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12.2: Characteristics and Steps of Infectious Diseases

  • Page ID
    31850
  • Learning Objectives

    • Distinguish between signs and symptoms of disease
    • Explain the difference between a communicable disease and a noncommunicable disease
    • Identify and describe the stages of an acute infectious disease in terms of number of pathogens present and severity of signs and symptoms
    • 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

    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. Microorganisms that can cause disease are known as pathogens. Infections can lead to disease, which causes signs and symptoms resulting in a deviation from the normal structure or functioning of the host. 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 \(\PageIndex{1}\) lists some of the prefixes and suffixes commonly used in naming syndromes.

    Table \(\PageIndex{1}\): 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

    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.

    Exercise \(\PageIndex{1}\)

    Explain the difference between signs and symptoms.

    Periods of Disease

    A graph titled “Periods of Disease” with time on the X axis and two separate Y-axes: number of pathogen particles (red) and severity of symptoms (blue). Both of these lines mirror each other and have a general bell shape. The first stage is incubation period when there are few pathogens and symptoms are mild. The next stage is prodromal period when the number of pathogens is increasing and symptoms are becoming more severe. The next stage is period of illness where numbers of pathogens and symptoms both continue to increase. The next stage is period of decline in infection where the number of pathogens is decreasing and symptoms are becoming less severe. The final stage is period of convalescence when symptoms go away and the number of pathogens decrease. Note that there are still pathogens present even after there are no more symptoms of the disease.
    Figure \(\PageIndex{1}\): 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 five periods of disease (sometimes referred to as stages or phases) include the incubation, prodromal, illness, decline, and convalescence periods (Figure \(\PageIndex{1}\)). 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.

    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, specific 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).

    Exercise \(\PageIndex{2}\)

    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.

    Exercise \(\PageIndex{3}\)

    Explain the difference between latent disease and chronic disease.

    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.

    A graph with “number of pathogenic agents (cells or virions)” on the X axis and Percent mortality in experimental group on the Y axis. The graph begins at 0,0 and increases until there is nearly 100% death at 10 to the 5. The line then plateaus at 100%.  A 50% death rate occurs at 10 to the 4. This is the LD 50.
    Figure \(\PageIndex{2}\): 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.

    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 \(\PageIndex{2}\), the percentage of animals that have been infected (for ID50) or killed (for LD50) is plotted against the concentration of pathogen inoculated. Figure \(\PageIndex{2}\) 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).

    Table \(\PageIndex{2}\) 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.

    Table \(\PageIndex{2}\): ID50 for Selected Foodborne Diseases1
    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
    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 <1,000>
    S. enterica serovar Typhimurium ≥1
    Shigella dysenteriae 10–200
    Vibrio cholerae (serotypes O139, O1) 1,000,000
    V. parahemolyticus 100,000,000
    Protozoa
    Giardia lamblia 1
    Cryptosporidium parvum 10–100

    Exercise \(\PageIndex{4}\)

    1. What is the difference between a pathogen’s infective dose and lethal dose?
    2. Which is more closely related to the severity of a disease?

    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.6 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.

    Exercise \(\PageIndex{5}\)

    1. Explain the difference between a primary pathogen and an opportunistic pathogen.
    2. 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.

    Exposure

    An encounter with a potential pathogen is known as exposure or contact. The food we eat and the objects we handle are all ways that we can come into contact with potential pathogens. Yet, not all contacts result in infection and disease. For a pathogen to cause disease, it needs to be able to gain access into host tissue. An anatomic site through which pathogens can pass into host tissue is called a portal of entry. These are locations where the host cells are in direct contact with the external environment. Major portals of entry are identified in Figure \(\PageIndex{3}\) and include the skin, mucous membranes, and parenteral routes.

    Portals of entry: eye (conjunctiva), nose, mouth, ear, needle, broken skin, insect bite, urethra, vagina, anus, placenta (portal of entry for fetus).
    Figure \(\PageIndex{3}\): Shown are different portals of entry where pathogens can gain access into the body. With the exception of the placenta, many of these locations are directly exposed to the external environment.

    Mucosal surfaces are the most important portals of entry for microbes; these include the mucous membranes of the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Although most mucosal surfaces are in the interior of the body, some are contiguous with the external skin at various body openings, including the eyes, nose, mouth, urethra, and anus.

    Most pathogens are suited to a particular portal of entry. A pathogen’s portal specificity is determined by the organism’s environmental adaptions and by the enzymes and toxins they secrete. The respiratory and gastrointestinal tracts are particularly vulnerable portals of entry because particles that include microorganisms are constantly inhaled or ingested, respectively.

