Chapter 15

Learning Objectives

• Distinguish between signs and symptoms of disease

• Explain the difference between a communicable disease and a noncommunicable disease

• Compare different types of infectious diseases, including iatrogenic, nosocomial, and zoonotic diseases

• Identify and describe the stages of an acute infectious disease in terms of number of pathogens present and severity of signs and symptoms

A disease is any condition in which the normal structure or functions of the body are damaged or impaired. Physical injuries or disabilities are not classified as disease, but there can be several causes for disease, including infection by a pathogen, genetics (as in many cancers or deficiencies), noninfectious environmental causes, or inappropriate immune responses. Our focus in this chapter will be on infectious diseases, although when diagnosing infectious diseases, it is always important to consider possible noninfectious causes.

Signs and Symptoms of Disease

An infection is the successful colonization of a host by a microorganism. Infections can lead to disease, which causes signs and symptoms resulting in a deviation from the normal structure or functioning of the host. Microorganisms that can cause disease are known as pathogens.

The signs of disease are objective and measurable, and can be directly observed by a clinician. Vital signs, which are used to measure the body’s basic functions, include body temperature (normally 37 °C [98.6 °F]), heart rate (normally 60–100 beats per minute), breathing rate (normally 12–18 breaths per minute), and blood pressure (normally between 90/60 and 120/80 mm Hg). Changes in any of the body’s vital signs may be indicative of disease. For example, having a fever (a body temperature significantly higher than 37 °C or 98.6 °F) is a sign of disease because it can be measured.

In addition to changes in vital signs, other observable conditions may be considered signs of disease. For example, the presence of antibodies in a patient’s serum (the liquid portion of blood that lacks clotting factors) can be observed and measured through blood tests and, therefore, can be considered a sign. However, it is important to note that the presence of antibodies is not always a sign of an active disease. Antibodies can remain in the body long after an infection has resolved; also, they may develop in response to a pathogen that is in the body but not currently causing disease.

Unlike signs, symptoms of disease are subjective. Symptoms are felt or experienced by the patient, but they cannot be clinically confirmed or objectively measured. Examples of symptoms include nausea, loss of appetite, and pain. Such symptoms are important to consider when diagnosing disease, but they are subject to memory bias and are difficult to measure precisely. Some clinicians attempt to quantify symptoms by asking patients to assign a numerical value to their symptoms. For example, the Wong-Baker Faces pain-rating scale asks patients to rate their pain on a scale of 0–10. An alternative method of quantifying pain is measuring skin conductance fluctuations. These fluctuations reflect sweating due to skin sympathetic nerve activity resulting from the stressor of pain.^[1]

A specific group of signs and symptoms characteristic of a particular disease is called a syndrome. Many syndromes are named using a nomenclature based on signs and symptoms or the location of the disease. Table 15.1 lists some of the prefixes and suffixes commonly used in naming syndromes.

Nomenclature of Symptoms

Table 15.1

Clinicians must rely on signs and on asking questions about symptoms, medical history, and the patient’s recent activities to identify a particular disease and the potential causative agent. Diagnosis is complicated by the fact that different microorganisms can cause similar signs and symptoms in a patient. For example, an individual presenting with symptoms of diarrhea may have been infected by one of a wide variety of pathogenic microorganisms. Bacterial pathogens associated with diarrheal disease include Vibrio cholerae, Listeria monocytogenes, Campylobacter jejuni, and enteropathogenic Escherichia coli (EPEC). Viral pathogens associated with diarrheal disease include norovirus and rotavirus. Parasitic pathogens associated with diarrhea include Giardia lamblia and Cryptosporidium parvum. Likewise, fever is indicative of many types of infection, from the common cold to the deadly Ebola hemorrhagic fever.

Finally, some diseases may be asymptomatic or subclinical, meaning they do not present any noticeable signs or symptoms. For example, most individual infected with herpes simplex virus remain asymptomatic and are unaware that they have been infected.

• Explain the difference between signs and symptoms.

1. F. Savino et al. “Pain Assessment in Children Undergoing Venipuncture: The Wong–Baker Faces Scale Versus Skin Conductance Fluctuations.” PeerJ 1 (2013):e37; https://peerj.com/articles/37/

Classifications of Disease

The World Health Organization’s (WHO) International Classification of Diseases (ICD) is used in clinical fields to classify diseases and monitor morbidity (the number of cases of a disease) and mortality (the number of deaths due to a disease). In this section, we will introduce terminology used by the ICD (and in health-care professions in general) to describe and categorize various types of disease.

An infectious disease is any disease caused by the direct effect of a pathogen. A pathogen may be cellular (bacteria, parasites, and fungi) or acellular (viruses, viroids, and prions). Some infectious diseases are also communicable, meaning they are capable of being spread from person to person through either direct or indirect mechanisms. Some infectious communicable diseases are also considered contagious diseases, meaning they are easily spread from person to person. Not all contagious diseases are equally so; the degree to which a disease is contagious usually depends on how the pathogen is transmitted. For example, measles is a highly contagious viral disease that can be transmitted when an infected person coughs or sneezes and an uninfected person breathes in droplets containing the virus. Gonorrhea is not as contagious as measles because transmission of the pathogen (Neisseria gonorrhoeae) requires close intimate contact (usually sexual) between an infected person and an uninfected person.

Diseases that are contracted as the result of a medical procedure are known as iatrogenic diseases. Iatrogenic diseases can occur after procedures involving wound treatments, catheterization, or surgery if the wound or surgical site becomes contaminated. For example, an individual treated for a skin wound might acquire necrotizing fasciitis (an aggressive, “flesh-eating” disease) if bandages or other dressings became contaminated by Clostridium perfringens or one of several other bacteria that can cause this condition.

Diseases acquired in hospital settings are known as nosocomial diseases. Several factors contribute to the prevalence and severity of nosocomial diseases. First, sick patients bring numerous pathogens into hospitals, and some of these pathogens can be transmitted easily via improperly sterilized medical equipment, bed sheets, call buttons, door handles, or by clinicians, nurses, or therapists who do not wash their hands before touching a patient. Second, many hospital patients have weakened immune systems, making them more susceptible to infections. Compounding this, the prevalence of antibiotics in hospital settings can select for drug-resistant bacteria that can cause very serious infections that are difficult to treat.

Certain infectious diseases are not transmitted between humans directly but can be transmitted from animals to humans. Such a disease is called zoonotic disease (or zoonosis). According to WHO, a zoonosis is a disease that occurs when a pathogen is transferred from a vertebrate animal to a human; however, sometimes the term is defined more broadly to include diseases transmitted by all animals (including invertebrates). For example, rabies is a viral zoonotic disease spread from animals to humans through bites and contact with infected saliva. Many other zoonotic diseases rely on insects or other arthropods for transmission. Examples include yellow fever (transmitted through the bite of mosquitoes infected with yellow fever virus) and Rocky Mountain spotted fever (transmitted through the bite of ticks infected with Rickettsia rickettsii).

