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Agents of Infectious Disease

Agents of Infectious Disease
The agents of infectious disease include prions, viruses, bacteria, Rickettsiaceae and Chlamydiaceae, fungi, and parasites. A summary of the salient characteristics of these human microbial pathogens is presented in Table 12.2.

In the past, microbiologists have assumed that all infectious agents must possess a genetic master plan (a genome of either ribonucleic acid [RNA] or deoxyribonucleic acid [DNA]) that codes for the production of the essential proteins and enzymes necessary for survival and reproduction. However, it is now known that infection can be transmitted solely by proteins and no nucleic acid. Prions, protein particles that lack any kind of a demonstrable genome, are able to transmit infection. A number of prion-associated diseases have been identified, including Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep, chronic wasting disease in deer and elk, and bovine spongiform encephalopathy (BSE or mad cow disease) in cattle. The various prion-associated diseases produce very similar pathologic processes and symptoms in the hosts and are collectively called transmissible neurodegenerative diseases (see Fig. 12.1). All are characterized by a slowly progressive, noninflammatory neuronal degeneration, leading to loss of coordination (ataxia), dementia, and death over a period ranging from months to years. In fact, evidence indicates that scrapie prion proteins (called PrPSC) are actually altered or mutated forms of a normal host protein called cellular PrPC. Differences in the posttranslational structure cause the two proteins to behave differently. The PrPSC is resistant to the action of proteases (enzymes that degrade excess or deformed proteins) and aggregates in the cytoplasm of affected neurons as amyloid fibrils. The normal PrPC is protease sensitive and appears on the cell surface.
Molecular pathogenesis of prion disorders

Prion diseases present significant challenges for management due to the pathogenic structure of PrPSC. It is very stable and, therefore, is resistant to many antibiotics. Studies investigating transmission of prion diseases in animals clearly demonstrate that prions replicate, leading researchers to investigate how proteins can reproduce in the absence of genetic material. Based on current models, it is believed that PrPSC binds to the normal PrPC on the cell surface, causing it to be processed into PrPSC, which is released from the cell and then aggregates into amyloid-like plaques in the brain. The cell then replenishes the PrPC and the cycle continues. As PrPSC accumulates, it spreads within the axons of the nerve cells, causing progressively greater damage of host neurons and the eventual incapacitation of the host. Prions lack reproductive and metabolic functions, so the currently available antimicro- bial agents are useless against them.

Viruses are the smallest obligate intracellular pathogens. They have no organized cellular structures but instead consist of a protein coat, or capsid, surrounding a nucleic acid core, or genome, of RNA or DNA never both (Fig. 12.2). Some viruses are enclosed within a lipoprotein envelope derived from the cytoplasmic membrane of the parasitized host cell. Enveloped viruses include members of the herpesvirus group and paramyxoviruses (e.g., influenza and poxviruses). Certain enveloped viruses are continuously shed from the infected cell surface enveloped in buds pinched from the cell membrane.
(A) The basic structure of a virus includes a protein coat surrounding an inner core of nucleic acid (DNA or RNA). (B) Some viruses may also be enclosed in a lipoprotein outer envelope.

The viruses of humans and animals have been categorized somewhat arbitrarily according to various characteristics. These include the type of viral genome (single-stranded or double-stranded DNA or RNA), physical characteristics (e.g., size, presence or absence of a membrane envelope), the mechanism of replication (e.g., retroviruses), the mode of transmission (e.g., arthropod-borne viruses, enteroviruses), target tissue, and the type of disease produced (e.g., hepatitis A, B, C, D, and E viruses), to name just a few.
Viruses are incapable of replication outside of a living cell. They must penetrate a susceptible living cell and use the biosynthetic structure of the cell to produce viral progeny.
Schematic representation of the many possible consequences of viral infection of host cells, including cell lysis (poliovirus), continuous release of budding viral particles, or latency (herpesviruses) and oncogenesis (papovaviruses).

The process of viral replication is shown in Figure 12.3. Not every viral agent causes lysis and death of the host cell during the course of replication. Some viruses enter the host cell and insert their genome into the host cell chromosome, where it remains in a latent, nonreplicating state for long periods without causing disease. Under the appropriate stimulation, the virus undergoes active replication and produces symptoms of disease months to years later. Members of the herpesvirus group and adenovirus are examples of latent viruses. Herpesviruses include the viral agents of chicken- pox and zoster (varicella–zoster), cold sores (herpes simplex virus [HSV] type 1), genital herpes (HSV type 2), cytomegalovirus infections, roseola (human herpesvirus 6), infectious mononucleosis   (IM)   (Epstein-Barr   virus   [EBV])   (see Fig. 12.4), and Kaposi sarcoma (herpesvirus 8). The resumption of the latent viral replication may produce symptoms of primary disease (e.g., genital herpes) or cause an entirely different symptomatology (e.g., shingles instead of chickenpox).
Role of Epstein-Barr virus (EBV) in infectious mononucleosis (IM), nasopharyngeal carcinoma, and Burkitt lymphoma

