BY RANJEET RAMAN

HOST MICROBE RELATIONSHIPS AND DISEASE

PROCESS - MICRO {ST1}

Pathogen – parasite capable of causing disease.

Host – an organism that harbors another organism

A. Symbiosis - two different organisms living together.

1. Commensalism - one organism benefits, the other is neither harmed or benefited. Many bacterial species fall into this category. Many individual bacterial species by themselves don't provide direct benefit to the host.

2. mutualism - both partners benefit. Ex. ruminants (cud-chewing animals) and

termites have microbial species that break down cellulose from plant cell walls so that it can be used for energy by the animal; this relationship is essential for the ruminant.

Ex. Large numbers of E. coli live in the large intestine of humans. These bacteria release vitamin K, which we use to make certain blood-clotting factors.

Ex. Collectively an organism’s natural flora protects the host by competing with and edging out many pathogens. This phenomenon is called microbial antagonism.

3. parasitism - host is harmed, the parasite benefits; microbial parasites = pathogens. A narrow definition of parasites would include only eukaryotic pathogens such as protozoa, helminths, and arthropods (ticks, lice, fleas). A broader definition of this term includes viruses, bacteria, and fungi.

B. Contamination , Infection, and Disease – A Sequence of Events

1. contamination – the microbes are present. 2. infection – multiplication of any parasitic

organism within or upon the host’s body; growth of normal flora is usually not considered an infection; infection does not always cause disease

3. disease – disturbance in the state of health (state of relative equilibrium in which the body's organ systems are functioning adequately); disease is characterized by changes in the host that interfere with normal function.

C. Types of Flora: (define and give specific examples for each)

1. Resident flora (= normal) - microbial species present in/on human body throughout life; permanent species; coexist with humans in a stable relationship

a. What does washing do to these guys? Reduces, but does not eliminate.

b. What parts of the body inhabited by normal flora? (external vs. internal surfaces)

External - skin, conjunctiva Internal - nose, mouth, intestinal tract,

vagina, urethra, ear

2.Transient flora - microbial species that can be cultured from body surfaces under certain circumstances, but are not permanent residents.

a. What does washing do to these guys? Usually eliminates.

b. Why aren't they part of the body's normal flora? Not well enough adapted to life on human body.

c. Nosocomial infections (hospital-acquired infections) - Hospital workers have a large transient flora population because of large number of pathogens they are exposed to every day (ex. pathogenic Staphylococcus aureus ); therefore, hospital workers must be extremely careful about hand washing.

3. Opportunists - microbial species that cause disease when the proper opportunity arises, but are usually harmless; infections usually occur when bacteria get into a place where they don’t belong (ex. nonpathogenic bacteria that are part of the normal flora of the colon go crazy when they get into the urinary tract.)

a. Name three opportunities for infection - breakdown in immune system, antibiotic treatment, bio implantation of artificial devices (catheters, pacemakers, artificial joints);

b. What's one reason for a vaginal yeast Superinfection? Antibiotic treatments reduce numbers of normal vaginal bacterial species; these bacteria usually keep the yeast Candida albicans in check.

D. Changing Flora - Examples:What is one good reason why mothers should

breastfeed? It’s not important just for the nutrients and the antibodies the baby receives in breast milk. While on breast milk, a baby's intestinal flora is composed mostly of Bifid bacterium, which metabolizes milk sugars into acetic and lactic acid.

These acids reduce the pH of the intestine, making it inhospitable to many disease-causing microbes, most importantly those causing diarrhea. The intestinal flora changes when the baby is on formula and the same protection is not provided.

What is the effect of estrogen on the vaginal pH? What effect does this have on the normal flora? Estrogen increases the growth of lactobacilli which produce an acidic vaginal environment, making it inhospitable to disease-causing microbes (ex. E. coli from feces).

Newborns have high estrogen levels from estrogen that crosses the placenta. In a few weeks, this estrogen level falls off. It doesn't increase again until puberty. This is important for when sexual activity could begin.

II. ESTABLISHING DISEASEPathogenicity is the capacity to produce

disease. An organism’s pathogenicity depends on its ability to invade a host, multiply in the host, and avoid being damaged by the host’s defenses. Virulence refers to the intensity of the disease produced by pathogens, and it varies among different microbial species.