In contrast to communicable infectious diseases, a noncommunicable infectious disease is not spread from one person to another. One example is tetanus, caused by Clostridium tetani, a bacterium that produces endospores that can survive in the soil for many years. This disease is typically only transmitted through contact with a skin wound; it cannot be passed from an infected person to another person. Similarly, Legionnaires disease is caused by Legionella pneumophila, a bacterium that lives within amoebae in moist locations like water-cooling towers. An individual may contract Legionnaires disease via contact with the contaminated water, but once infected, the individual cannot pass the pathogen to other individuals.

In addition to the wide variety of noncommunicable infectious diseases, noninfectious diseases (those not caused by pathogens) are an important cause of morbidity and mortality worldwide. Noninfectious diseases can be caused by a wide variety factors, including genetics, the environment, or immune system dysfunction, to name a few. For example, sickle cell anemia is an inherited disease caused by a genetic mutation that can be passed from parent to offspring (Figure 15.2). Other types of noninfectious diseases are listed in Table 15.2.

Types of Noninfectious Diseases

Table 15.2

Figure 15.2 Blood smears showing two diseases of the blood. (a) Malaria is an infectious, zoonotic disease caused by the protozoan pathogen Plasmodium falciparum (shown here) and several other species of the genus Plasmodium. It is transmitted by mosquitoes to humans. (b) Sickle cell disease is a noninfectious genetic disorder that results in abnormally shaped red blood cells, which can stick together and obstruct the flow of blood through the circulatory system. It is not caused by a pathogen, but rather a genetic mutation. (credit a: modification of work by Centers for Disease Control and Prevention; credit b: modification of work by Ed Uthman)

• Describe how a disease can be infectious but not contagious.

• Explain the difference between iatrogenic disease and nosocomial disease.

Periods of Disease

The five periods of disease (sometimes referred to as stages or phases) include the incubation, prodromal, illness, decline, and convalescence periods (Figure 15.3). The incubation period occurs in an acute disease after the initial entry of the pathogen into the host (patient). It is during this time the pathogen begins multiplying in the host. However, there are insufficient numbers of pathogen particles (cells or viruses) present to cause signs and symptoms of disease. Incubation periods can vary from a day or two in acute disease to months or years in chronic disease, depending upon the pathogen. Factors involved in determining the length of the incubation period are diverse, and can include strength of the pathogen, strength of the host immune defenses, site of infection, type of infection, and the size infectious dose received. During this incubation period, the patient is unaware that a disease is beginning to develop.

Figure 15.3 The progression of an infectious disease can be divided into five periods, which are related to the number of pathogen particles (red) and the severity of signs and symptoms (blue).

The prodromal period occurs after the incubation period. During this phase, the pathogen continues to multiply and the host begins to experience general signs and symptoms of illness, which typically result from activation of the immune system, such as fever, pain, soreness, swelling, or inflammation. Usually, such signs and symptoms are too general to indicate a particular disease. Following the prodromal period is the period of illness, during which the signs and symptoms of disease are most obvious and severe.

The period of illness is followed by the period of decline, during which the number of pathogen particles begins to decrease, and the signs and symptoms of illness begin to decline. However, during the decline period, patients may become susceptible to developing secondary infections because their immune systems have been weakened by the primary infection. The final period is known as the period of convalescence. During this stage, the patient generally returns to normal functions, although some diseases may inflict permanent damage that the body cannot fully repair.

Infectious diseases can be contagious during all five of the periods of disease. Which periods of disease are more likely to associated with transmissibility of an infection depends upon the disease, the pathogen, and the mechanisms by which the disease develops and progresses. For example, with meningitis (infection of the lining of brain), the periods of infectivity depend on the type of pathogen causing the infection. Patients with bacterial meningitis are contagious during the incubation period for up to a week before the onset of the prodromal period, whereas patients with viral meningitis become contagious when the first signs and symptoms of the prodromal period appear. With many viral diseases associated with rashes (e.g., chickenpox, measles, rubella, roseola), patients are contagious during the incubation period up to a week before the rash develops. In contrast, with many respiratory infections (e.g., colds, influenza, diphtheria, strep throat, and pertussis) the patient becomes contagious with the onset of the prodromal period. Depending upon the pathogen, the disease, and the individual infected, transmission can still occur during the periods of decline, convalescence, and even long after signs and symptoms of the disease disappear. For example, an individual recovering from a diarrheal disease may continue to carry and shed the pathogen in feces for some time, posing a risk of transmission to others through direct contact or indirect contact (e.g., through contaminated objects or food).

• Name some of the factors that can affect the length of the incubation period of a particular disease.

Acute and Chronic Diseases

The duration of the period of illness can vary greatly, depending on the pathogen, effectiveness of the immune response in the host, and any medical treatment received. For an acute disease, pathologic changes occur over a relatively short time (e.g., hours, days, or a few weeks) and involve a rapid onset of disease conditions. For example, influenza (caused by Influenzavirus) is considered an acute disease because the incubation period is approximately 1–2 days. Infected individuals can spread influenza to others for approximately 5 days after becoming ill. After approximately 1 week, individuals enter the period of decline.

For a chronic disease, pathologic changes can occur over longer time spans (e.g., months, years, or a lifetime). For example, chronic gastritis (inflammation of the lining of the stomach) is caused by the gram-negative bacterium Helicobacter pylori. H. pylori is able to colonize the stomach and persist in its highly acidic environment by producing the enzyme urease, which modifies the local acidity, allowing the bacteria to survive indefinitely.^[2] Consequently, H. pylori infections can recur indefinitely unless the infection is cleared using antibiotics.^[3] Hepatitis B virus can cause a chronic infection in some patients who do not eliminate the virus after the acute illness. A chronic infection with hepatitis B virus is characterized by the continued production of infectious virus for 6 months or longer after the acute infection, as measured by the presence of viral antigen in blood samples.

In latent diseases, as opposed to chronic infections, the causal pathogen goes dormant for extended periods of time with no active replication. Examples of diseases that go into a latent state after the acute infection include herpes (herpes simplex viruses [HSV-1 and HSV-2]), chickenpox (varicella-zoster virus [VZV]), and mononucleosis (Epstein-Barr virus [EBV]). HSV-1, HSV-2, and VZV evade the host immune system by residing in a latent form within cells of the nervous system for long periods of time, but they can reactivate to become active infections during times of stress and immunosuppression. For example, an initial infection by VZV may result in a case of childhood chickenpox, followed by a long period of latency. The virus may reactivate decades later, causing episodes of shingles in adulthood. EBV goes into latency in B cells of the immune system and possibly epithelial cells; it can reactivate years later to produce B-cell lymphoma.

• Explain the difference between latent disease and chronic disease.

2. J.G. Kusters et al. Pathogenesis of Helicobacter pylori Infection. Clinical Microbiology Reviews 19 no. 3 (2006):449–490.