A family of viruses that has gained a great deal of attention is the Orthomyxoviridae or flu viruses. There has been attention focused on the H5N1 variant, commonly known as the avian influenza virus, and the H1N1 variant, commonly known as swine flu. The avian influenza viruses differ from the usual human influenza viruses by the hosts they normally infect.
Avian influenza viruses typically infect wild birds. However, on occasion a new virus may result from genetic rearrangements that make it better fit to infect humans. When this occurs, the human population is more susceptible because the virus is unfamiliar to most of our immune systems. The H1N1 or swine flu was most notable in 2009. This influenza A virus was susceptible to oseltamivir (Tamiflu), but resistant to amantadine. Rapid influenza diagnostic tests (RITs) have been developed to diagnose a person with H1N1 and other influenza viruses.
Since the early 1980s, members of the retrovirus group have received considerable attention after identification of the human immunodeficiency viruses (HIV) as the causative agent of acquired immunodeficiency syndrome (AIDS). The retro-viruses have a unique mechanism of replication. After entry into the host cell, the viral RNA genome is first translated into DNA by a viral enzyme called reverse transcriptase. The viral DNA copy is then integrated into the host chromosome where it exists in a latent state, similar to the herpesviruses. Reactivation and replication require a reversal of the entire process. Some retroviruses lyse the host cell during the process of replication. In the case of HIV, the infected cells regulate the immunologic defense system of the host, and their lysis leads to a permanent suppression of the immune response.
In addition to causing infectious diseases, certain viruses also have the ability to transform normal host cells into malignant cells during the replication cycle. This group of viruses is referred to as oncogenic and includes certain retroviruses and DNA viruses, such as the herpesviruses, adenoviruses, and papovaviruses. Human papillomaviruses (HPVs), members of the papovavirus family, cause cutaneous and genital warts, and several genotypes are associated with cervical cancer. The first vaccine (Gardasil) to prevent cervical cancer, precancerous genital lesions, genital warts, and anal and oropharyngeal cancers due to HPV types 6, 11, 16, and 18 was developed in 2006.

Bacteria are autonomously replicating unicellular organisms known as prokaryotes because they lack an organized nucleus. Compared with nucleated eukaryotic cells, the bacterial cell is small and structurally relatively primitive. Similar to eukaryotic cells, but unlike viruses, bacteria contain both DNA and RNA. They are the smallest of all living cells and range from 0.1 to 10 µm. They contain no organized intracellular organelles, and the genome consists of only a single chromosome of DNA. Many bacteria transiently harbor smaller extrachromosomal pieces of circular DNA called plasmids. Occasionally, plasmids contain genetic information that increases the virulence or antibiotic resistance of the organism.
The prokaryotic cell is organized into an internal compartment called the cytoplasm, which contains the reproductive and metabolic machinery of the cell. The cytoplasm is surrounded by a flexible lipid membrane, called the cytoplasmic membrane. This in turn is enclosed within a rigid cell wall. The structure and synthesis of the cell wall determine the microscopic shape of the bacterium (e.g., spherical [cocci], helical [spirilla], or elongate [bacilli]). Most bacteria produce a cell wall composed of a distinctive polymer known as peptidoglycan. This polymer is produced only by prokaryotes and is therefore an attractive target for antibacterial therapy. Several bacteria synthesize an extracellular capsule composed of protein or carbohydrate. The capsule protects the organism from environmental hazards such as the immunologic defenses of the host.
Certain bacteria are motile as the result of external whiplike appendages called flagella. The flagella rotate like a propeller, transporting the organism through a liquid environment. Bacteria can also produce hairlike structures projecting from the cell surface called pili or fimbriae, which enable the organism to adhere to surfaces such as mucous membranes or other bacteria.
Most prokaryotes reproduce asexually by simple cellular division. The manner in which an organism divides can influence the microscopic morphology. For instance, when the cocci divide in chains, they are called streptococci; in pairs, diplococci; and in clusters, staphylococci. The growth rate of bacteria varies significantly among different species and depends greatly on physical growth conditions and the availability of nutrients. In the laboratory, a single bacterium placed in a suitable growth environment, such as an agar plate, reproduces to the extent that it forms a visible colony com- posed of millions of bacteria within a few hours (Fig. 12.5).

