The pathogenesis of bacterial infection includes initiation of the infectious process and the mechanisms that lead to the development of signs and symptoms of disease. The biochemical, structural, and genetic factors that play important roles in bacterial pathogenesis are introduced in this chapter and may be revisited in the organism-specific sections. Characteristics of bacteria that are pathogens include transmissibility, adherence to host cells, persistence, invasion of host cells and tissues, toxigenicity, and the ability to evade or survive the host’s immune system. Resistance to antimicrobials and disinfectants can also contribute to virulence, or an organism’s capacity to cause disease. Many infections caused by bacteria that are commonly considered to be pathogens are inapparent or asymptomatic. Disease occurs if the bacteria or immunologic reactions to their presence cause sufficient harm to the person.

Terms frequently used in describing aspects of pathogenesis are defined in the Glossary (see below). Refer to the Glossary in Chapter 8 for definitions of terms used in immunology and in describing aspects of the host’s response to infection.

Humans and animals have abundant normal microbiota that usually do not produce disease (see Chapter 10) but achieve a balance that ensures the survival, growth, and propagation of both the bacteria and the host. Some bacteria that are important causes of disease are cultured commonly with the normal microbiota (eg, Streptococcus pneumoniae, Staphylococcus aureus). Sometimes bacteria that are clearly pathogens (eg, Salmonella serotype Typhi) are present, but infection remains latent or subclinical, and the host is a “carrier” of the bacteria.

It can be difficult to show that a specific bacterial species is the cause of a particular disease. In 1884, Robert Koch proposed a series of postulates that have been applied broadly to link many specific bacterial species with particular diseases. Koch’s postulates are summarized in Table 9-1.

Koch’s postulates have remained a mainstay of microbiology; however, since the late 19th century, many microorganisms that do not meet the criteria of the postulates have been shown to cause disease. For example, Treponema pallidum (syphilis) and Mycobacterium leprae (leprosy) cannot be grown in vitro; however, there are animal models of infection with these agents. In another example, there is no animal model of Neisseria gonorrhoeae (gonorrhea) infection even though the bacteria can readily be cultured in vitro; experimental infection in humans has been produced that substitutes for an animal model.

In other instances, Koch’s postulates have been at least partially satisfied by showing bacterial pathogenicity in an in vitro model of infection rather than in an animal model. For example, some forms of Escherichia coli (E coli)–induced diarrhea (see Chapter 15) have been defined by the interaction of the E coli with host cells in tissue culture.

The host’s immune responses also should be considered when an organism is being investigated as the possible cause of a disease. Thus, development of a rise in specific antibody during recovery from disease is an important adjunct to Koch’s postulates.

Modern-day microbial genetics has opened new frontiers to study pathogenic bacteria and differentiate them from nonpathogens. Molecular cloning has allowed investigators to isolate and modify specific virulence genes and study them with models of infection. The ability to study genes associated with virulence has led to a proposed form of molecular Koch’s postulates. These postulates are summarized in Table 9-1.

Some pathogens are difficult or impossible to grow in culture, and for that reason, it is not possible with Koch’s postulates or the molecular Koch’s postulates to establish the cause of their associated diseases. The polymerase chain reaction is used to amplify microorganism-specific nucleic acid sequences from host tissues or fluids. The sequences are used to identify the infecting organisms. The molecular guidelines for establishing microbial disease causation are listed in Table 9-1. This approach has been used to establish the causes of several diseases, including Whipple disease (Tropheryma whipplei), bacillary angiomatosis (Bartonella henselae), human monocytic ehrlichiosis (Ehrlichia chaffeensis), hantavirus pulmonary syndrome (Sin Nombre virus), and Kaposi sarcoma (human herpesvirus 8).

Analysis of infection and disease through the application of principles such as Koch’s postulates leads to classification of bacteria as pathogens, opportunistic pathogens, or nonpathogens. Some bacterial species are always considered to be pathogens, and their presence is abnormal; examples include Mycobacterium tuberculosis (tuberculosis) and Yersinia pestis (plague). Such bacteria readily meet the criteria of Koch’s postulates. Other species are commonly part of the normal microbiota of humans (and animals) but also can frequently cause disease. For example, E coli is part of the gastrointestinal microbiota of normal humans but is also a common cause of urinary tract infections, traveler’s diarrhea, and other diseases. Strains of E coli that cause disease are differentiated from those that do not by determining (1) whether they are virulent in animals or in vitro models of infection and (2) whether they have a genetic makeup that is significantly associated with production of disease. Other bacteria (eg, Pseudomonas species, Stenotrophomonas maltophilia, and many yeasts and molds) only cause disease in immunosuppressed and debilitated persons and are opportunistic pathogens.