    Pathogens can also enter through a breach in the protective barriers of the skin and mucous membranes. Pathogens that enter the body in this way are said to enter by the parenteral route. For example, the skin is a good natural barrier to pathogens, but breaks in the skin (e.g., wounds, insect bites, animal bites, needle pricks) can provide a parenteral portal of entry for microorganisms.

    In pregnant women, the placenta normally prevents microorganisms from passing from the mother to the fetus. However, a few pathogens are capable of crossing the blood-placental barrier. The gram-positive bacterium Listeria monocytogenes, which causes the foodborne disease listeriosis, is one example that poses a serious risk to the fetus and can sometimes lead to spontaneous abortion. Other pathogens that can pass the placental barrier to infect the fetus are known collectively by the acronym TORCH (Table \(\PageIndex{3}\)).

    Transmission of infectious diseases from mother to baby is also a concern at the time of birth when the baby passes through the birth canal. Babies whose mothers have active chlamydia or gonorrhea infections may be exposed to the causative pathogens in the vagina, which can result in eye infections that lead to blindness. To prevent this, it is standard practice to administer antibiotic drops to infants’ eyes shortly after birth.

    Table \(\PageIndex{3}\): Pathogens Capable of Crossing the Placental Barrier (TORCH Infections)

      Disease Pathogen
    T Toxoplasmosis Toxoplasma gondii (protozoan)
    O7

    Syphilis

    Chickenpox

    Hepatitis B

    HIV

    Fifth disease (erythema infectiosum)

    Treponema pallidum (bacterium)

    Varicella-zoster virus (human herpesvirus 3)

    Hepatitis B virus (hepadnavirus)

    Retrovirus

    Parvovirus B19

    R Rubella (German measles) Togavirus
    C Cytomegalovirus Human herpesvirus 5
    H Herpes Herpes simplex viruses (HSV) 1 and 2

    Clinical Focus: part 2

    At the clinic, a physician takes down Michael’s medical history and asks about his activities and diet over the past week. Upon learning that Michael became sick the day after the party, the physician orders a blood test to check for pathogens associated with foodborne diseases. After tests confirm that presence of a gram-positive rod in Michael’s blood, he is given an injection of a broad-spectrum antibiotic and sent to a nearby hospital, where he is admitted as a patient. There he is to receive additional intravenous antibiotic therapy and fluids.

    Exercise \(\PageIndex{6}\)

    1. Is this bacterium in Michael’s blood part of normal microbiota?
    2. What portal of entry did the bacteria use to cause this infection?

    Adhesion

    Following the initial exposure, the pathogen adheres at the portal of entry. The term adhesion refers to the capability of pathogenic microbes to attach to the cells of the body using adhesion factors, and different pathogens use various mechanisms to adhere to the cells of host tissues.

    Molecules (either proteins or carbohydrates) called adhesins are found on the surface of certain pathogens and bind to specific receptors (glycoproteins) on host cells. Adhesins are present on the fimbriae and flagella of bacteria, the cilia of protozoa, and the capsids or membranes of viruses. Protozoans can also use hooks and barbs for adhesion; spike proteins on viruses also enhance viral adhesion. The production of glycocalyces (slime layers and capsules) (Figure \(\PageIndex{4}\)), with their high sugar and protein content, can also allow certain bacterial pathogens to attach to cells.

    Biofilm growth can also act as an adhesion factor. A biofilm is a community of bacteria that produce a glycocalyx, which contributes to the extrapolymeric substances (EPS) that allows the biofilm to attach to a surface. Persistent Pseudomonas aeruginosa infections are common in patients suffering from cystic fibrosis, burn wounds, and middle-ear infections (otitis media) because P. aeruginosa produces a biofilm. The EPS allows the microbe to adhere to the host cells and makes it harder for the host to physically remove the pathogen. The EPS not only allows for attachment but provides protection against the immune system and antibiotic or antimicrobial treatments, preventing the medications from reaching the cells within the biofilm. In addition, not all bacteria in a biofilm are rapidly growing; some are in stationary phase. Since antibiotics are most effective against rapidly growing bacteria, portions of bacteria in a biofilm are protected against antibiotics.8

    clipboard_e90a6ea9f14f14b935006d2e2e4378a88.png
    Figure \(\PageIndex{4}\): Glycocalyx produced by bacteria in a biofilm allows the cells to adhere to host tissues and to medical devices such as the catheter surface shown here. (credit: modification of work by Centers for Disease Control and Prevention)

    Invasion

    Once adhesion is successful, invasion can proceed. Invasion involves the dissemination of a pathogen throughout local tissues or the body. Pathogens may produce exoenzymes or toxins, which serve as virulence factors that allow them to colonize and damage host tissues as they spread deeper into the body. Pathogens may also produce virulence factors that protect them against immune system defenses. A pathogen’s specific virulence factors determine the degree of tissue damage that occurs. Figure \(\PageIndex{5}\) shows the invasion of H. pylori into the tissues of the stomach, causing damage as it progresses.