3. N.R. Salama et al. “Life in the Human Stomach: Persistence Strategies of the Bacterial Pathogen Helicobacter pylori.” Nature Reviews Microbiology 11 (2013):385–399.

Learning Objectives

• Summarize Koch’s postulates and molecular Koch’s postulates, respectively, and explain their significance and limitations

• Explain the concept of pathogenicity (virulence) in terms of infectious and lethal dose

• Distinguish between primary and opportunistic pathogens and identify specific examples of each

• Summarize the stages of pathogenesis

• Explain the roles of portals of entry and exit in the transmission of disease and identify specific examples of these portals

For most infectious diseases, the ability to accurately identify the causative pathogen is a critical step in finding or prescribing effective treatments. Today’s physicians, patients, and researchers owe a sizable debt to the physician Robert Koch (1843–1910), who devised a systematic approach for confirming causative relationships between diseases and specific pathogens.

Koch’s Postulates

In 1884, Koch published four postulates (Table 15.3) that summarized his method for determining whether a particular microorganism was the cause of a particular disease. Each of Koch’s postulates represents a criterion that must be met before a disease can be positively linked with a pathogen. In order to determine whether the criteria are met, tests are performed on laboratory animals and cultures from healthy and diseased animals are compared (Figure 15.4).

Koch’s Postulates

Table 15.3

Figure 15.4 The steps for confirming that a pathogen is the cause of a particular disease using Koch’s postulates.

In many ways, Koch’s postulates are still central to our current understanding of the causes of disease. However, advances in microbiology have revealed some important limitations in Koch’s criteria. Koch made several assumptions that we now know are untrue in many cases. The first relates to postulate 1, which assumes that pathogens are only found in diseased, not healthy, individuals. This is not true for many pathogens. For example, H. pylori, described earlier in this chapter as a pathogen causing chronic gastritis, is also part of the normal microbiota of the stomach in many healthy humans who never develop gastritis. It is estimated that upwards of 50% of the human population acquires H. pylori early in life, with most maintaining it as part of the normal microbiota for the rest of their life without ever developing disease.

Koch’s second faulty assumption was that all healthy test subjects are equally susceptible to disease. We now know that individuals are not equally susceptible to disease. Individuals are unique in terms of their microbiota and the state of their immune system at any given time. The makeup of the resident microbiota can influence an individual’s susceptibility to an infection. Members of the normal microbiota play an important role in immunity by inhibiting the growth of transient pathogens. In some cases, the microbiota may prevent a pathogen from establishing an infection; in others, it may not prevent an infection altogether but may influence the severity or type of signs and symptoms. As a result, two individuals with the same disease may not always present with the same signs and symptoms. In addition, some individuals have stronger immune systems than others. Individuals with immune systems weakened by age or an unrelated illness are much more susceptible to certain infections than individuals with strong immune systems.

Koch also assumed that all pathogens are microorganisms that can be grown in pure culture (postulate 2) and that animals could serve as reliable models for human disease. However, we now know that not all pathogens can be grown in pure culture, and many human diseases cannot be reliably replicated in animal hosts. Viruses and certain

bacteria, including Rickettsia and Chlamydia, are obligate intracellular pathogens that can grow only when inside a host cell. If a microbe cannot be cultured, a researcher cannot move past postulate 2. Likewise, without a suitable nonhuman host, a researcher cannot evaluate postulate 2 without deliberately infecting humans, which presents obvious ethical concerns. AIDS is an example of such a disease because the human immunodeficiency virus (HIV) only causes disease in humans.

• Briefly summarize the limitations of Koch’s postulates.

Molecular Koch’s Postulates

In 1988, Stanley Falkow (1934–) proposed a revised form of Koch’s postulates known as molecular Koch’s postulates. These are listed in the left column of Table 15.4. The premise for molecular Koch’s postulates is not in the ability to isolate a particular pathogen but rather to identify a gene that may cause the organism to be pathogenic.

Falkow’s modifications to Koch’s original postulates explain not only infections caused by intracellular pathogens but also the existence of pathogenic strains of organisms that are usually nonpathogenic. For example, the predominant form of the bacterium Escherichia coli is a member of the normal microbiota of the human intestine and is generally considered harmless. However, there are pathogenic strains of E. coli such as enterotoxigenic E. coli (ETEC) and enterohemorrhagic E. coli (O157:H7) (EHEC). We now know ETEC and EHEC exist because of the acquisition of new genes by the once-harmless E. coli, which, in the form of these pathogenic strains, is now capable of producing toxins and causing illness. The pathogenic forms resulted from minor genetic changes. The right-side column of Table 15.4 illustrates how molecular Koch’s postulates can be applied to identify EHEC as a pathogenic bacterium.

Molecular Koch’s Postulates Applied to EHEC

Table 15.4

As with Koch’s original postulates, the molecular Koch’s postulates have limitations. For example, genetic manipulation of some pathogens is not possible using current methods of molecular genetics. In a similar vein, some diseases do not have suitable animal models, which limits the utility of both the original and molecular postulates.

• Explain the differences between Koch’s original postulates and the molecular Koch’s postulates.

Pathogenicity and Virulence

The ability of a microbial agent to cause disease is called pathogenicity, and the degree to which an organism is pathogenic is called virulence. Virulence is a continuum. On one end of the spectrum are organisms that are avirulent (not harmful) and on the other are organisms that are highly virulent. Highly virulent pathogens will almost always lead to a disease state when introduced to the body, and some may even cause multi-organ and body system failure in healthy individuals. Less virulent pathogens may cause an initial infection, but may not always cause severe illness. Pathogens with low virulence would more likely result in mild signs and symptoms of disease, such as low-grade fever, headache, or muscle aches. Some individuals might even be asymptomatic.

An example of a highly virulent microorganism is Bacillus anthracis, the pathogen responsible for anthrax. B. anthracis can produce different forms of disease, depending on the route of transmission (e.g., cutaneous injection, inhalation, ingestion). The most serious form of anthrax is inhalation anthrax. After B. anthracis spores are inhaled, they germinate. An active infection develops and the bacteria release potent toxins that cause edema (fluid buildup in tissues), hypoxia (a condition preventing oxygen from reaching tissues), and necrosis (cell death and inflammation). Signs and symptoms of inhalation anthrax include high fever, difficulty breathing, vomiting and coughing up blood, and severe chest pains suggestive of a heart attack. With inhalation anthrax, the toxins and bacteria enter the bloodstream, which can lead to multi-organ failure and death of the patient. If a gene (or genes) involved in pathogenesis is inactivated, the bacteria become less virulent or nonpathogenic.