A pathogen must overcome the following seven challenges if it is to survive on or in a human host & cause disease. Pathogenesis, a microbe's ability to cause disease, depends upon its meeting all of these challenges. The seven challenges are:

A. Maintain a reservoir (a place in which a pathogenic microorganism is maintained between infections).

1. Human reservoirs - ex. pertussis, measles, gonorrhea, common cold.

A person who is ill from an infection is a reservoir. Healthy people can also be reservoirs - called carriers.

incubatory carrier - in early symptomless stages of illness (most diseases have specific incubation periods associated with them; you may not realize you have an infection, but you can still be contagious).

chronic carrier - person who harbors a pathogen for an extended period of time without becoming ill (ex. people who are HIV+ but have not developed AIDS); this group also includes people who recover from an illness, but harbor the pathogen (ex. Hepatitis B); people with herpes are also chronic carriers.

2. Animal reservoirs - ex. for rabies the animal reservoirs are skunks, possums, bats, raccoons, etc.; in this case, the pathogen is spread through the bite of the rabid animal reservoir; insect vectors can also be involved in spreading pathogens from animal reservoirs to humans - ex. Lyme disease (Borrelia uses deer and mice as a reservoir; a tick is the vector).

Zoonosis - a human disease caused by a pathogen that maintains an animal reservoir. Mutations & genetic variation can occur in the reservoir, causing new strains to emerge.

3. Environmental reservoirs - ex. soil, water, house dust; Clostridium tetani uses soil - it's able to survive in this environment because of its ability to produce endospores; Vibrio cholerae uses water.

B. Leave its reservoir & enter the body of a human host.

Disease transmission takes place when a pathogen leaves a reservoir and enters the body of a host. Most have a preferred portal of entry. The number of pathogens that reach the portal of entry influences the likelihood of successful disease transmission.

The number of microbes that must enter the body to establish infection in 50% of test animals is expressed as the ID50 (infection dose). The LD50 (lethal dose) measures fatal infections - the number of microbes that must enter the body to cause death in 50% of test animals.

The most common portals of entry for disease-causing microbes are external & internal body surfaces: skin, conjunctivae (around eyes), nasal cavity & nasopharynx, mouth, intestinal tract, vagina, urinary tract, etc. Others include tissues below the skin in the case of an open wound or the placenta.

Transmission can occur in several ways:1. Human-to-human (communicable diseases

transmitted from one person to another)a. Respiratory droplets expelled by coughing,

sneezing, talking; ex. Bordetella pertussis (whooping cough); more human diseases are transmitted by respiratory transmission than by any other method.

b. Direct body contact or person-to-person or horizontal transmission - transmission by touching, kissing, sexual intercourse; includes STD's (sexually transmitted diseases); ex. gonorrhea; herpes is most commonly spread by kissing or exchange of saliva (common in young children).

c. Vertical transmission - transmission from mother to infant; prenatal transmission - occurs across the placenta; perinatal transmission - occurs during passage through the birth canal; ex. STD's such as syphilis, gonorrhea, HIV, Herpes.

d. Fecal-oral route – can involve direct contact (ex. a person does not wash his hands after defecating and then shakes hands with someone); this transmission can also be by vehicles such as water, food, fomites, or vectors (flies, etc.); (crops and water supplies may be contaminated with fecal matter).

2. Airborne Transmission - these pathogens are hardy enough to withstand prolonged drying; can be transmitted across great distances (greater than a meter); can remain viable in dust & reenter the air; ex. Mycobacterium tuberculosis.

3. Vehicle Transmission (objects such as food, water, fomites) Fomites - inanimate objects such as cups, towels, bedding, eating utensils, bedding, & handkerchiefs; ex. common cold viruses.

4. Parenteral Transmission - occurs when a biological arthropod vector introduces pathogens during a skin-penetrating bite or when breaks in the skin or mucous membranes provide microbes with access to deeper tissues; can also occur from penetration with a hypodermic needle;

ex. HIV, hepatitis B virus, Plasmodium (a protozoan that causes malaria; mosquito vector), Clostridium tetani (causes tetanus when anaerobic conditions are created in deep wounds)

5. Vectors - usually insects or other arthropods (mosquito, tsetse fly, tick, flea, lice, etc.)

a. mechanical vector - ex. a fly lays its eggs in dog feces and then lands on your sandwich.

b. biological vector – ex. the protozoan parasite that causes malaria goes through a stage in its life cycle in the mosquito. Could bacteria use biological vectors?