    Diagram of H. pylori invading the lining of the stomach. In the first image the H. pylori (an oval cell with 3 flagella is not able to penetrate the gastric mucin gel on top of the epithelial cells. Contact with stomach acid keeps the mucin lining the epithelial cell layer in a spongy gel-like state. This consistency is impermeable to the bacterium H. pylori. The second image shows the bacterium entering the lining. The bacterium releases urease, which neutralizes the stomach acid. This causes the mucin to liquefy and the bacterium can swim right through it.
    Figure \(\PageIndex{5}\): H. pylori is able to invade the lining of the stomach by producing virulence factors that enable it pass through the mucin layer covering epithelial cells. (credit: modification of work by Zina Deretsky, National Science Foundation)

    Intracellular pathogens achieve invasion by entering the host’s cells and reproducing. Some are obligate intracellular pathogens (meaning they can only reproduce inside of host cells) and others are facultative intracellular pathogens (meaning they can reproduce either inside or outside of host cells). By entering the host cells, intracellular pathogens are able to evade some mechanisms of the immune system while also exploiting the nutrients in the host cell.

    Entry to a cell can occur by endocytosis. For most kinds of host cells, pathogens use one of two different mechanisms for endocytosis and entry. One mechanism relies on effector proteins secreted by the pathogen; these effector proteins trigger entry into the host cell. This is the method that Salmonella and Shigella use when invading intestinal epithelial cells. When these pathogens come in contact with epithelial cells in the intestine, they secrete effector molecules that cause protrusions of membrane ruffles that bring the bacterial cell in. This process is called membrane ruffling. The second mechanism relies on surface proteins expressed on the pathogen that bind to receptors on the host cell, resulting in entry. For example, Yersinia pseudotuberculosis produces a surface protein known as invasin that binds to beta-1 integrins expressed on the surface of host cells.

    Some host cells, such as white blood cells and other phagocytes of the immune system, actively endocytose pathogens in a process called phagocytosis. Although phagocytosis allows the pathogen to gain entry to the host cell, in most cases, the host cell kills and degrades the pathogen by using digestive enzymes. Normally, when a pathogen is ingested by a phagocyte, it is enclosed within a phagosome in the cytoplasm; the phagosome fuses with a lysosome to form a phagolysosome, where digestive enzymes kill the pathogen. However, some intracellular pathogens have the ability to survive and multiply within phagocytes. Examples include Listeria monocytogenes and Shigella; these bacteria produce proteins that lyse the phagosome before it fuses with the lysosome, allowing the bacteria to escape into the phagocyte’s cytoplasm where they can multiply. Bacteria such as Mycobacterium tuberculosis, Legionella pneumophila, and Salmonella species use a slightly different mechanism to evade being digested by the phagocyte. These bacteria prevent the fusion of the phagosome with the lysosome, thus remaining alive and dividing within the phagosome.

    Infection

    Following invasion, successful multiplication of the pathogen leads to infection. Infections can be described as local, focal, or systemic, depending on the extent of the infection. A local infection is confined to a small area of the body, typically near the portal of entry. For example, a hair follicle infected by Staphylococcus aureus infection may result in a boil around the site of infection, but the bacterium is largely contained to this small location. Other examples of local infections that involve more extensive tissue involvement include urinary tract infections confined to the bladder or pneumonia confined to the lungs.

    In a focal infection, a localized pathogen, or the toxins it produces, can spread to a secondary location. For example, a dental hygienist nicking the gum with a sharp tool can lead to a local infection in the gum by Streptococcus bacteria of the normal oral microbiota. These Streptococcus spp. may then gain access to the bloodstream and make their way to other locations in the body, resulting in a secondary infection.

    When an infection becomes disseminated throughout the body, we call it a systemic infection. For example, infection by the varicella-zoster virus typically gains entry through a mucous membrane of the upper respiratory system. It then spreads throughout the body, resulting in the classic red skin lesions associated with chickenpox. Since these lesions are not sites of initial infection, they are signs of a systemic infection.

