Symbiosis Type	Organism 1	Organism 2	Example
Mutualism	Benefits	Benefits	Escherichia coli in human large intestine
Commensalism	Benefits	Neither harmed, nor helped	Many microbes that make up the normal flora of the human skin and mucous membranes
Parasitism	Benefits	Harmed	Tuberculosis bacterium in the human lung; certain protozoans, fungi, and helminths
Amensalism	Not affected	Impedes or restricts	Penicillium (mold) secretes penicillin, which kills certain bacteria

• Mutualism: Mutualism is a relationship between two organisms in which both members benefit from the interaction. For example, in the large intestine of humans, Escherichia coli releases vitamins during the breakdown of nutrients that are not digestible by the human gastrointestinal (GI) tract, but necessary for the survival of the bacteria. The vitamins released by E. coli can easily be absorbed by the intestinal epithelium of the human large intestine. As shown in the Life Application, probiotics are also examples of mutualism between specific bacterial species and the human gastrointestinal tract.

• Commensalism: Commensalism is a term used for a symbiotic relationship in which one of the organisms benefits and the other is neither harmed nor helped. Many microorganisms in the normal flora of the human skin and mucous membranes are commensals. Examples include certain saprophytic mycobacteria that inhabit the ear and external genitals, living on secretions and removed cells. These organisms do not appear to bring benefit or harm to the host.

• Parasitism: In parasitism one organism benefits, while the other is harmed, either slightly or to such an extreme that the host will be killed. A parasite that is capable of causing disease is called a pathogen. Species of bacteria, protozoans, algae, and fungi all can be microscopic human pathogens. Larger pathogens include the parasitic worms and biting arthropods.

• Amensalism: Amensalism is an interaction between two species in which one organism can hamper or prevent the growth and/or survival of another, without being positively or negatively affected by the other organism. A familiar example is Penicillium, a mold that secretes penicillin, a chemical capable of killing a wide range of bacteria (see Chapter 22, Antimicrobial Drugs).

Normal Flora (Microbiota)

A newborn’s first contact with microorganisms occurs while traveling through the birth canal, where lactobacilli residing in the mother’s vagina will become the predominant organisms in the newborn’s intestine. The next exposure of the newborn to microorganisms occurs with the beginning of breathing, and this is soon followed by feeding. From then on, other orally acquired bacteria such as E. coli will begin to colonize the large intestine and will remain there throughout life. In other words, starting at birth the human body enters a state of dynamic equilibrium with microorganisms. In addition, throughout a person’s life, other microorganisms will establish residency in mucous membranes that are open to the external environment, on the skin and its derivatives (Figure 9.1). Mucous membranes open to the external environment include those of the respiratory tract (Figure 9.2), gastrointestinal tract (Figure 9.3), and urogenital tract (Figure 9.4). The microbes that establish themselves on the skin and mucous membranes usually do not cause disease and constitute the normal flora (microbiota) of the human body. This normal flora consists of resident or transient microbes:

FIGURE 9.1 Skin.
Micrograph of the skin, showing the protective layer of epidermis with the underlying connective tissue of the dermis.

FIGURE 9.2 Ciliated epithelium (mucous membrane) of the respiratory tract.

FIGURE 9.3 Typical epithelial lining (mucous membrane) of the gastrointestinal tract.

FIGURE 9.4 Mucous membrane of the urogenital tract.

• A resident flora remains part of the normal flora throughout the life of a person. An example would be Staphylococcus epidermidis, a resident of the skin, or E. coli, which is part of the intestinal flora. A detailed listing of the various organisms that reside in/on the human body is provided in Table 9.2.

