MECHANISMS of PATHOGENESIS



MECHANISMS of PATHOGENESIS

Part I

Host-Microbe Relationships

and Disease Processes

Chapter 14

Definitions

NORMAL FLORA or MICROBIOTA

HOST – any organism that harbors another organism

NORMAL FLORA - permanent and usually not pathogenic microorganisms

RESIDENT FLORA – always present on or in the human body

TRANSIENT FLORA - come & go

For a few hours to a few months

In utero - germ-free

Birth - microorganisms being to establish themselves

Lactobacilli from mother’s vagina

Feeding and breathing - colonization of URT and GIT

NORMAL FLORA

HOST & NORMAL FLORA exist together

The normal flora live in SYMBIOSIS with the human body

SYMBIOSIS – association between two or more species

COMMENSALISM = one organism benefits - the other is not affected

EX: Staphylococcus epidermidis - on our skin

The normal flora usually benefits the host by prevents pathogens from overgrowing

NORMAL FLORA - HOST INTERACTIONS

MUTUALISM = both organisms benefit

EX: E. coli in intestines produce vitamin K & some B vitamins

ANTAGONISM = competition between the microorganisms

Active competition ie between normal flora & pathogen

BACTERIOCINS = proteins secreted by E. coli in the large intestine to inhibit other bacteria

PARASITISM = one organism (microorganism) benefits - the other is harmed

EX: Any successful pathogenic microorganism

NORMAL FLORA INTERACTIONS

SYNERGISM = the effect of 2 organisms acting together is greater than the effect of either one acting alone

EX: Mycoplasma fermentans & HIV - if 1 cell is infected by both the cell will die much faster than when infected by either one alone

OPPORTUNISTS

OPPORTUNISTIC ORGANISMS = do not usually cause a disease but can become pathogenic under certain circumstances

OPPORTUNITY KNOCKS:

Normal flora disrupted /destroyed

Host defense mechanisms compromised

Normal protective barriers of host are disupted

EX: S. aureus - causes toxic shock syndrome (TSS)

EX: Pneumocystis carinii - causes pneumonia in AIDS patients

Evidence of Disease

Symptoms: changes in body functions such as pain and malaise

.Signs: changes that can be seen by an observer such as rash, fever, swelling

.Syndrome: specific symptoms and signs associated with a disease

TYPES of DISEASES

INFECTIOUS

Caused by bacteria, viruses, fungi, protozoa and helminths

COMMUNICABLE INFECTIOUS DISEASES

Contagious – can be spread from one host to another

NON-COMMUNICABLE INFECTIOUS DISEASES

Caused by: individual’s normal flora; ingestion of pre-formed toxins; organisms found in the environment

Not “caught” from another person

NON-INFECTIOUS

Caused by any other factor than infectious organisms

Occurrence of Diseases

Sporadic: occurs occasionally in a population

Endemic: a disease that is always found in the region

Epidemic: a disease that many people acquire in a very short period of time

Pandemic: is an epidemic that occurs worldwide

CLASSIFYING INFECTIOUS DISEASES: DURATION

ACUTE DISEASES = short duration (flu, cold)

CHRONIC DISEASES = longer duration (AIDS, leprosy)

SUBACUTE DISEASES = intermediate duration

LATENT DISEASES = causative agent becomes latent

Characterized by a period of time of no symptoms

VZV - chicken pox then shingles

SPREAD of INFECTION

THE INFECTIOUS AGENT:

WHERE DOES IT COME FROM?

HOW DOES IT GET INTO THE BODY?

HOW DOES IT GET OUT OF THE BODY?

HOW IS IT TRANSMITTED?

WHERE IS IT BETWEEN & DURING DISEASE?

Many pathogens can not survive outside the host long enough to serve as a source of infection

There must be sites where the pathogen can persist and maintain infectivity

RESERVOIR = a continual source of the disease causing organisms, it can be living or inanimate objects

LIVING RESERVOIRS of INFECTION

HUMAN RESERVOIRS:

May transmit M/O directly or indirectly

Carriers (asymptomatic people)

AIDS, diptheria, typhoid fever, hepatitis, gonorrhea

Convalescing patients

ANIMAL RESERVOIRS:

Wild and/or domestic

ZOONOSES = a disease that occurs PRIMARILY in animals but that CAN BE TRANSMITTED to HUMANS