    Sometimes a primary infection, the initial infection caused by one pathogen, can lead to a secondary infection by another pathogen. For example, the immune system of a patient with a primary infection by HIV becomes compromised, making the patient more susceptible to secondary diseases like oral thrush and others caused by opportunistic pathogens. Similarly, a primary infection by Influenzavirus damages and decreases the defense mechanisms of the lungs, making patients more susceptible to a secondary pneumonia by a bacterial pathogen like Haemophilus influenzae or Streptococcus pneumoniae. Some secondary infections can even develop as a result of treatment for a primary infection. Antibiotic therapy targeting the primary pathogen can cause collateral damage to the normal microbiota, creating an opening for opportunistic pathogens (see Case in Point: A Secondary Yeast Infection below).

    A Secondary Yeast Infection

    Anita, a 36-year-old mother of three, goes to an urgent care center complaining of pelvic pressure, frequent and painful urination, abdominal cramps, and occasional blood-tinged urine. Suspecting a urinary tract infection (UTI), the physician requests a urine sample and sends it to the lab for a urinalysis. Since it will take approximately 24 hours to get the results of the culturing, the physician immediately starts Anita on the antibiotic ciprofloxacin. The next day, the microbiology lab confirms the presence of E. coli in Anita’s urine, which is consistent with the presumptive diagnosis. However, the antimicrobial susceptibility test indicates that ciprofloxacin would not effectively treat Anita’s UTI, so the physician prescribes a different antibiotic.

    After taking her antibiotics for 1 week, Anita returns to the clinic complaining that the prescription is not working. Although the painful urination has subsided, she is now experiencing vaginal itching, burning, and discharge. After a brief examination, the physician explains to Anita that the antibiotics were likely successful in killing the E. coli responsible for her UTI; however, in the process, they also wiped out many of the “good” bacteria in Anita’s normal microbiota. The new symptoms that Anita has reported are consistent with a secondary yeast infection by Candida albicans, an opportunistic fungus that normally resides in the vagina but is inhibited by the bacteria that normally reside in the same environment.

    To confirm this diagnosis, a microscope slide of a direct vaginal smear is prepared from the discharge to check for the presence of yeast. A sample of the discharge accompanies this slide to the microbiology lab to determine if there has been an increase in the population of yeast causing vaginitis. After the microbiology lab confirms the diagnosis, the physician prescribes an antifungal drug for Anita to use to eliminate her secondary yeast infection.

    Exercise \(\PageIndex{7}\)

    1. Why was Candida not killed by the antibiotics prescribed for the UTI?
    2. List three conditions that could lead to a secondary infection.

    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 \(\PageIndex{6}\)). 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.

    Portals of exit: eye (tears), needle,  mammary glands (milk, secretions), placenta (transmission to fetus), vagina (secretions, blood), urethra (urine), broken skin,  broken skin (blood), skin (flakes), nose (secretions), mouth (saliva, sputum), ear (earwax), urethra (urine, semen, secretions), anus (feces).
    Figure \(\PageIndex{6}\): Pathogens leave the body of an infected host through various portals of exit to infect new hosts.

    Key Concepts and Summary

    • 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.
    • 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.
    • 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.

    Footnotes

    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/
    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.
    4. C. Owens. “P. aeruginosa survives in sinks 10 years after hospital outbreak.” 2015. www.healio.com/infectious-dis...pital-outbreak
    5. Food and Drug Administration. “Bad Bug Book, Foodborne Pathogenic Microorganisms and Natural Toxins.” 2nd ed. Silver Spring, MD: US Food and Drug Administration; 2012.
    6. M. Otto. “Staphylococcus epidermidis--The ‘Accidental’ Pathogen.” Nature Reviews Microbiology 7 no. 8 (2009):555–567.
    7. The O in TORCH stands for “other.”
    8. D. Davies. “Understanding Biofilm Resistance to Antibacterial Agents.” Nature Reviews Drug Discovery 2 (2003):114–122.

    Contributor

    • Nina Parker, (Shenandoah University), Mark Schneegurt (Wichita State University), Anh-Hue Thi Tu (Georgia Southwestern State University), Philip Lister (Central New Mexico Community College), and Brian M. Forster (Saint Joseph’s University) with many contributing authors. Original content via Openstax (CC BY 4.0; Access for free at https://openstax.org/books/microbiology/pages/1-introduction)