Microbiology Review Questions PDF

14 Review Questions 587 resistant, HIV is typically treated with a to various antimicrobial drugs. However, the combination of several antiretroviral drugs, zones of inhibition measured must be correlated which may include reverse transcriptase...

14 Review Questions 587 resistant, HIV is typically treated with a to various antimicrobial drugs. However, the combination of several antiretroviral drugs, zones of inhibition measured must be correlated which may include reverse transcriptase to known standards to determine susceptibility inhibitors, protease inhibitors, integrase and resistance, and do not provide information inhibitors, and drugs that interfere with viral on bactericidal versus bacteriostatic activity, or binding and fusion to initiate infection. allow for direct comparison of drug potencies. Antibiograms are useful for monitoring local 14.5 Drug Resistance trends in antimicrobial resistance/susceptibility Antimicrobial resistance is on the rise and is the and for directing appropriate selection of empiric result of selection of drug-resistant strains in antibacterial therapy. clinical environments, the overuse and misuse of There are several laboratory methods available antibacterials, the use of subtherapeutic doses of for determining the minimum inhibitory antibacterial drugs, and poor patient compliance concentration (MIC) of an antimicrobial drug with antibacterial drug therapies. against a specific microbe. The minimal Drug resistance genes are often carried on bactericidal concentration (MBC) can also be plasmids or in transposons that can undergo determined, typically as a follow-up experiment vertical transfer easily and between microbes to MIC determination using the tube dilution through horizontal gene transfer. method. Common modes of antimicrobial drug resistance 14.7 Current Strategies for Antimicrobial include drug modification or inactivation, prevention of cellular uptake or efflux, target Discovery modification, target overproduction or enzymatic Current research into the development of bypass, and target mimicry. antimicrobial drugs involves the use of high- Problematic microbial strains showing extensive throughput screening and combinatorial antimicrobial resistance are emerging; many of chemistry technologies. these strains can reside as members of the New technologies are being developed to normal microbiota in individuals but also can discover novel antibiotics from soil cause opportunistic infection. The transmission microorganisms that cannot be cultured by of many of these highly resistant microbial standard laboratory methods. strains often occurs in clinical settings, but can Additional strategies include searching for also be community-acquired. antibiotics from sources other than soil, identifying new antibacterial targets, using 14.6 Testing the Effectiveness of combinatorial chemistry to develop novel drugs, Antimicrobials developing drugs that inhibit resistance The Kirby-Bauer disk diffusion test helps mechanisms, and developing drugs that target determine the susceptibility of a microorganism virulence factors and hold infections in check. Review Questions Multiple Choice 1. A scientist discovers that a soil bacterium he has C. synthetic been studying produces an antimicrobial that D. natural kills gram-negative bacteria. She isolates and purifies the antimicrobial compound, then 2. Which of the following antimicrobial drugs is chemically converts a chemical side chain to a synthetic? hydroxyl group. When she tests the antimicrobial A. sulfanilamide properties of this new version, she finds that this B. penicillin antimicrobial drug can now also kill gram- C. actinomycin positive bacteria. The new antimicrobial drug D. neomycin with broad-spectrum activity is considered to be which of the following? 3. Which of the following combinations would most A. resistant likely contribute to the development of a B. semisynthetic superinfection? 588 14 Review Questions A. long-term use of narrow-spectrum activity of DNA gyrase? antimicrobials A. polymyxin B B. long-term use of broad-spectrum B. clindamycin antimicrobials C. nalidixic acid C. short-term use of narrow-spectrum D. rifampin antimicrobials D. short-term use of broad-spectrum 10. Which of the following is not an appropriate antimicrobials target for antifungal drugs? A. ergosterol 4. Which of the following routes of administration B. chitin would be appropriate and convenient for home C. cholesterol administration of an antimicrobial to treat a D. β(1→3) glucan systemic infection? A. oral 11. Which of the following drug classes specifically B. intravenous inhibits neuronal transmission in helminths? C. topical A. quinolines D. parenteral B. avermectins C. amantadines 5. Which clinical situation would be appropriate for D. imidazoles treatment with a narrow-spectrum antimicrobial drug? 12. Which of the following is a nucleoside analog A. treatment of a polymicrobic mixed commonly used as a reverse transcriptase infection in the intestine inhibitor in the treatment of HIV? B. prophylaxis against infection after a A. acyclovir surgical procedure B. ribavirin C. treatment of strep throat caused by C. adenine-arabinoside culture identified Streptococcus pyogenes D. azidothymidine D. empiric therapy of pneumonia while waiting for culture results 13. Which of the following is an antimalarial drug that is thought to increase ROS levels in target 6. Which of the following terms refers to the ability cells? of an antimicrobial drug to harm the target A. artemisinin microbe without harming the host? B. amphotericin b A. mode of action C. praziquantel B. therapeutic level D. pleconaril C. spectrum of activity D. selective toxicity 14. Which of the following resistance mechanisms describes the function of β-lactamase? 