~150 are known: anthrax, bubonic plaque, Lyme disease

Transmitted: bites, contaminated hides/feathers, food, insect vectors

NONLIVING RESERVOIRS of INFECTION

SOIL

Many fungal diseases

Clostridium tetani, Bacillus anthracis

WATER

HAV, pathogenic E. coli, polio and various gastrointestinal diseases, typhoid fever

MODES of DISEASE TRANSMISSION

New cases of infectious diseases

Pathogen must leave reservoir or portal of exit ( portal of entry in the new host

Three categories:

Contact transmission

Vehicle transmission

Vector transmission

CONTACT TRANSMISSION

DIRECT: person-to-person

HORIZONTAL transmission = from one person to another OR from one part of the host to another part of the host

Kissing, sexual contact, touching sores, shaking hands; direct fecal-oral transmission

VERTICAL transmission = from parent to offspring

In egg or sperm; placenta; breast milk; birth canal

INDIRECT TRANSMISSION:

FOMITES ie nonliving object

Syringe, drinking glass, contaminated linens, toys

DROPLET TRANSMISSION:

Coughing, sneezing, talking

VEHICLE TRANSMISSION

Is transmission through a medium

A non-living carrier of an infectious agent from its reservoir to a susceptible host

WATER

Often due to fecal contamination

Ex: Cholera, shigellosis, leptospirosis

FOOD

Often due to incompletely cooked food or improperly refrigerated foods ( food poisoning

Ex: Botulism, typhoid fever

AIR

Mucus droplets – can travel a long distance

Ex: Histoplasmosis, the flu, measles, tuberculosis

BODY FLUIDS

VECTOR TRANSMISSION

Usually an arthropod (insect)

Transfer of M/O from feet or other body parts of insects to food or skin of person

Or person can be bitten by insects that are harboring these M/O and thus introduce them to the body

BIOLOGICAL transmission

M/O replicates in vector (or at least part of the M/Os replicative cycle occurs in the vector)

Ex: Lyme disease, malaria

MECHANICAL transmission

Passive – no replication of M/O within vector

Ex: shigellosis, typhoid fever

Emerging Infectious Diseases

Diseases that are either new or changing

Many different factors

A new strain of pathogen that is more virulent

Overuse of antibiotics promotes resistant strains

Global warming increases survival of reservoirs and vectors

Modern transportation

Natural disasters

Animal control measures increase # of animals that carry microbes

Failure to comply with public health measures

AGE OF ANTIBIOTICS = NO DISEASE?

EMERGING INFECTIOUS DISEASES

New or changing diseases

E. coli O157:H7

HIV

Ebola virus

Hepatitis C Virus

Drug resistant T.B.



NOSOCOMIAL INFECTIONS

Hospital or other medical facility acquired

5-15% of patients affected

~2 million (10%) in American Hospitals

20,000 or more patients die/year

THREE FACTORS:

M/O in hospital

Patient’s general health

Chain of transmission

NOSOCOMIAL MICROORGANISMS

Often the most pathogenic will be in the hospital

S. aureus - urinary & respiratory infections

Pseudomonas aeruginosa - burns & surgical wounds

E. coli - urinary tract, neonatal meningitis

Enterococcus - urinary tract & wound

Many M/O contain R plasmids = antibiotic resistance

Endogenous infections

Caused by opportunistic M/O among patient’s own normal flora

Exogenous infections

Caused by M/O that enter the patient through the environment

HOSPITAL PATIENTS

Host is usually immunocompromised

Resistance to infection is reduced

Broken skin or mucous membranes

Surgery, burns, catheters

Suppressed immune system

Drugs, diabetes, stress, HIV etc

CHAIN of TRANSMISSION

Hospital staff ---> patient

Patient ---> patient

Fomites ---> patient

Ventilation system ---> patient

CONTROL:

Educate personnel

Practice good techniques

Monitor for drug resistance

HOW VIRUSES CAUSE DISEASE

Evade host immune system

Sometimes can destroy cells of the immune system (cytocidal)

CPE: Cytopathic Effects

Abnormalities in the host cell induced by virus

Inhibition of DNA, RNA and protein synthesis

Inclusion bodies

Small granules containing viral nucleic acids & proteins; found in nucleus and cytoplasm

Syncytia formation (giant cells)

Cause several host cells to fuse together

EXTENT of HOST INVOLVEMENT

SEPTICEMIA – “blood poisoning”