Virulence of a pathogen can be quantified using controlled experiments with laboratory animals. Two important indicators of virulence are the median infectious dose (ID₅₀) and the median lethal dose (LD₅₀), both of which are typically determined experimentally using animal models. The ID₅₀ is the number of pathogen cells or virions required to cause active infection in 50% of inoculated animals. The LD₅₀ is the number of pathogenic cells, virions, or amount of toxin required to kill 50% of infected animals. To calculate these values, each group of animals is inoculated with one of a range of known numbers of pathogen cells or virions. In graphs like the one shown in Figure 15.5, the percentage of animals that have been infected (for ID₅₀) or killed (for LD₅₀) is plotted against the concentration of pathogen inoculated. Figure 15.5 represents data graphed from a hypothetical experiment measuring the LD₅₀ of a pathogen. Interpretation of the data from this graph indicates that the LD₅₀ of the pathogen for the test animals is 104 pathogen cells or virions (depending upon the pathogen studied).

Figure 15.5 A graph like this is used to determine LD₅₀ by plotting pathogen concentration against the percent of infected test animals that have died. In this example, the LD₅₀ = 104 pathogenic particles.

Table 15.5 lists selected foodborne pathogens and their ID₅₀ values in humans (as determined from epidemiologic data and studies on human volunteers). Keep in mind that these are median values. The actual infective dose for an individual can vary widely, depending on factors such as route of entry; the age, health, and immune status of the host; and environmental and pathogen-specific factors such as susceptibility to the acidic pH of the stomach. It is also important to note that a pathogen’s infective dose does not necessarily correlate with disease severity. For example, just a single cell of Salmonella enterica serotype Typhimurium can result in an active infection. The resultant disease, Salmonella gastroenteritis or salmonellosis, can cause nausea, vomiting, and diarrhea, but has a mortality rate of less than 1% in healthy adults. In contrast, S. enterica serotype Typhi has a much higher ID₅₀, typically requiring as many as 1,000 cells to produce infection. However, this serotype causes typhoid fever, a much more systemic and severe disease that has a mortality rate as high as 10% in untreated individuals.

ID₅₀ for Selected Foodborne Diseases^[4]

Table 15.5

• What is the difference between a pathogen’s infective dose and lethal dose?

• Which is more closely related to the severity of a disease?

4. Food and Drug Administration. “Bad Bug Book, Foodborne Pathogenic Microorganisms and Natural Toxins.” 2nd ed. Silver Spring, MD: US Food and Drug Administration; 2012.

Primary Pathogens versus Opportunistic Pathogens

Pathogens can be classified as either primary pathogens or opportunistic pathogens. A primary pathogen can cause disease in a host regardless of the host’s resident microbiota or immune system. An opportunistic pathogen, by contrast, can only cause disease in situations that compromise the host’s defenses, such as the body’s protective barriers, immune system, or normal microbiota. Individuals susceptible to opportunistic infections include the very young, the elderly, women who are pregnant, patients undergoing chemotherapy, people with immunodeficiencies (such as acquired immunodeficiency syndrome [AIDS]), patients who are recovering from surgery, and those who have had a breach of protective barriers (such as a severe wound or burn).

An example of a primary pathogen is enterohemorrhagic E. coli (EHEC), which produces a virulence factor known as Shiga toxin. This toxin inhibits protein synthesis, leading to severe and bloody diarrhea, inflammation, and renal failure, even in patients with healthy immune systems. Staphylococcus epidermidis, on the other hand, is an opportunistic pathogen that is among the most frequent causes of nosocomial disease.^[5] S. epidermidis is a member of the normal microbiota of the skin, where it is generally avirulent. However, in hospitals, it can also grow in biofilms that form on catheters, implants, or other devices that are inserted into the body during surgical procedures. Once inside the body, S. epidermidis can cause serious infections such as endocarditis, and it produces virulence factors that promote the persistence of such infections.

Other members of the normal microbiota can also cause opportunistic infections under certain conditions. This often occurs when microbes that reside harmlessly in one body location end up in a different body system, where they cause disease. For example, E. coli normally found in the large intestine can cause a urinary tract infection if it enters the bladder. This is the leading cause of urinary tract infections among women.

Members of the normal microbiota may also cause disease when a shift in the environment of the body leads to overgrowth of a particular microorganism. For example, the yeast Candida is part of the normal microbiota of the skin, mouth, intestine, and vagina, but its population is kept in check by other organisms of the microbiota. If an individual is taking antibacterial medications, however, bacteria that would normally inhibit the growth of Candida can be killed off, leading to a sudden growth in the population of Candida, which is not affected by antibacterial medications because it is a fungus. An overgrowth of Candida can manifest as oral thrush (growth on mouth, throat, and tongue), a vaginal yeast infection, or cutaneous candidiasis. Other scenarios can also provide opportunities for Candida infections. Untreated diabetes can result in a high concentration of glucose in the saliva, which provides an optimal environment for the growth of Candida, resulting in thrush. Immunodeficiencies such as those seen in patients with HIV, AIDS, and cancer also lead to higher incidence of thrush. Vaginal yeast infections can result from decreases in estrogen levels during the menstruation or menopause. The amount of glycogen available to lactobacilli in the vagina is controlled by levels of estrogen; when estrogen levels are low, lactobacilli produce less lactic acid. The resultant increase in vaginal pH allows overgrowth of Candida in the vagina.

• Explain the difference between a primary pathogen and an opportunistic pathogen.

• Describe some conditions under which an opportunistic infection can occur.

Stages of Pathogenesis

To cause disease, a pathogen must successfully achieve four steps or stages of pathogenesis: exposure (contact), adhesion (colonization), invasion, and infection. The pathogen must be able to gain entry to the host, travel to the location where it can establish an infection, evade or overcome the host’s immune response, and cause damage (i.e., disease) to the host. In many cases, the cycle is completed when the pathogen exits the host and is transmitted to a new host.

5. M. Otto. “Staphylococcus epidermidis--The ‘Accidental’ Pathogen.” Nature Reviews Microbiology 7 no. 8 (2009):555–567.

Transmission of Disease

For a pathogen to persist, it must put itself in a position to be transmitted to a new host, leaving the infected host through a portal of exit (Figure 15.9). As with portals of entry, many pathogens are adapted to use a particular portal of exit. Similar to portals of entry, the most common portals of exit include the skin and the respiratory, urogenital, and gastrointestinal tracts. Coughing and sneezing can expel pathogens from the respiratory tract. A single sneeze can send thousands of virus particles into the air. Secretions and excretions can transport pathogens out of other portals of exit. Feces, urine, semen, vaginal secretions, tears, sweat, and shed skin cells can all serve as vehicles for a pathogen to leave the body. Pathogens that rely on insect vectors for transmission exit the body in the blood extracted by a biting insect. Similarly, some pathogens exit the body in blood extracted by needles.

Figure 15.9 Pathogens leave the body of an infected host through various portals of exit to infect new hosts.

Learning Objectives

• Explain how virulence factors contribute to signs and symptoms of infectious disease

• Differentiate between endotoxins and exotoxins

• Describe and differentiate between various types of exotoxins

• Describe the mechanisms viruses use for adhesion and antigenic variation

In the previous section, we explained that some pathogens are more virulent than others. This is due to the unique virulence factors produced by individual pathogens, which determine the extent and severity of disease they may cause. A pathogen’s virulence factors are encoded by genes that can be identified using molecular Koch’s postulates. When genes encoding virulence factors are inactivated, virulence in the pathogen is diminished. In this section, we examine various types and specific examples of virulence factors and how they contribute to each step of pathogenesis.