7. Which of the following is not a type of β-lactam A. efflux pump antimicrobial? B. target mimicry A. penicillins C. drug inactivation B. glycopeptides D. target overproduction C. cephalosporins D. monobactams 15. Which of the following resistance mechanisms is commonly effective against a wide range of 8. Which of the following does not bind to the 50S antimicrobials in multiple classes? ribosomal subunit? A. efflux pump A. tetracyclines B. target mimicry B. lincosamides C. target modification C. macrolides D. target overproduction D. chloramphenicol 16. Which of the following resistance mechanisms is 9. Which of the following antimicrobials inhibits the the most nonspecific to a particular class of Access for free at openstax.org  14 Review Questions 589 antimicrobials? used to determine the minimum inhibitory A. drug modification concentration of an antimicrobial drug against a B. target mimicry particular microbe? C. target modification A. Etest D. efflux pump B. microbroth dilution test C. Kirby-Bauer disk diffusion test 17. Which of the following types of drug-resistant D. macrobroth dilution test bacteria do not typically persist in individuals as a member of their intestinal microbiota? 20. The utility of an antibiogram is that it shows A. MRSA antimicrobial susceptibility trends B. VRE A. over a large geographic area. C. CRE B. for an individual patient. D. ESBL-producing bacteria C. in research laboratory strains. D. in a localized population. 18. In the Kirby-Bauer disk diffusion test, the _______ of the zone of inhibition is measured 21. Which of the following has yielded compounds and used for interpretation. with the most antimicrobial activity? A. diameter A. water B. microbial population B. air C. circumference C. volcanoes D. depth D. soil 19. Which of the following techniques cannot be True/False 22. Narrow-spectrum antimicrobials are commonly 25. If drug A produces a larger zone of inhibition used for prophylaxis following surgery. than drug B on the Kirby-Bauer disk diffusion test, drug A should always be prescribed. 23. β-lactamases can degrade vancomycin. 26. The rate of discovery of antimicrobial drugs has 24. Echinocandins, known as “penicillin for fungi,” decreased significantly in recent decades. target β(1→3) glucan in fungal cell walls. Fill in the Blank 27. The group of soil bacteria known for their ability effective against the influenza virus by to produce a wide variety of antimicrobials is preventing viral escape from host cells are called called the ________. ________. 28. The bacterium known for causing 31. Staphylococcus aureus, including MRSA strains, pseudomembranous colitis, a potentially deadly may commonly be carried as a normal member superinfection, is ________. of the ________ microbiota in some people. 29. Selective toxicity antimicrobials are easier to 32. The method that can determine the MICs of develop against bacteria because they are multiple antimicrobial drugs against a microbial ________ cells, whereas human cells are strain using a single agar plate is called the eukaryotic. ________. 30. Antiviral drugs, like Tamiflu and Relenza, that are Short Answer 33. Where do antimicrobials come from naturally? the patient’s health history should the clinician Why? ask about and why? 34. Why was Salvarsan considered to be a “magic 36. When is using a broad-spectrum antimicrobial bullet” for the treatment of syphilis? drug warranted? 35. When prescribing antibiotics, what aspects of 37. If human cells and bacterial cells perform 590 14 Review Questions transcription, how are the rifamycins specific for niclosamide aid its effectiveness as a treatment bacterial infections? for tapeworm infection? 38. What bacterial structural target would make an 41. Why does the length of time of antimicrobial antibacterial drug selective for gram-negative treatment for tuberculosis contribute to the rise bacteria? Provide one example of an of resistant strains? antimicrobial compound that targets this 42. What is the difference between multidrug structure. resistance and cross-resistance? 39. How does the biology of HIV necessitate the 43. How is the information from a Kirby-Bauer disk need to treat HIV infections with multiple drugs? diffusion test used for the recommendation of 40. Niclosamide is insoluble and thus is not readily the clinical use of an antimicrobial drug? absorbed from the stomach into the 44. What is the difference between MIC and MBC? bloodstream. How does the insolubility of Critical Thinking 45. In nature, why do antimicrobial-producing microbes commonly also have antimicrobial resistance genes? 