Pathogens are present and multiplying in the blood

BACTEREMIA - presence of bacteria in the blood

Bacteria are being transported but are NOT multiplying in the blood

VIREMIA - presence of viruses in the blood

Viruses are being transported but are NOT multiplying in the blood

TOXEMIA - presence of toxins in the blood causing symptoms

Definitions

PATHOGENICITY: Is the ability of an organism to cause disease

VIRULENCE: Is the degree of pathogenicity

PORTALS of ENTRY

Organisms need to ENTER to establish disease

These portals of entry differ for different M/O

Some M/O have only 1 portal and some have several portals

MUCOUS MEMBRANES

Respiratory, GI, & genitourinary tracts, conjunctiva (eyes)

SKIN

Largest organ & outermost protective layer

PARENTERAL ROUTE

Deposition directly under the skin into the tissues beneath skin or mucous membranes

Bites, burns, injections etc.

ENTRY of M/O into HOST

PREFERRED PORTALS of ENTRY

Route of entry that is required for establishment of disesase

NUMBERS of INVADING M/O

Number required for disease may vary from person to person

ADHERENCE

To tissue surfaces to establish infection

ADHESINS = surface molecules on the pathogen that bind to RECEPTORS on the surface of the host cell/tissues

Can be found on capsules, fimbriae, capsid, or envelope of a virus

PORTALS of EXIT

Usually pathogens leave host with body fluids or feces

Gastrointestinal tract

Diarrhea, vomitting

Urogenital tract

Sexual contact, urine

Blood

Insects, needles

Wounds

Respiratory tract

Coughing, sneezing, speaking

ESTABLISHMENT of DISEASE

To cause an infection or disease, microorganisms need to:

ENTER the organism (Portal of Entry – Chpt 15)

ADHERE to tissues

PENETRATE the tissues

DAMAGE CELLS to establish disease

HOW BACTERIA CAUSE DISEASE

VIRULENCE FACTORS – characteristics that help M/O cause infection and disease

Structural: pili for adhesion

Physiological: enzymes help to evade host defenses; toxins

DIRECT ACTIONS by BACTERIA

Adhesins – proteins/glycoproteins allow M/O to adhere to host cells

Colonization – growth of M/O on epithelial cell surfaces (skin, mucous membranes)

Invasiveness – degree to which a M/O can invade and grow in host tissues – related to virulence factors

Toxins – any substance poisonous to other organisms

HOW BACTERIA CAUSE DISEASE

VIRULENCE FACTORS – characteristics that help M/O cause infection and disease

Structural: pili for adhesion

Physiological: enzymes help to evade host defenses; toxins

DIRECT ACTIONS by BACTERIA

Adhesins – proteins/glycoproteins allow M/O to adhere to host cells

Colonization – growth of M/O on epithelial cell surfaces (skin, mucous membranes)

Invasiveness – degree to which a M/O can invade and grow in host tissues – related to virulence factors

Toxins – any substance poisonous to other organisms

BACTERIAL VIRULENCE FACTORS

CAPSULES – resist host defenses

Phagocytosis and complement

CELL WALL COMPONENTS – some may help

Streptococcus pyogenes - protein M

Mycobacteria – waxes (mycolic acid)

ENZYMES – extracellular enzymes

Help to breakdown and dissolve material found between/around cells

Hyaluronidase – “spreading factor”

Streptococci produce - digests hyaluronic acid

Coagulase – increases clotting (coagulation)

Staphylococcus aureus produces – keeps organism from spreading BUT also walls off M/O from immune system

BACTERIAL VIRULENCE FACTORS cont’d

Streptokinase – dissolves clots (digests fibrin)

Streptococcus pyogenes- pathogens trapped in clots free themselves to spread to other tissues

Collagenases – breaks down collagen

Produced by some Clostridia

Hemolysins – hemolyze RBCs

Alpha – partially digests hemoglobin ( greenish color

Beta – completely digests hemoglobin ( clear area

Staphylococci, Streptococci, Clostridium perfringes

Streptolysin O (SLO) is sensitive to oxygen

Streptolysin S (SLS) is not sensitive to oxygen

Leukocidins – destroys neutrophils

A type of WBC important for phagocytosis

Produced by Staphylococci and Streptococci

BACTERIAL TOXINS

TOXINS: poisonous substances produced by some M/O

Some produce fever, cardiovascular disturbances; neurological disturbances; diarrhea, shock

INTOXICATION

Diseases due to ingestion of the toxin (vs the M/O)