C. Adhere firmly to the surface of the host's body and thereby colonize it.

Pathogens, like normal flora, attach to specific types of target cells by means of adhesins (protein molecules that are very specific for the receptors that they bind to on target cell surfaces);

many adhesins are molecular components of capsules or pili, thus these structures are responsible for the virulence of many strain of bacteria; some bacteria have a repertoire of adhesins - this versatility makes them extremely virulent.

D. Invade the body in order to enter cells or deeper tissues.

Only a few pathogens cause disease by colonizing surfaces; most have additional virulence factor that enable the pathogen to invade tissues (in other words, most pathogens are invasive - they penetrate the body's surface to enter cells or deeper tissues).

This ability allows them to escape certain host defenses and to gain access to a nutrient-rich environment that is free of competing microbes. Streptococcus produces the enzyme hyaluronidase that digests hyaluronic acid, a glue like substance that helps hold the cells of certain tissues together.

Some pathogens actually enter cells to live and multiply inside them; they are called intracellular pathogens. Ex. of intracellular pathogenic bacteria - Rickettsias (ex. Rocky Mt. Spotted Fever) & Chlamydias. Some bacteria gain entry into cells by adhering to surface receptors that fold into the cell during endocytosis.

Most eukaryotic pathogens do not invade cells. An example of one that does is Plasmodium (a sporozoan, protozoan that causes malaria); this parasite enter red blood cells.

E. Evade the body's elaborate defenses against microbial invaders. Here are just a few of the ways:

1. Protection Against Phagocytosis by White Blood Cells.

a. capsules - make bacteria slippery and hard for wbc’s to phagocytize; some bacteria are virulent only if they produce a capsule; ex. Streptococcus pneumoniae, Haemophilus influenzae.

b. surface proteins - interference with phagocytosis; ex. Streptococcus pyogenes - produces M proteins - hairlike projections on the surface of its cell wall (kind of makes them prickly); because of these projections, these guys can be phagocytized only if antibodies bind to the bacteria, masking the M proteins.

c. living inside the phagocyte (white blood cell) - only pathogens that possess special adaptations can survive the enzymes produced by the phagocyte; ex. Mycobacterium tuberculosis - survives because the phagocyte's enzymes cannot break through its waxy outer layer.

Antigenic Variation - some microbes mutate & change their surface antigens; a person may be immune to one strain, but not to another. Ex. Neisseria gonorrhoeae, HIV, cold virus, influenza virus

Production of Exoenzymes (enzymes produced and then released by bacteria) – Ex. Coagulase – triggers blood clotting mechanism, allowing bacteria protection from immune

defenses. Ex. StaphylococcusIgA Proteases - enzymes produced by

bacteria that destroy the IgA class of antibody.

Ex. Neisseria.Streptokinase – dissolves blood clots so

bacteria can spread to other tissues.F. Multiply within the body, perhaps

producing toxic products or stimulating host reactions that cause disease.

The 2 most common forms of bacterial pathogenesis are

1. the production of toxins (poisonous products that harm human cells and tissues ) & exoenzymes.

2. stimulation of the body's defenses.

1. ExotoxinsProduced by G(+) or G(-) bacteria.Bind to receptors on the surfaces of different

types of cells.Specific for the cells they infect (ex.

neurotoxins, such as tetanus & botulinum toxins effect only nervous tissue. Enterotoxins, such as those produced by Vibrio cholerae & Shigella effect only epithelial cells lining the intestinal tract).

After binding, the enzymes enter the cell & disrupt cellular function, usually by inhibiting one specific metabolic reaction.

Some exotoxins are unbelievably potent; ex. tetanus toxin - an amount about equal to the size of the period at the end of this sentence can kill an adult!

Some exotoxins enter the bloodstream, causing systemic disease or toxemia (tissues throughout the body are affected).

Diseases that result from the ingestion of a toxin are termed intoxications rather than infections. Ex. botulism food poisoning is the result of injesting toxins made by pathogens.

Exotoxins can be neutralized with special antibodies called antitoxins. Certain exotoxins can be modified in the lab by treatment with heat or chemicals such as formaldehyde to produce toxoids; these molecules that have lost their disease-causing properties, but still stimulate the immune system to produce antitoxins (antibodies against toxin); vaccines can be produced from toxoids (ex. tetanus).