46. Why are yeast infections a common type of superinfection that results from long-term use of broad-spectrum antimicrobials? 47. Too often patients will stop taking antimicrobial drugs before the prescription is finished. What are factors that cause a patient to stop too soon, and what negative impacts could this have? 48. In considering the cell structure of prokaryotes compared with that of eukaryotes, propose one possible reason for side effects in humans due to treatment of bacterial infections with protein synthesis inhibitors. 49. Which of the following molecules is an example of a nucleoside analog? 50. Why can’t drugs used to treat influenza, like amantadines and neuraminidase inhibitors, be used to treat a wider variety of viral infections? 51. Can an Etest be used to find the MBC of a drug? Explain. 52. Who should be responsible for discovering and developing new antibiotics? Support your answer with reasoning. Access for free at openstax.org CHAPTER 15 Microbial Mechanisms of Pathogenicity FIGURE 15.1 Although medical professionals rely heavily on signs and symptoms to diagnose disease and prescribe treatment, many diseases can produce similar signs and symptoms. (credit left: modification of work by U.S. Navy) CHAPTER OUTLINE 15.1 Characteristics of Infectious Disease 15.2 How Pathogens Cause Disease 15.3 Virulence Factors of Bacterial and Viral Pathogens 15.4 Virulence Factors of Eukaryotic Pathogens INTRODUCTION Jane woke up one spring morning feeling not quite herself. Her throat felt a bit dry and she was sniffling. She wondered why she felt so lousy. Was it because of a change in the weather? The pollen count? Was she coming down with something? Did she catch a bug from her coworker who sneezed on her in the elevator yesterday? The signs and symptoms we associate with illness can have many different causes. Sometimes they are the direct result of a pathogenic infection, but in other cases they result from a response by our immune system to a pathogen or another perceived threat. For example, in response to certain pathogens, the immune system may release pyrogens, chemicals that cause the body temperature to rise, resulting in a fever. This response creates a less-than- favorable environment for the pathogen, but it also makes us feel sick. Medical professionals rely heavily on analysis of signs and symptoms to determine the cause of an ailment and prescribe treatment. In some cases, signs and symptoms alone are enough to correctly identify the causative agent of a disease, but since few diseases produce truly unique symptoms, it is often necessary to confirm the identity of the infectious agent by other direct and indirect diagnostic methods. 15.1 Characteristics of Infectious Disease LEARNING OBJECTIVES By the end of this section, you will be able to: 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 592 15 Microbial Mechanisms of Pathogenicity CLINICAL FOCUS Part 1 Michael, a 10-year-old boy in generally good health, went to a birthday party on Sunday with his family. He ate many different foods but was the only one in the family to eat the undercooked hot dogs served by the hosts. Monday morning, he woke up feeling achy and nauseous, and he was running a fever of 38 °C (100.4 °F). His parents, assuming Michael had caught the flu, made him stay home from school and limited his activities. But after 4 days, Michael began to experience severe headaches, and his fever spiked to 40 °C (104 °F). Growing worried, his parents finally decide to take Michael to a nearby clinic. What signs and symptoms is Michael experiencing? What do these signs and symptoms tell us about the stage of Michael’s disease? Jump to the next Clinical Focus box. 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. 1 These fluctuations reflect sweating due to skin sympathetic nerve activity resulting from the stressor of pain. 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. 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/ Access for free at openstax.org  15.1 Characteristics of Infectious Disease 593 Nomenclature of Symptoms Affix Meaning Example cyto- cell cytopenia: reduction in the number of blood cells hepat- of the liver hepatitis: inflammation of the liver -pathy disease neuropathy: a disease affecting nerves -emia of the blood bacteremia: presence of bacteria in blood -itis inflammation colitis: inflammation of the colon -lysis destruction hemolysis: destruction of red blood cells -oma tumor lymphoma: cancer of the lymphatic system -osis diseased or abnormal condition leukocytosis: abnormally high number of white blood cells -derma of the skin keratoderma: a thickening of the skin 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. CHECK YOUR UNDERSTANDING Explain the difference between signs and symptoms. 