Virulence Factors for Adhesion

As discussed in the previous section, the first two steps in pathogenesis are exposure and adhesion. Recall that an adhesin is a protein or glycoprotein found on the surface of a pathogen that attaches to receptors on the host cell. Adhesins are found on bacterial, viral, fungal, and protozoan pathogens. One example of a bacterial adhesin is type 1 fimbrial adhesin, a molecule found on the tips of fimbriae of enterotoxigenic E. coli (ETEC). Recall that fimbriae are hairlike protein bristles on the cell surface. Type 1 fimbrial adhesin allows the fimbriae of ETEC cells to attach to the mannose glycans expressed on intestinal epithelial cells. Table 15.7 lists common adhesins found in some of the pathogens we have discussed or will be seeing later in this chapter.

Some Bacterial Adhesins and Their Host Attachment Sites

Table 15.7

was the only one in the family to partake of the hot dogs, the physician suspects that Michael is suffering from a case of listeriosis.

Listeria monocytogenes, the facultative intracellular pathogen that causes listeriosis, is a common contaminant in ready-to-eat foods such as lunch meats and dairy products. Once ingested, these bacteria invade intestinal epithelial cells and translocate to the liver, where they grow inside hepatic cells. Listeriosis is fatal in about one in five normal healthy people, and mortality rates are slightly higher in patients with pre-existing conditions that weaken the immune response. A cluster of virulence genes encoded on a pathogenicity island is responsible for the pathogenicity of L. monocytogenes. These genes are regulated by a transcriptional factor known as peptide chain release factor 1 (PrfA). One of the genes regulated by PrfA is hyl, which encodes a toxin known as listeriolysin O (LLO), which allows the bacterium to escape vacuoles upon entry into a host cell. A second gene regulated by PrfA is actA, which encodes for a surface protein known as actin assembly-inducing protein (ActA). ActA is expressed on the surface of Listeria and polymerizes host actin. This enables the bacterium to produce actin tails, move around the cell’s cytoplasm, and spread from cell to cell without exiting into the extracellular compartment.

Michael’s condition has begun to worsen. He is now experiencing a stiff neck and hemiparesis (weakness of one side of the body). Concerned that the infection is spreading, the physician decides to conduct additional tests to determine what is causing these new symptoms.

• What kind of pathogen causes listeriosis, and what virulence factors contribute to the signs and symptoms Michael is experiencing?

• Is it likely that the infection will spread from Michael’s blood? If so, how might this explain his new symptoms?

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Bacterial Exoenzymes and Toxins as Virulence Factors

After exposure and adhesion, the next step in pathogenesis is invasion, which can involve enzymes and toxins. Many pathogens achieve invasion by entering the bloodstream, an effective means of dissemination because blood vessels pass close to every cell in the body. The downside of this mechanism of dispersal is that the blood also includes numerous elements of the immune system. Various terms ending in –emia are used to describe the presence of pathogens in the bloodstream. The presence of bacteria in blood is called bacteremia. Bacteremia involving pyogens (pus-forming bacteria) is called pyemia. When viruses are found in the blood, it is called viremia. The term toxemia describes the condition when toxins are found in the blood. If bacteria are both present and multiplying in the blood, this condition is called septicemia.

Patients with septicemia are described as septic, which can lead to shock, a life-threatening decrease in blood pressure (systolic pressure <90 mm Hg) that prevents cells and organs from receiving enough oxygen and nutrients. Some bacteria can cause shock through the release of toxins (virulence factors that can cause tissue damage) and lead to low blood pressure. Gram-negative bacteria are engulfed by immune system phagocytes, which then release tumor necrosis factor, a molecule involved in inflammation and fever. Tumor necrosis factor binds to blood capillaries to increase their permeability, allowing fluids to pass out of blood vessels and into tissues, causing swelling, or edema (Figure 15.10). With high concentrations of tumor necrosis factor, the inflammatory reaction is severe and enough fluid is lost from the circulatory system that blood pressure decreases to dangerously low levels. This can have dire consequences because the heart, lungs, and kidneys rely on normal blood pressure for proper function; thus, multi- organ failure, shock, and death can occur.

Figure 15.10 This patient has edema in the tissue of the right hand. Such swelling can occur when bacteria cause the release of pro-inflammatory molecules from immune cells and these molecules cause an increased permeability of blood vessels, allowing fluid to escape the bloodstream and enter tissue.

Virulence Factors for Survival in the Host and Immune Evasion

Evading the immune system is also important to invasiveness. Bacteria use a variety of virulence factors to evade phagocytosis by cells of the immune system. For example, many bacteria produce capsules, which are used in adhesion but also aid in immune evasion by preventing ingestion by phagocytes. The composition of the capsule prevents immune cells from being able to adhere and then phagocytose the cell. In addition, the capsule makes the bacterial cell much larger, making it harder for immune cells to engulf the pathogen (Figure 15.17). A notable capsule-producing bacterium is the gram-positive pathogen Streptococcus pneumoniae, which causes pneumococcal pneumonia, meningitis, septicemia, and other respiratory tract infections. Encapsulated strains of S. pneumoniae are more virulent than nonencapsulated strains and are more likely to invade the bloodstream and cause septicemia and meningitis.

Some pathogens can also produce proteases to protect themselves against phagocytosis. As described in Adaptive Specific Host Defenses, the human immune system produces antibodies that bind to surface molecules found on specific bacteria (e.g., capsules, fimbriae, flagella, LPS). This binding initiates phagocytosis and other mechanisms of antibacterial killing and clearance. Proteases combat antibody-mediated killing and clearance by attacking and digesting the antibody molecules (Figure 15.17).

In addition to capsules and proteases, some bacterial pathogens produce other virulence factors that allow them to evade the immune system. The fimbriae of certain species of Streptococcus contain M protein, which alters the surface of Streptococcus and inhibits phagocytosis by blocking the binding of the complement molecules that assist phagocytes in ingesting bacterial pathogens. The acid-fast bacterium Mycobacterium tuberculosis (the causative agent of tuberculosis) produces a waxy substance known as mycolic acid in its cell envelope. When it is engulfed by phagocytes in the lung, the protective mycolic acid coat enables the bacterium to resist some of the killing mechanisms within the phagolysosome.

