory response hinders 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 following phases?

fluidic

Which phase of the acute inflammatory response is responsible for phagocytosis and and killing of microbes by neutrophils and macrophages?

cellular

What intracellular process is used by phagocytes to kill microbes?

phagosome-lysosome fusion

What 3 mechanisms are used by microbes to penetrate the mucus layer and gaina ccess to target cells?

• penetrating motility

• digestion of mucus via enzymes

• the consumption of mucus as an energy source

How does mucus provide a pathogenic advantage for bacteria?

• mucin oligosaccharide represents direct source of some nutrients

• bacteria that colonize mucus avoid rapid expulsion

• adhesion to specific mlecules within mucin facilitates colonization

What is the term for the ability to enzymatically degrade mucus, which appears to be a common trait among bacteria, and provides access to readily available sources of carbon and energy?

microbial mucolysis

What are outcomes/consequences of successful microbial infections on target cells?

• cell death

• cellular dysfunction

• inflammation

• structural injury

• persistent infection

• latent infection

• cell proliferation

• malignant transformation

Which microbes are too small to visualize?

• viruses

• prions

Which microbes can be visualized?

• baceria

• fungus

• protozoa

Virulence factors are molecules derived from what?

bacterial genes

The pathogenicity of a bacterium is regulated by its what?

virulence factors

What is the process of bacteria attaching to cells, tissue, and biologic substances?

adhesion

What is the term for adherence, multiplication, and establishment of bacteria?

colonization

What is the term for the abliity of bacteria to invade tissues?

invasiveness

What is the term for the ability of bacteria to produce toxins?

toxigenesis

What is the lifespan of epithelial cells of skin and mucosa?

48 hours

Uropathogenic and enterotoxic E coli expresses what fimbrial and pilus adhesins?

fibrial type 1, P, and S/F1C

pilus K99

In the urinary tract, what allowed E coli to attach to the transitional epithelium of the bladder and cause the disease known as acute necrohemorrhagic urocystitis?

P fimbria (attachment adhesin)

What virulence factors of E coli cause necrosis and hemorrhage later in the disease process?

alpha - hemolysin

cytotoxic necrotizing factor type 1

In the small intestine, what allows E colu to adhere to enterocytes and reduces their loss in number via intestinal peristalsis?

K99 pilus adhesin

When numerous E coli are attached to the small intestine, they produce other virulence factors like what that act directly on enterocytes to cause diarrhea?

enterotoxin

What toxins are secreted by living gram positive bacteria?

exotoxin

What is released from dead gram positive bacteria?

lipoteichoic acid

What is released from dead gram negative bacteria?

endotoxins

Which exotoxins bind to cell membranes and form pores through which cell lysis occurs?

surface acting exotoxins

What is located in the cell wall of gram positive bacteria and behaves as a gram positive endotoxin because its actions mimic LPS?

lipoteichoic acid

Which bacteria has pore forming cytotoxins called alpha toxin?

S aureus

Whihc virulence factor of S aureus binds to endothelial cells, interacts with circulating antibodies, activates the complement cascade, and triggers the relase of reactive oxygen and nitrogen species, acid hydrolyses, highly cationic proteinases, bactericidal cationic peptides, growth factors, and cytotoxic cytokines from neutrophils and macrophages?

lipoteichoic acid

Endotoxin most commonly refers to what?

LPS complex

Toxicity of LPS is attributable to what component?

lipid A