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 594 15 Microbial Mechanisms of Pathogenicity 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 Type Definition Example Inherited A genetic disease Sickle cell anemia Congenital Disease that is present at or before birth Down syndrome Degenerative Progressive, irreversible loss of function Parkinson disease (affecting central nervous system) TABLE 15.2 Access for free at openstax.org  15.1 Characteristics of Infectious Disease 595 Types of Noninfectious Diseases Type Definition Example Nutritional Impaired body function due to lack of Scurvy (vitamin C deficiency) deficiency nutrients Endocrine Disease involving malfunction of glands Hypothyroidism – thyroid does not produce that release hormones to regulate body enough thyroid hormone, which is important for functions metabolism Neoplastic Abnormal growth (benign or malignant) Some forms of cancer Idiopathic Disease for which the cause is unknown Idiopathic juxtafoveal retinal telangiectasia (dilated, twisted blood vessels in the retina of the eye) 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) LINK TO LEARNING Lists of common infectious diseases can be found at the following Centers for Disease Control and Prevention (https://openstax.org/l/22CDCdis) (CDC), World Health Organization (https://openstax.org/l/22WHOdis) (WHO), and International Classification of Diseases (https://openstax.org/l/22WHOclass) websites. CHECK YOUR UNDERSTANDING 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 596 15 Microbial Mechanisms of Pathogenicity 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, Access for free at openstax.org  15.2 How Pathogens Cause Disease 597 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). CHECK YOUR UNDERSTANDING 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 2 producing the enzyme urease, which modifies the local acidity, allowing the bacteria to survive indefinitely. 3 Consequently, H. pylori infections can recur indefinitely unless the infection is cleared using antibiotics. 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. CHECK YOUR UNDERSTANDING Explain the difference between latent disease and chronic disease. 15.2 How Pathogens Cause Disease LEARNING OBJECTIVES By the end of this section, you will be able to: 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 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. 598 15 Microbial Mechanisms of Pathogenicity 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 (1) The suspected pathogen must be found in every case of disease and not be found in healthy individuals. (2) The suspected pathogen can be isolated and grown in pure culture. (3) A healthy test subject infected with the suspected pathogen must develop the same signs and symptoms of disease as seen in postulate 1. (4) The pathogen must be re-isolated from the new host and must be identical to the pathogen from postulate 2. 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, Access for free at openstax.org  15.2 How Pathogens Cause Disease 599 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. Similarly, when Alice Katherine Evans discovered that Brucellis bacteria found in cows was responsible for a common human disease, she noted that the infected cattle could pass on the infection whether or not they displayed symptoms. This is an important distinction: Even without knowledge of microbiology, many people would not consume milk from a visibly sick cow, but the concept of a healthy cow being infectious is critical to understanding the risks posed by pathogens. 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 3 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. CHECK YOUR UNDERSTANDING 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. 600 15 Microbial Mechanisms of Pathogenicity Molecular Koch’s Postulates Applied to EHEC Molecular Koch’s Postulates Application to EHEC (1) The phenotype (sign or symptom of EHEC causes intestinal inflammation and diarrhea, whereas disease) should be associated only with nonpathogenic strains of E. coli do not. pathogenic strains of a species. (2) Inactivation of the suspected gene(s) One of the genes in EHEC encodes for Shiga toxin, a bacterial associated with pathogenicity should result toxin (poison) that inhibits protein synthesis. Inactivating this in a measurable loss of pathogenicity. gene reduces the bacteria’s ability to cause disease. (3) Reversion of the inactive gene should By adding the gene that encodes the toxin back into the genome restore the disease phenotype. (e.g., with a phage or plasmid), EHEC’s ability to cause disease is restored. 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. CHECK YOUR UNDERSTANDING 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 Access for free at openstax.org  15.2 How Pathogens Cause Disease 601 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. 4 ID50 for Selected Foodborne Diseases Pathogen ID50 Viruses Hepatitis A virus 10–100 Norovirus 1–10 Rotavirus 10–100 Bacteria Escherichia coli, enterohemorrhagic (EHEC, serotype O157) 10–100 E. coli, enteroinvasive (EIEC) 200–5,000 TABLE 15.5 602 15 Microbial Mechanisms of Pathogenicity 4 ID50 for Selected Foodborne Diseases Pathogen ID50 E. coli, enteropathogenic (EPEC) 10,000,000–10,000,000,000 E. coli, enterotoxigenic (ETEC) 10,000,000–10,000,000,000 Salmonella enterica serovar Typhi