8. V. Meka. “Panton-Valentine Leukocidin.” http://www.antimicrobe.org/h04c.files/history/PVL-S-aureus.asp

Figure 15.17 (a) A micrograph of capsules around bacterial cells. (b) Antibodies normally function by binding to antigens, molecules on the surface of pathogenic bacteria. Phagocytes then bind to the antibody, initiating phagocytosis. (c) Some bacteria also produce proteases, virulence factors that break down host antibodies to evade phagocytosis. (credit a: modification of work by Centers for Disease Control and Prevention)

Some bacteria produce virulence factors that promote infection by exploiting molecules naturally produced by the host. For example, most strains of Staphylococcus aureus produce the exoenzyme coagulase, which exploits the natural mechanism of blood clotting to evade the immune system. Normally, blood clotting is triggered in response to blood vessel damage; platelets begin to plug the clot, and a cascade of reactions occurs in which fibrinogen, a soluble protein made by the liver, is cleaved into fibrin. Fibrin is an insoluble, thread-like protein that binds to blood platelets, cross-links, and contracts to form a mesh of clumped platelets and red blood cells. The resulting clot prevents further loss of blood from the damaged blood vessels. However, if bacteria release coagulase into the bloodstream, the fibrinogen-to-fibrin cascade is triggered in the absence of blood vessel damage. The resulting clot coats the bacteria in fibrin, protecting the bacteria from exposure to phagocytic immune cells circulating in the bloodstream.

Whereas coagulase causes blood to clot, kinases have the opposite effect by triggering the conversion of plasminogen to plasmin, which is involved in the digestion of fibrin clots. By digesting a clot, kinases allow pathogens trapped in the clot to escape and spread, similar to the way that collagenase, hyaluronidase, and DNAse facilitate the spread of infection. Examples of kinases include staphylokinases and streptokinases, produced by Staphylococcus aureus and Streptococcus pyogenes, respectively. It is intriguing that S. aureus can produce both coagulase to promote clotting and staphylokinase to stimulate the digestion of clots. The action of the coagulase provides an important protective barrier from the immune system, but when nutrient supplies are diminished or other conditions signal a need for the pathogen to escape and spread, the production of staphylokinase can initiate this process.

A final mechanism that pathogens can use to protect themselves against the immune system is called antigenic variation, which is the alteration of surface proteins so that a pathogen is no longer recognized by the host’s immune system. For example, the bacterium Borrelia burgdorferi, the causative agent of Lyme disease, contains a surface lipoprotein known as VlsE. Because of genetic recombination during DNA replication and repair, this bacterial protein undergoes antigenic variation. Each time fever occurs, the VlsE protein in B. burgdorferi can differ so much that antibodies against previous VlsE sequences are not effective. It is believed that this variation in the VlsE contributes to the ability B. burgdorferi to cause chronic disease. Another important human bacterial pathogen that uses antigenic variation to avoid the immune system is Neisseria gonorrhoeae, which causes the sexually transmitted disease gonorrhea. This bacterium is well known for its ability to undergo antigenic variation of its type IV pili to avoid immune defenses.

• Name at least two ways that a capsule provides protection from the immune system.

• Besides capsules, name two other virulence factors used by bacteria to evade the immune system.

Viral Virulence

Although viral pathogens are not similar to bacterial pathogens in terms of structure, some of the properties that contribute to their virulence are similar. Viruses use adhesins to facilitate adhesion to host cells, and certain enveloped viruses rely on antigenic variation to avoid the host immune defenses. These virulence factors are discussed in more detail in the following sections.

Learning Objectives

• Describe virulence factors unique to fungi and parasites

• Compare virulence factors of fungi and bacteria

• Explain the difference between protozoan parasites and helminths

• Describe how helminths evade the host immune system

Although fungi and parasites are important pathogens causing infectious diseases, their pathogenic mechanisms and virulence factors are not as well characterized as those of bacteria. Despite the relative lack of detailed mechanisms, the stages of pathogenesis and general mechanisms of virulence involved in disease production by these pathogens are similar to those of bacteria.

Fungal Virulence

Pathogenic fungi can produce virulence factors that are similar to the bacterial virulence factors that have been discussed earlier in this chapter. In this section, we will look at the virulence factors associated with species of Candida, Cryptococcus, Claviceps, and Aspergillus.

Candida albicans is an opportunistic fungal pathogen and causative agent of oral thrush, vaginal yeast infections, and cutaneous candidiasis. Candida produces adhesins (surface glycoproteins) that bind to the phospholipids of epithelial and endothelial cells. To assist in spread and tissue invasion, Candida produces proteases and phospholipases (i.e., exoenzymes). One of these proteases degrades keratin, a structural protein found on epithelial cells, enhancing the ability of the fungus to invade host tissue. In animal studies, it has been shown that the addition of a protease inhibitor led to attenuation of Candida infection.^[9] Similarly, the phospholipases can affect the integrity of host cell membranes to facilitate invasion.

The main virulence factor for Cryptococcus, a fungus that causes pneumonia and meningitis, is capsule production. The polysaccharide glucuronoxylomannan is the principal constituent of the Cryptococcus capsule. Similar to encapsulated bacterial cells, encapsulated Cryptococcus cells are more resistant to phagocytosis than nonencapsulated Cryptococcus, which are effectively phagocytosed and, therefore, less virulent.

Like some bacteria, many fungi produce exotoxins. Fungal toxins are called mycotoxins. Claviceps purpurea, a fungus that grows on rye and related grains, produces a mycotoxin called ergot toxin, an alkaloid responsible for the disease known as ergotism. There are two forms of ergotism: gangrenous and convulsive. In gangrenous ergotism, the ergot toxin causes vasoconstriction, resulting in improper blood flow to the extremities, eventually leading to gangrene. A famous outbreak of gangrenous ergotism occurred in Eastern Europe during the 5th century AD due to the consumption of rye contaminated with C. purpurea. In convulsive ergotism, the toxin targets the central nervous system, causing mania and hallucinations.

The mycotoxin aflatoxin is a virulence factor produced by the fungus Aspergillus, an opportunistic pathogen that can enter the body via contaminated food or by inhalation. Inhalation of the fungus can lead to the chronic pulmonary disease aspergillosis, characterized by fever, bloody sputum, and/or asthma. Aflatoxin acts in the host as both a mutagen (a substance that causes mutations in DNA) and a carcinogen (a substance involved in causing cancer), and has been associated with the development of liver cancer. Aflatoxin has also been shown to cross the blood-placental barrier.^[10] A second mycotoxin produced by Aspergillus is gliotoxin. This toxin promotes virulence by inducing host cells to self-destruct and by evading the host’s immune response by inhibiting the function of phagocytic cells as well as the pro-inflammatory response. Like Candida, Aspergillus also produces several proteases. One is elastase, which breaks down the protein elastin found in the connective tissue of the lung, leading to the development of lung disease.

9. K. Fallon et al. “Role of Aspartic Proteases in Disseminated Candida albicans Infection in Mice.” Infection and Immunity 65 no. 2 (1997):551–556.

10. C.P. Wild et al. “In-utero exposure to aflatoxin in west Africa.” Lancet 337 no. 8757 (1991):1602.

Another is catalase, an enzyme that protects the fungus from hydrogen peroxide produced by the immune system to destroy pathogens.