TABLE 9.2

Normal Flora in Selected Regions of the Human Body

Region	Genera	Observation
Skin	Staphylococcus, Propionibacterium, Corynebacterium, Micrococcus, Acinetobacter, Candida (fungus), Malassezia (fungus)	The varied environment of the skin results in locally dense or sparse populations, depending on moisture, temperature, and exposure to the environment. In general, the microbes live on the outer layer of the skin, in hair follicles, and in pores of glands
Eyes (conjunctiva)	Staphylococcus, Propionibacterium, Micrococcus, Corynebacterium	Although the microbiota is similar to that of the skin, tears reduce the normal flora and prevent others from colonizing
Upper respiratory tract	Fusobacterium, Haemophilus, Lactobacillus, Moraxella, Staphylococcus, Streptococcus	Microbes that are part of the normal flora are potential pathogens, but are generally kept at bay by an intact immune system, by nasal secretions, and by the ciliary escalator of the trachea
Mouth (upper digestive tract)	Fusobacterium, Haemophilus, Lactobacillus, Staphylococcus, Streptococcus, Actinomyces, Treponema, Corynebacterium, Candida (fungus)	Although saliva does contain antimicrobial substances, the moisture, warmth, and continuous supply of food support many microorganisms. Normally these microbes do not cause infections, but some of them are potential pathogens
Lower digestive tract	Escherichia coli, Bacteroides, Fusobacterium, Lactobacillus, Enterococcus, Enterobacter, Bifidobacterium, Citrobacter, Proteus, Klebsiella, Candida (fungus)	The large intestine contains the largest amount of resident microbes. Bacteria are mostly anaerobes but some facultative anaerobes also present
Female urogenital tract	Lactobacillus, Bacteroides, Clostridium, Staphylococcus, Streptococcus, Candida (fungus), Trichomonas (protozoan)	As the pH of the vagina changes so does the microbial flora. Flow of urine prevents extensive colonization of the urethra and urinary bladder
Male urogenital tract	Lactobacillus, Bacteroides, Fusobacterium, Mycobacterium, Peptostreptococcus, Staphylococcus, Streptococcus	Flow of urine prevents excessive colonization of microbes in the urethra or urinary bladder

• A transient flora can be found in the same locations as the resident flora, but remains in the body for only a few hours, days, or months before it vanishes. These organisms cannot survive for reasons such as competition with other microorganisms for nutrients, elimination by the host’s immune system, or chemical and physical changes in the body of the host. An example would be Bacillus laterosporus, sometimes found in the intestines; when present the organism helps to keep fungal populations such as Candida in check.

LIFE APPLICATION

Probiotics: Yogurt as Medicine?

One often-used definition of probiotics, developed by the World Health Organization (WHO), is that they are live microorganisms, mostly bacteria, which when taken in proper amounts result in a health benefit for the host. These bacteria are called “friendly” or “good” bacteria and are the same or similar to the normal flora found in healthy individuals. For centuries, home remedies and medicinal folklore have suggested that some fermented milk products conferred a certain health benefit to the user. Modern probiotic products have taken forms other than just milk products, such as by the addition of probiotics to juices and soy beverages. Capsules, tablets, and powders are also available and can be added to food products or directly ingested. The list of potential health benefits of probiotics is growing, some of which have specific potential in the control of infectious diseases. These include competition of “friendly” bacteria with pathogens, replenishment of normal intestinal flora after depletion caused by antibiotics, and stimulation of certain immune system components. Thus far research has uncovered some rather minor side effects such as mild digestive discomfort, but there is also a potential infection problem when introducing bacteria into a host with an already depressed immune system. In these cases the normally “friendly” bacteria may become opportunistic pathogens and require treatment with antibiotics. Concerns have also been raised about overstimulation of the immune system, effects of metabolic activities as a result of increased bacterial numbers, or gene transfers between pathogens and probiotic microorganisms.

Opportunistic Pathogens

In general, this balance between the normal flora and the human host can be maintained, but when the balance is interrupted for whatever reason, the microorganisms can cause infection and disease. They become opportunistic pathogens. An opportunistic pathogen does not cause disease in its normal habitat in a healthy person, but can cause infection under conditions of immune suppression, changes in the normal flora, or when a member of the normal flora gains access into an area of the body it normally does not inhabit.

• Compromised immune system immune suppression (see Chapter 20, The Immune System): Any factors that suppress or weaken the immune system can enable opportunistic pathogens to cause infections and disease. These factors include acute and chronic diseases, especially those involving the immune system directly (e.g., AIDS); malnutrition, stress (emotional and physical), age (very young or very old), the use of radiation and chemotherapy in the treatment of cancer, or the use of immunosuppressive drugs in transplant patients.

• Changes in the normal flora: The normal flora plays a somewhat protective role regarding pathogens, because it takes up space, uses available nutrients, and releases toxic waste products, all of which present a problem for arriving pathogens, which must compete well enough to become established to infect and cause disease in the desired host. This condition is acknowledged as microbial competition or antagonism. When the normal flora changes for any reason it may allow one of the members to become an opportunistic pathogen and thrive. Examples include vaginal yeast infections by Candida albicans in women after prolonged antibiotic therapy, or oral thrush also caused by Candida spp. in cancer patients after chemotherapy. Other conditions that change the normal flora include hormonal changes, stress, changes in the diet, or exposure to an excessive number of pathogenic organisms.