Bacteria (and other microorganisms) can adapt to a variety of environments that include external sources such as soil, water, and organic matter or internal milieu as found within insect vectors, animals, and humans, where they normally reside and subsist. In doing so, the bacteria ensure their survival and enhance the possibility of transmission. By producing asymptomatic infection or mild disease rather than death of the host, microorganisms that normally live in people enhance the possibility of transmission from one person to another.

Some bacteria that commonly cause disease in humans exist primarily in animals and incidentally infect humans. For example, Salmonella and Campylobacter species typically infect animals and are transmitted in food products to humans. Other bacteria produce infection of humans that is inadvertent, a mistake in the normal life cycle of the organism; the organisms have not adapted to humans, and the disease they produce may be severe. For example, Y pestis (plague) has a well-established life cycle in rodents and rodent fleas, and transmission by the fleas to humans is inadvertent; Bacillus anthracis (anthrax) lives in the environment, occasionally infects animals, and is transmitted to humans by products such as raw hair from infected animals. The Clostridium species are ubiquitous in the environment and are transmitted to humans by ingestion (eg, Clostridium perfringens gastroenteritis and Clostridium botulinum [botulism]) or when wounds are contaminated by soil (eg, C perfringens [gas gangrene] and Clostridium tetani [tetanus]). Both B anthracis and the Clostridium species elaborate spores to protect the organisms’ nucleic acid from harsh environmental factors such as ultraviolet light, desiccation, chemical detergents, and pH extremes. These spores ensure survival in external environments including foods ingested by humans. After being ingested or inoculated, the spores germinate into the vegetative, metabolically active form of the pathogen.

The clinical manifestations of diseases (eg, diarrhea, cough, genital discharge) produced by microorganisms often promote transmission of the agents. Examples of clinical syndromes and how they enhance transmission of the causative bacteria are as follows: Vibrio cholerae can cause voluminous diarrhea, which may contaminate salt and fresh water; drinking water or seafood such as oysters and crabs may be contaminated; ingestion of contaminated water or seafood can produce infection and disease. Similarly, contamination of food products with sewage containing E coli that causes diarrhea results in transmission of the bacteria. M tuberculosis (tuberculosis) naturally infects only humans; it produces respiratory disease with cough and production of aerosols, resulting in transmission of the bacteria from one person to another.

Many bacteria are transmitted from one person to another on hands. A person with S aureus carriage in the anterior nares may rub his nose, pick up the staphylococci on the hands, and spread the bacteria to other parts of the body or to another person, where infection results. Many opportunistic pathogens that cause nosocomial infections are transmitted from one patient to another on the hands of hospital personnel. Handwashing is thus an important component of infection control.

The most frequent portals of entry of pathogenic bacteria into the body are the sites where mucous membranes meet with the skin, which are the respiratory (upper and lower airways), gastrointestinal (primarily mouth), genital, and urinary tracts. Abnormal areas of mucous membranes and skin (eg, cuts, burns, and other injuries) are also frequent sites of entry. Normal skin and mucous membranes provide the primary defense against infection. To cause disease, pathogens must overcome these barriers.

In the body, most bacteria that cause disease do so first by attaching or adhering to host cells, usually epithelial cells. After the bacteria have established a primary site of infection, they multiply and spread directly through tissues or via the lymphatic system to the bloodstream. This infection (bacteremia) can be transient or persistent. Bacteremia allows bacteria to spread widely in the body and permits them to reach tissues particularly suitable for their multiplication.

Pneumococcal pneumonia is an example of the infectious process. S pneumoniae can be cultured from the nasopharynx of 5–40% of healthy people. Occasionally, pneumococci from the nasopharynx are aspirated into the lungs; aspiration occurs most commonly in debilitated people and in settings such as coma when normal gag and cough reflexes are diminished. Infection develops in the terminal air spaces of the lungs in persons who do not have protective antibodies against that particular pneumococcal capsular polysaccharide type. Multiplication of the pneumococci and resultant inflammation lead to pneumonia. The pneumococci enter the lymphatics of the lung and move to the bloodstream. Between 10% and 20% of persons with pneumococcal pneumonia have bacteremia at the time the diagnosis of pneumonia is made. When bacteremia occurs, the pneumococci can spread to secondary sites of infection (eg, cerebrospinal fluid, heart valves, and joint spaces). The major complications of pneumococcal pneumonia are meningitis, septic arthritis, and rarely endocarditis.