• List virulence factors common to bacteria and fungi.

• What functions do mycotoxins perform to help fungi survive in the host?

Protozoan Virulence

Protozoan pathogens are unicellular eukaryotic parasites that have virulence factors and pathogenic mechanisms analogous to prokaryotic and viral pathogens, including adhesins, toxins, antigenic variation, and the ability to survive inside phagocytic vesicles.

Protozoans often have unique features for attaching to host cells. The protozoan Giardia lamblia, which causes the intestinal disease giardiasis, uses a large adhesive disc composed of microtubules to attach to the intestinal mucosa. During adhesion, the flagella of G. lamblia move in a manner that draws fluid out from under the disc, resulting in an area of lower pressure that facilitates adhesion to epithelial cells. Giardia does not invade the intestinal cells but rather causes inflammation (possibly through the release of cytopathic substances that cause damage to the cells) and shortens the intestinal villi, inhibiting absorption of nutrients.

Some protozoans are capable of antigenic variation. The obligate intracellular pathogen Plasmodium falciparum (one of the causative agents of malaria) resides inside red blood cells, where it produces an adhesin membrane protein known as PfEMP1. This protein is expressed on the surface of the infected erythrocytes, causing blood cells to stick to each other and to the walls of blood vessels. This process impedes blood flow, sometimes leading to organ failure, anemia, jaundice (yellowing of skin and sclera of the eyes due to buildup of bilirubin from lysed red blood cells), and, subsequently, death. Although PfEMP1 can be recognized by the host’s immune system, antigenic variations in the structure of the protein over time prevent it from being easily recognized and eliminated. This allows malaria to persist as a chronic infection in many individuals.

The virulence factors of Trypanosoma brucei, the causative agent of African sleeping sickness, include the abilities to form capsules and undergo antigenic variation. T. brucei evades phagocytosis by producing a dense glycoprotein coat that resembles a bacterial capsule. Over time, host antibodies are produced that recognize this coat, but T. brucei is able to alter the structure of the glycoprotein to evade recognition.

• Explain how antigenic variation by protozoan pathogens helps them survive in the host.

Helminth Virulence

Helminths, or parasitic worms, are multicellular eukaryotic parasites that depend heavily on virulence factors that allow them to gain entry to host tissues. For example, the aquatic larval form of Schistosoma mansoni, which causes schistosomiasis, penetrates intact skin with the aid of proteases that degrade skin proteins, including elastin.

To survive within the host long enough to perpetuate their often-complex life cycles, helminths need to evade the immune system. Some helminths are so large that the immune system is ineffective against them. Others, such as adult roundworms (which cause trichinosis, ascariasis, and other diseases), are protected by a tough outer cuticle.

Over the course of their life cycles, the surface characteristics of the parasites vary, which may help prevent an effective immune response. Some helminths express polysaccharides called glycans on their external surface; because

these glycans resemble molecules produced by host cells, the immune system fails to recognize and attack the helminth as a foreign body. This “glycan gimmickry,” as it has been called, serves as a protective cloak that allows the helminth to escape detection by the immune system.^[11]

In addition to evading host defenses, helminths can actively suppress the immune system. S. mansoni, for example, degrades host antibodies with proteases. Helminths produce many other substances that suppress elements of both innate nonspecific and adaptive specific host defenses. They also release large amounts of material into the host that may locally overwhelm the immune system or cause it to respond inappropriately.

• Describe how helminths avoid being destroyed by the host immune system.

Summary

1. Characteristics of Infectious Disease

   • In an infection, a microorganism enters a host and begins to multiply. Some infections cause disease, which is any deviation from the normal function or structure of the host.

   • Signs of a disease are objective and are measured. Symptoms of a disease are subjective and are reported by the patient.

   • Diseases can either be noninfectious (due to genetics and environment) or infectious (due to pathogens). Some infectious diseases are communicable (transmissible between individuals) or contagious (easily transmissible between individuals); others are noncommunicable, but may be contracted via contact with environmental reservoirs or animals (zoonoses)

   • Nosocomial diseases are contracted in hospital settings, whereas iatrogenic disease are the direct result of a medical procedure

   • An acute disease is short in duration, whereas a chronic disease lasts for months or years. Latent diseases last for years, but are distinguished from chronic diseases by the lack of active replication during extended dormant periods.

   • The periods of disease include the incubation period, the prodromal period, the period of illness, the period of decline, and the period of convalescence. These periods are marked by changes in the number of infectious agents and the severity of signs and symptoms.

2. How Pathogens Cause Disease

   • Koch’s postulates are used to determine whether a particular microorganism is a pathogen. Molecular Koch’s postulates are used to determine what genes contribute to a pathogen’s ability to cause disease.

   • Virulence, the degree to which a pathogen can cause disease, can be quantified by calculating either the ID₅₀

or LD₅₀ of a pathogen on a given population.

• Primary pathogens are capable of causing pathological changes associated with disease in a healthy individual, whereas opportunistic pathogens can only cause disease when the individual is compromised by a break in protective barriers or immunosuppression.

• Infections and disease can be caused by pathogens in the environment or microbes in an individual’s resident microbiota.

• Infections can be classified as local, focal, or systemic depending on the extent to which the pathogen spreads in the body.

11. I. van Die, R.D. Cummings. “Glycan Gimmickry by Parasitic Helminths: A Strategy for Modulating the Host Immune Response?”

Glycobiology 20 no. 1 (2010):2–12.

• A secondary infection can sometimes occur after the host’s defenses or normal microbiota are compromised by a primary infection or antibiotic treatment.

• Pathogens enter the body through portals of entry and leave through portals of exit. The stages of pathogenesis include exposure, adhesion, invasion, infection, and transmission.

3. Virulence Factors of Bacterial and Viral Pathogens

   • Virulence factors contribute to a pathogen’s ability to cause disease.

   • Exoenzymes and toxins allow pathogens to invade host tissue and cause tissue damage. Exoenzymes are classified according to the macromolecule they target and exotoxins are classified based on their mechanism of action.

   • Bacterial toxins include endotoxin and exotoxins. Endotoxin is the lipid A component of the LPS of the gram- negative cell envelope. Exotoxins are proteins secreted mainly by gram-positive bacteria, but also are secreted by gram-negative bacteria.

   • Bacterial pathogens may evade the host immune response by producing capsules to avoid phagocytosis, surviving the intracellular environment of phagocytes, degrading antibodies, or through antigenic variation.

   • Viral pathogens use adhesins for initiating infections and antigenic variation to avoid immune defenses.

   • Influenza viruses use both antigenic drift and antigenic shift to avoid being recognized by the immune system.

4. Virulence Factors of Eukaryotic Pathogens

   • Fungal and parasitic pathogens use pathogenic mechanisms and virulence factors that are similar to those of bacterial pathogens

   • Fungi initiate infections through the interaction of adhesins with receptors on host cells. Some fungi produce toxins and exoenzymes involved in disease production and capsules that provide protection of phagocytosis.