In most exotoxin-caused diseases, such as cholera, tetanus, E. coli diarrhea, shigellosis, & pertussis, occur only if the bacteria multiply in the body. In other diseases, such as botulism (food poisoning caused by Clostridium botulinum ), the toxin is produced outside the body & is ingested with contaminated food – called a food intoxication.

Some are enzymes. Ex. Hemolysins which lyse red blood cells. Alpha-hemolysin partially breaks down hemoglobin (the oxygen-carrying protein in rbc’s), leaving a greenish halo around colonies grown on blood plates. Beta-hemolysin completely breaks down hemoglobin, leaving a clear ring around colonies. Hemolysins are produced by streptococci and staphylococci.

Leukocidins produced by stretptococci and staphylococci damage or destroy certain kinds of white blood cells. While most diseases are characterized by an elevated white cell count, some may result in a decrease in numbers of wbc's.

May be named after the part of the body they affect. Ex. neurotoxin, enterotoxin

2. EndotoxinsReleased only by G(-) bacteria; all G(-)

bacteria produce endotoxins.Endotoxins are lipopolysaccharides molecules

(LPS’s) in the outer membrane.

Its effects include: fever, increased or decreased #'s of wbc's, shock, death, diarrhea

Endotoxins are not secreted by bacteria, but are released into the environment when the bacterial cell dies.

Unlike exotoxins, endotoxins are not proteins, so they are relatively heat stable.

Unlike exotoxins, endotoxins don't stimulate the immune system to produce antibody; therefore, toxoid vaccines would be useless.

Unlike exotoxins, endotoxins are not specific for the cells they effect.

Normally clinically significant only when large numbers of dying bacteria are circulating in the bloodstream; paradoxically, agents that kill G(-) bacteria (antibiotics, etc.) may actually increase endotoxin-mediated damage.

3. Stimulation of the Body's DefensesEx. Streptococcus pneumoniae - when it

multiplies in the lungs, phagocytes (white blood cells) come to combat the infection; however, this bacteria is protected by a capsule so more and more phagocytes arrive to help; dead bacteria & phagocytes accumulate in the lungs, impairing normal gas exchange & making breathing difficult.

G. Leave the body and return to a reservoir &/or enter a new host.

The anatomic route through which a pathogen usually leaves the body of its host is called its portal of exit.

For most respiratory pathogens, the portal of exit is the same as the portal of entry.

For most gastrointestinal pathogens, the portal of entry is the mouth & the portal of exit is the anus.

STD's exit the same way they enter - across the mucous membrane surfaces of the genital tract.

Parenterally transmitted pathogens exit the same way they enter - in the blood.

III. TYPES OF INFECTIOUS DISEASEAcute disease – develops rapidly and runs its

course quicklyChronic disease – develops more slowly, is

usually less severe, and persists for a long period.

Latent disease – characterized by period of inactivity (ex. Herpes)

Local infection – confined to a specific area

Systemic infection – generalized infection; affects most of the body.

Septicemia – pathogens are present in and multiply in the blood

Primary infection – initial infection in a previously healthy person.

Secondary infection – follows a primary infection (ex. a bacterial infection following a cold).

Superinfection – secondary infection that results from the destruction of normal microflora and often follows the use of broad-spectrum antibiotics.

Mixed infection - caused by several species of organisms present at the same time.

IV. STAGES OF INFECTIOUS DISEASE A. INCUBATION PERIOD – Time between

infection and the appearance of signs and symptoms. Although the infected person is not aware of the presence of an infectious agent, she can spread the disease to others. Each infectious disease has a typical incubation period.

B.PRODROMAL PHASE (prodromos = forerunner) - Short period during which nonspecific, often mild, symptoms such as malaise and headache sometimes appear. You feel like you’re coming down with something.

C. INVASIVE PHASE – Period during which the individual experiences the typical signs and symptoms of the disease (fever, nausea, rash, cough, etc.). During the acme part of this phase, signs and symptoms reach their greatest intensity.

In some diseases this phase may be fulminating (sudden and severe), in others it may be persistent or chronic. A period of chills followed by fever marks the acme of many diseases. The battle between pathogens and host defenses is at its height during this stage.

D. DECLINE PHASE – Symptoms begin to subside as the host defenses and the effects of treatment if being administered finally overcome the pathogen. Secondary infections may occur during this phase.

E. CONVALESCENCE PERIOD – Tissues are repaired, healing takes place, and the body regains strength and recovers. Individuals no longer have disease symptoms, but they may still be able to transmit pathogens to others.