EXOTOXINS

Produced by bacterial and released into the surrounding medium

ENDOTOXIN

Lipid A portion of LPS released from cell wall of Gram –ve bacteria

BACTERIAL ENDOTOXIN

ENDOTOXIN -

Causes chills, fever, weakness, aches & sometimes shock and death

Two outcomes possible:

Fever or pyrogenic response

Septic shock

ENDOTOXIN & the PYROGENIC RESPONSE

Pyrogenic or Fever Response

Macrophage phagocytosis Gram -ve cell

Cell degraded releasing endotoxin

Endotoxin stimulates macrophage to secrete IL-1

IL-1 = INTERLEUKIN 1 (Endogenous pyrogen)

IL-1 causes the hypothalamus of brain to produce prostaglandins

PGs causes the body temperature to rise

ENDOTOXIC (SEPTIC) SHOCK #1

Reaction is due to a cascade of events

Fairly high fatality rate

100,000 die / year (USA)

13th leading cause of death in the USA

Macrophage may also secrete tumor necrosis factor (TNF) or cachetin in response to endotoxin

TNF + IL-1 activate other cells in the immune system which release MEDIATORS

Constriction of small blood vessels & increased permeability of capillaries

Rapid decrease in blood pressure (HYPOTENSION)

Impaired blood flow to the kidneys

ENDOTOXIC (SEPTIC) SHOCK #2

RESULTS: Chills, fever, vomitting, diarrhea, rapid decrease in b.p., convulsions, shock ± death

NORMAL? - a low level response allows for cells of the immune system to leave the blood and enter the site of infection

MAJOR PRODUCERS

P. aeruginosa

E. coli

Klebsiella

Proteus

Enterobacter

Salmonella typhi

BACTERIAL EXOTOXINS #1

EXOTOXINS –

Usually proteins and enzymes, mainly produced by Gram +ve bacteria

Genes often carried on plasmids or bacteriophages

Easily diffuse to blood & lymph

Exotoxins can be destroyed by heat or chemicals to become TOXOIDS.used as vaccines

Three categories of exotoxins based on effect:

CYTOTOXINS - Kill cells & affect their function

NEUROTOXINS - Interfere with normal nerve impulses

ENTEROTOXINS - Affect the GI tract

BACTERIAL EXOTOXINS #2

DIPTHERIA Toxin - Corynebacterium diptheria

Infected with a lysogenic phage

Cytotoxin that inhibits protein synthesis, AB toxin

Polypeptide B binds to cells; Polypeptide A inhibits protein synthesis

ERYTHROGENIC Toxin – Streptococcus pyogenes

3 types: A, B and C

Damages blood capillaries under the skin ( rash of Scarlet Fever

BOTULINUM Toxin – Clostridium botulinum

Neurotoxin acts at neuromuscular junction

Prevents impulses from nerve ( muscle and inhibits release of acetylcholine ( flaccid paralysis

BACTERIAL EXOTOXINS #3

TETANUS Toxin – Clostridium tetani

Neurotoxin (tetanospasmin) – inhibits nerve cell impulses for muscle relaxtion ( uncontrollable muscle contractions

VIBRIO Enterotoxin (Cholera Toxin)

Vibrio cholerae – AB toxin

Polypeptide B binds to cells; Polypeptide A induces formation of cAMP ( release of large amounts of fluid & electrolytes ( “rice water stools”

STAPHYLOCOCCAL Enterotoxin

Affects intestinal tract similar manner to cholera toxin

STAPHYLOCOCCAL TSS Toxin

Toxic Shock Syndrome Toxin

EXOTOXINS vs. ENDOTOXINS

Gram positive and gram negative bacteria

Protein

Neurotoxin, cytotoxin, enterotoxin

Destroyed by heat

Can be made into TOXOID, neutralized by antitoxin

Only gram negative bacteria

Lipid

Found in LPS of gram negative cells, LIPID A

Fever, toxic shock

Cannot be destroyed by heat

Cannot be made into toxoid, no neutralizing Ab.

PLASMIDS, LYSOGENY & PATHOGENICITY

R factors - antibiotic resistance increases pathogenicity

Plasmids that code for virulence factors

Staph enterotoxin

Certain fimbriae of E. coli

Tetanus toxin

LYSOGENY = incorporation of a phage into a bacterial chromosome often containing gene for toxins

C. diptheriae - prophage beta codes for diptheria toxin

Streptococcus pneumoniae - phage codes for capsule

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