   • Protozoa adhere to target cells through complex mechanisms and can cause cellular damage through release of cytopathic substances. Some protozoa avoid the immune system through antigenic variation and production of capsules.

   • Helminthic worms are able to avoid the immune system by coating their exteriors with glycan molecules that make them look like host cells or by suppressing the immune system.

Review Questions

Multiple Choice

1. Which of the following would be a sign of an infection?

   1. muscle aches

   2. headache

   3. fever

   4. nausea

2. Which of the following is an example of a noncommunicable infectious disease?

   5. infection with a respiratory virus

   6. food poisoning due to a preformed bacterial toxin in food

   7. skin infection acquired from a dog bite

   8. infection acquired from the stick of a contaminated needle

3. During an oral surgery, the surgeon nicked the patient’s gum with a sharp instrument. This allowed Streptococcus, a bacterium normally present in the mouth, to gain access to the blood. As a result, the patient developed bacterial endocarditis (an infection of the heart). Which type of disease is this?

   9. iatrogenic

   10. nosocomial

   11. vectors

   12. zoonotic

4. Which period is the stage of disease during which the patient begins to present general signs and symptoms?

   13. convalescence

   14. incubation

   15. illness

   16. prodromal

5. A communicable disease that can be easily transmitted from person to person is which type of disease?

   17. contagious

   18. iatrogenic

   19. acute

   20. nosocomial

6. Which of the following is a pathogen that could not be identified by the original Koch’s postulates?

   21. Staphylococcus aureus

   22. Pseudomonas aeruginosa

   23. Human immunodeficiency virus

   24. Salmonella enterica serovar Typhimurium

7. Pathogen A has an ID₅₀ of 50 particles, pathogen B has an ID₅₀ of 1,000 particles, and pathogen C has an ID₅₀ of 1 × 106 particles. Which pathogen is most virulent?

   25. pathogen A

   26. pathogen B

   27. pathogen C

8. Which of the following choices lists the steps of pathogenesis in the correct order?

   28. invasion, infection, adhesion, exposure

   29. adhesion, exposure, infection, invasion

   30. exposure, adhesion, invasion, infection

   31. disease, infection, exposure, invasion

9. Which of the following would be a virulence factor of a pathogen?

   32. a surface protein allowing the pathogen to bind to host cells

   33. a secondary host the pathogen can infect

   34. a surface protein the host immune system recognizes

   35. the ability to form a provirus

10. You have recently identified a new toxin. It is produced by a gram-negative bacterium. It is composed mostly of protein, has high toxicity, and is not heat stable. You also discover that it targets liver cells. Based on these characteristics, how would you classify this toxin?

    36. superantigen

    37. endotoxin

    38. exotoxin

    39. leukocidin

Fill in the Blank

11. Which of the following applies to hyaluronidase?

    40. It acts as a spreading factor.

    41. It promotes blood clotting.

    42. It is an example of an adhesin.

    43. It is produced by immune cells to target pathogens.

12. Phospholipases are enzymes that do which of the following?

    44. degrade antibodies

    45. promote pathogen spread through connective tissue.

    46. degrade nucleic acid to promote spread of pathogen

    47. degrade cell membranes to allow pathogens to escape phagosomes

13. Which of the following is a major virulence factor for the fungal pathogen Cryptococcus?

    48. hemolysin

    49. capsule

    50. collagenase

    51. fimbriae

14. Which of the following pathogens undergoes antigenic variation to avoid immune defenses?

    52. Candida

    53. Cryptococcus

    54. Plasmodium

    55. Giardia

15. A difference between an acute disease and chronic disease is that chronic diseases have an extended period of

.

16. A person steps on a rusty nail and develops tetanus. In this case, the person has acquired a(n)

disease.

17. A(n) pathogen causes disease only when conditions are favorable for the microorganism because of transfer to an inappropriate body site or weakened immunity in an individual.

18. The concentration of pathogen needed to kill 50% of an infected group of test animals is the .

19. A(n) infection is a small region of infection from which a pathogen may move to another part of the body to establish a second infection.

20. Cilia, fimbriae, and pili are all examples of structures used by microbes for .

21. The glycoprotein adhesion gp120 on HIV must interact with on some immune cells as the first step in the process of infecting the cell.

22. Adhesins are usually located on of the pathogen and are composed mainly of and

.

23. The Shiga and diphtheria toxins target in host cells.

24. Antigenic is the result of reassortment of genes responsible for the production of influenza virus spike proteins between different virus particles while in the same host, whereas antigenic is the result of point mutations in the spike proteins.

25. Candida can invade tissue by producing the exoenzymes and .

26. The larval form of Schistosoma mansoni uses a to help it gain entry through intact skin.

Short Answer

27. Brian goes to the hospital after not feeling well for a week. He has a fever of 38 °C (100.4 °F) and complains of nausea and a constant migraine. Distinguish between the signs and symptoms of disease in Brian’s case.

28. Describe the virulence factors associated with the fungal pathogen Aspergillus.

29. Explain how helminths evade the immune system.

Critical Thinking

30. Two periods of acute disease are the periods of illness and period of decline. (a) In what way are both of these periods similar? (b) In terms of quantity of pathogen, in what way are these periods different? (c) What initiates the period of decline?

31. In July 2015, a report^[12] was released indicating the gram-negative bacterium Pseudomonas aeruginosa was found on hospital sinks 10 years after the initial outbreak in a neonatal intensive care unit. P. aeruginosa usually causes localized ear and eye infections but can cause pneumonia or septicemia in vulnerable individuals like newborn babies. Explain how the current discovery of the presence of this reported P. aeruginosa could lead to a recurrence of nosocomial disease.

32. Diseases that involve biofilm-producing bacteria are of serious concern. They are not as easily treated compared with those involving free-floating (or planktonic) bacteria. Explain three reasons why biofilm formers are more pathogenic.

33. A microbiologist has identified a new gram-negative pathogen that causes liver disease in rats. She suspects that the bacterium’s fimbriae are a virulence factor. Describe how molecular Koch’s postulates could be used to test this hypothesis.

12. C. Owens. “P. aeruginosa survives in sinks 10 years after hospital outbreak.” 2015. http://www.healio.com/infectious-disease/ nosocomial-infections/news/online/%7B5afba909-56d9-48cc-a9b0-ffe4568161e8%7D/p-aeruginosa-survives-in-sinks-10-years-after- hospital-outbreak

34. Acupuncture is a form of alternative medicine that is used for pain relief. Explain how acupuncture could facilitate exposure to pathogens.

35. Two types of toxins are hemolysins and leukocidins. (a) How are these toxins similar? (b) How do they differ?

36. Imagine that a mutation in the gene encoding the cholera toxin was made. This mutation affects the A-subunit, preventing it from interacting with any host protein. (a) Would the toxin be able to enter into the intestinal epithelial cell? (b) Would the toxin be able to cause diarrhea?