The infectious process in cholera involves ingestion of V cholerae, chemotactic attraction of the bacteria to the gut epithelium, motility of the bacteria by a single polar flagellum, and penetration of the mucous layer on the intestinal surface. The V cholerae adherence to the epithelial cell surface is mediated by pili and possibly other adhesins. Production of cholera toxin results in flow of chloride and water into the lumen of the gut, causing diarrhea and electrolyte imbalance.

Bacteria are haploid (see Chapter 7) and limit genetic interactions that might change their chromosomes and potentially disrupt their adaptation and survival in specific environmental niches. One important result of the conservation of chromosomal genes in bacteria is that the organisms are clonal. For many pathogens, there are only one or a few clonal types that are spread in the world during a period of time. For example, epidemic serogroup A meningococcal meningitis occurs in Asia, the Middle East, and Africa and occasionally spreads into Northern Europe and the Americas. On several occasions, over a period of decades, single clonal types of serogroup A Neisseria meningitidis have been observed to appear in one geographic area and subsequently spread to others with resultant epidemic disease. There are two clonal types of Bordetella pertussis, both associated with disease. There are, however, mechanisms that bacteria use, or have used a long time in the past, to transmit virulence genes from one to another.

Mobile Genetic Elements

Primary mechanisms for exchange of genetic information between bacteria include natural transformation and transmissible mobile genetic elements such as plasmids, transposons, and bacteriophages (often referred to as “phages”). Transformation occurs when DNA from one organism is released into the environment and is taken up by a different organism that is capable of recognizing and binding DNA. In other cases, the genes that encode many bacterial virulence factors are carried on plasmids, transposons, or phages. Plasmids are extrachromosomal pieces of DNA and are capable of replicating. Transposons are highly mobile segments of DNA that can move from one part of the DNA to another. This can result in recombination between extrachromosomal DNA and the chromosome (illegitimate or nonhomologous recombination; Chapter 7). If this recombination occurs, the genes coding for virulence factors may become chromosomal. Finally, bacterial viruses or phages are another mechanism by which DNA can be moved from one organism to another. Transfer of these mobile genetic elements between members of one species or, less commonly, between species can result in transfer of virulence factors, including antimicrobial resistance genes. A few examples of plasmid- and phage-encoded virulence factors are given in Table 9-2.

Pathogenicity Islands

Large groups of genes that are associated with pathogenicity and are located on the bacterial chromosome are termed pathogenicity islands (PAIs). They are large organized groups of genes, usually 10–200 kb in size. The major properties of PAIs are as follows: they have one or more virulence genes; they are present in the genome of pathogenic members of a species but absent in the nonpathogenic members; they are large; they typically have a different guanine plus cytosine (G + C) content than the rest of the bacterial genome; they are commonly associated with tRNA genes; they are often found with parts of the genome associated with mobile genetic elements; they often have genetic instability; and they often represent mosaic structures with components acquired at different times. Collectively, the properties of PAIs suggest that they originate from gene transfer from foreign species. A few examples of PAI virulence factors are provided in Table 9-3.

Pathogenic bacteria (and other pathogens) have adapted both to saprophytic or free-living states, possibly environments outside the body, and to the human host. They have evolved complex signal transduction systems to regulate the genes important for virulence. Environmental signals often control the expression of the virulence genes. Common signals include temperature, iron availability, osmolality, growth phase, pH, and specific ions (eg, Ca²⁺) or nutrient factors. A few examples are presented in the following paragraphs.

The gene for diphtheria toxin from Corynebacterium diphtheriae is carried on temperate bacteriophages. Toxin is produced only by strains lysogenized by the phages. Toxin production is greatly enhanced when C diphtheriae is grown in a medium with low iron.

Expression of virulence genes of B pertussis is enhanced when the bacteria are grown at 37°C and suppressed when they are grown at lower temperatures or in the presence of high concentrations of magnesium sulfate or nicotinic acid.