• Entrance of a member of the normal flora into areas of the body where it is not present under normal conditions: This can occur after injury, in burn victims, or even when an intestinal organism such as E. coli enters the urethra, where it then becomes opportunistic.

Stages of Infection

In terms of infection in the human body, contamination refers to the presence of microbes in or on the body, or on objects. Contaminants can reach the body in food, drink, by air, or they can be introduced by wounds, insect bites, and sexual intercourse. The outcome of a contamination varies. Some microbes remain at the site at which they first came in contact with the body, such as on the skin and mucous membranes; they do not cause harm and become part of the resident (normal) flora, or a transient flora. To initiate an infection the microorganism must gain entry into the host and its tissues. The term infection refers to the presence and growth of a microorganism in the body, with the exception of organisms in/on the normal flora. Notably, an infection may or may not cause disease.

Portal of Entry

The site where a pathogen enters the body is referred to as the portal of entry, which can be the skin, mucous membranes, the placenta, or the so-called parenteral route (other then the digestive tract route). The source of the infectious agent can be exogenous, from outside the body, or endogenous, in which case the organism is already in the body, such as in the normal flora.

Portals of entry are generally the same areas that support normal flora: the skin and the mucous membranes of the gastrointestinal, respiratory, and urogenital tracts (Figure 9.5). The majority of pathogens have their preferred portal of entry, which provides the necessary habitat for further growth and eventual spreading. Most often, if a pathogen enters the wrong portal, infection will not occur. For example, influenza virus uses the respiratory mucosa as its portal of entry, where it may successfully infect its host, but when limited to contact with the skin only, influenza virus will not cause an infection. Some infectious agents can enter via more than one portal of entry, such as the skin and mucous membranes, where the infection then can lead to various diseases. For example, Streptococcus and Staphylococcus have adapted to several portals of entry such as the skin and the urogenital and respiratory tracts.

Skin

The top layer of the skin, the epidermis, consists of a thick layer of keratinized dead cells that is the first line of defense against microbial invasion; however, some pathogens can enter the body through natural openings in the skin, such as hair follicles and sweat glands. Damage to the skin in the form of abrasions, cuts, punctures, and scrapes opens the skin to contaminants, which ultimately can cause infection. Moreover, larvae of some parasitic worms burrow through the skin to get to the underlying tissues, and some fungi use digestive enzymes to gain entry to the soft tissues.

Mucous Membranes

Mucous membranes line all the body cavities and the canals that come in contact with the outside, such as the canals of the gastrointestinal, respiratory, and urogenital tracts, as well as the conjunctiva, the thin membrane covering the eye and the underside of the eyelids. The skin and the outer layer of the mucous membranes are composed of tightly packed epithelial cells. However, in contrast to the epidermis, the mucosal lining is thin, moist, and warm, and composed of living cells.

• The gastrointestinal (GI) tract serves as the portal of entry for pathogens present in food, liquid, and other ingested substances. Microorganisms that can survive in the GI tract are adapted to survive the action of digestive enzymes and environments that undergo drastic changes in the pH. Enteric bacterial pathogens include Salmonella, Shigella, Vibrio, and certain strains of E. coli. Viruses using the GI tract as a portal of entry include poliovirus, hepatitis A virus, echovirus, and rotavirus. The most common enteric protozoans are Entamoeba histolytica and Giardia lamblia. Helminths, although not considered microbes, are infectious agents entering through the GI tract and include trematodes, cestodes, and nematodes (see Chapter 8, Eukaryotic Microorganisms).

• The respiratory tract is the most frequently used portal of entry. Pathogens are able to enter the mouth and nose by air, via dust particles, moisture, and respiratory droplets from an infected person. Mucous membranes that line the upper respiratory tract are continuous with the membranes of the sinuses and of the auditory tubes, and pathogens can be transferred from one site to the other. Examples of bacteria using this portal of entry include the causative agents of sore throat, meningitis, diphtheria, and whooping cough. Examples of viral agents include those causing the common cold, influenza, measles, meningitis, mumps, rubella, and chickenpox (see Chapter 11, Infections of the Respiratory System).

• The urogenital tract is a portal of entry for pathogens that are generally contracted by sexual contact (see Chapter 17, Sexually Transmitted Infections/Diseases). However, girls and women who are not sexually active are also susceptible to lower urinary tract infections because of the close proximity of the anus to the female urethra. Therefore urinary tract infections caused by E. coli, as opportunistic organisms, are more common in women than men. Vaginal yeast infections are common in women who are under stress; taking birth control pills, antibiotics, and/or steroids; who are pregnant; or because of other factors. Vaginal yeast infections are usually due to an overgrowth of Candida albicans.

• The conjunctiva is generally a good barrier against infectious agents, but some bacteria such as Haemophilus aegyptius (pinkeye), Chlamydia trachomatis, and Neisseria gonorrhoeae can easily attach to this membrane.

Placenta

The placenta, an organ formed by maternal and fetal tissues, is usually an effective barrier against microorganisms that may be present in the maternal circulation. However, some microbes can cross the placenta and infect the embryo or fetus, sometimes causing spontaneous abortions, birth defects, or premature births.

HEALTHCARE APPLICATION
Pathogens That Cross the Placenta

Microbe	Pathogen	Condition	Effect on Unborn
RNA viruses	Lentivirus (HIV)	AIDS	Immunosuppression (AIDS)
RNA viruses	Rubivirus	German measles	Severe birth defects or death
DNA viruses	Cytomegalovirus	Usually asymptomatic	Deafness, microcephaly, mental retardation
DNA viruses	Parvovirus B-19	Erythema infectiosum	Abortion
Bacteria	Treponema pallidum	Syphilis	Abortion, multiorgan birth defects, syphilis
Bacteria	Listeria monocytogenes	Listeriosis	Granulomatosis infantiseptica, death
Protozoans	Toxoplasma gondii	Toxoplasmosis	Abortion, epilepsy, encephalitis, microcephaly, mental retardation, blindness, anemia, jaundice, rash, pneumonia, diarrhea, hypothermia, deafness

Parenteral Route

Technically the parenteral route is not a portal of entry, but a means of bypassing other portals of entry. In this manner, pathogens are introduced directly into the subcutaneous tissue, as happens with punctures by a nail, thorn, or contaminated needles. This way of pathogen entry can also be achieved by cuts, bites, stab wounds, deep abrasions, or surgery.

Virulence and Pathogenicity

After pathogens have gained entry into the body they must undergo adhesion and several other steps to be able to multiply, thereby causing an infection and possible disease.

Virulence refers to the degree of pathogenicity or disease-evoking power of a specific microbe. Virulence therefore is the degree of pathogenicity of a microbe and is based on virulence factors. A pathogen is a microorganism that is capable of causing disease. The ability of a microorganism to cause disease is directly related to the number of infecting organisms, the portal of entry, the host defense mechanisms (see Chapter 20, The Immune System), and the intrinsic characteristics of the bacteria and their virulence factors. These include the following:

• Adhesion: Adhesion is the first and probably the most crucial step in infection, because without adhesion to the host cells or tissue, the microbes will be removed by ciliary motion (see Chapter 3, Cell Structure and Function), sneezing, coughing, swallowing, urine flow, flow of tears, or intestinal peristalsis. Bacteria must first bind to the host cell, via pili, fimbriae, or specific membrane receptor sites. Viral adhesion occurs by capsid or envelope proteins. The mechanism of the adhesion process can be nonspecific or specific:

• Nonspecific adhesion involves nonspecific attractive forces or interactions the microorganism uses to move toward the eukaryotic host. These interactions and forces can include the following:

• Hydrophobic interactions

• Electrostatic attraction

• Atomic and molecular vibrations

• Brownian movement

• Recruitment and trapping by biofilms (see Chapter 6, Bacteria and Archaea)

• Specific adhesion involves a permanent lock-and-key interaction between complementary molecules on each cell surface and under normal physiological conditions this attachment becomes irreversible. Examples of such specific attachments/adhesions are illustrated in Table 9.3.

TABLE 9.3

Examples of Specific Adhesions of Bacteria to the Host

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Species	Adhesion Factor	Host Receptor	Site	Disease
Chlamydia	Unknown	Sialic acid	Conjunctival or urethral epithelium	Conjunctivitis or urethritis
Bordetella pertussis	Fimbriae