In nature, however, bacteria rarely exist as single cells floating in an aqueous environment. Rather, bacteria prefer to stick to and colonize environmental surfaces, producing structured communities called biofilms. The organization and structure of biofilms permit access to available nutrients and elimination of metabolic waste. Within the biofilm, individual organisms use chemical signaling as a form of primitive intercellular communication to represent the state of the environment. These signals inform members of the community when sufficient nutrients are available for proliferation or when environmental conditions warrant dormancy or evacuation. Examples of biofilms abound in nature and are found on surfaces of aquatic environments and on humans. Eighty percent of all chronic infections are due to the presence of biofilms.
The physical appearance of a colony of bacteria grown on an agar plate can be quite distinctive for different species. Bacteria are also identified according to how they divide. Some bacteria produce pigments that give colonies a unique color; some produce highly resistant spores when faced with an unfavorable environment. The spores can exist in a quiescent state almost indefinitely until suitable growth conditions are encountered, at which time the spores germinate and the organism resumes normal metabolism and replication.
Bacteria are extremely adaptable life forms. They are found not just in humans and other hosts but in almost every environ- mental extreme on earth. However, each individual bacterial species has a well-defined set of growth parameters, including nutrition, temperature, light, humidity, and atmosphere. Bacteria with extremely strict growth requirements are called fastidious. For example, Neisseria gonorrhoeae, the bacterium that causes gonorrhea, cannot live for extended periods outside the human body. Some bacteria require oxygen for growth and metabolism and are called aerobes. Others cannot survive in an oxygen-containing environment and are called anaerobes. An organism capable of adapting its metabolism to aerobic or anaerobic conditions is called facultatively anaerobic.
In the laboratory, bacteria are generally classified according to the microscopic appearance and staining properties of the cell. The Gram stain is the most widely used staining procedure. Bacteria are designated as gram-positive organisms if they are stained purple by a primary basic dye (usually crystal violet). Those that are not stained by the crystal violet but are counterstained red by a second dye (safranin) are called gram-negative organisms. Staining characteristics and microscopic morphology are used in combination to describe bacteria. For example, Streptococcus pyogenes, the agent of scarlet fever and rheumatic fever, is a gram-positive streptococcal organism that is spherical, grows in chains, and stains purple by Gram stain. Legionella pneumophila, the bacterium responsible for Legionnaire disease, is a gram-negative rod.
Another means of classifying bacteria according to microscopic staining properties is the acid-fast stain. Because of their unique cell membrane fatty acid content and composition, certain bacteria are resistant to the decolorization of a primary stain (either carbol fuchsin or a combination of auramine and rhodamine) when treated with a solution of acid alcohol. These organisms are termed acid-fast and include a number of significant human pathogens, most notably Mycobacterium tuberculosis and other mycobacteria.
For purposes of taxonomy (i.e., identification and classification), each member of the bacterial kingdom is categorized into a small group of biochemically and genetically related organisms called the genus and further subdivided into distinct individuals within the genus called species. The genus and species assignment of the organism is reflected in its name (e.g., Staphylococcus [genus] aureus [species]).

Spirochetes. The spirochetes are an eccentric category of bacteria that are mentioned separately because of their unusual cellular morphology and distinctive mechanism of motility. Technically, the spirochetes are gram-negative rods but are unique in that the cell’s shape is helical and the length of the organism is many times its width. A series of filaments are wound about the cell wall and extend the entire length of the cell. These filaments propel the organism through an aqueous environment in a corkscrew motion.
Spirochetes are anaerobic organisms and comprise three genera: Leptospira, Borrelia, and Treponema. Each genus has saprophytic and pathogenic strains. The pathogenic leptospires infect a wide variety of wild and domestic animals. Infected animals shed the organisms into the environment through the urinary tract. Transmission to humans occurs by contact with infected animals or urine-contaminated surroundings. Leptospires gain access to the host directly through mucous membranes or breaks in the skin and can produce a severe and potentially fatal illness called Weil syndrome. In contrast, the borreliae are transmitted from infected animals to humans through the bite of an arthropod vector such as lice or ticks. Included in the genus Borrelia are the agents of relapsing fever (Borrelia recurrentis) and Lyme disease (B. burgdorferi).
Pathogenic Treponema species require no intermediates and are spread from person to person by direct contact. The most important member of the genus is Treponema pallidum, the causative agent of syphilis.

Mycoplasmas. The mycoplasmas are unicellular prokaryotes capable of independent replication. These organisms are less than one third the size of bacteria at approximately 0.3 µm at their largest diameter and contain a small DNA genome approximately one half the size of the bacterial chromosome. The cell is composed of cytoplasm surrounded by a membrane but, unlike bacteria, the mycoplasmas do not produce a rigid peptidoglycan cell wall. As a consequence, the microscopic appearance of the cell is highly variable, ranging from coccoid forms to filaments, and the mycoplasmas are resistant to cell-wall–inhibiting antibiotics, such as penicillins and cephalosporins.
The mycoplasmas affecting humans are divided into three genera: Mycoplasma, Ureaplasma, and Acholeplasma. The first two require cholesterol from the environment to produce the cell membrane; the acholeplasmas do not. In the human host, mycoplasmas are commensals. However, a number of species are capable of producing serious diseases, including pneumonia (Mycoplasma pneumoniae), genital infections (Mycoplasma hominis and Ureaplasma urealyticum), and maternally transmitted respiratory infections to infants with low birth weight (U. urealyticum). not produce disease in the cells of certain arthropods such as fleas, ticks, and lice. The organisms are accidentally transmitted to humans through the bite of the arthropod (i.e., the vector) and produce a number of potentially lethal diseases, including Rocky Mountain spotted fever and epidemic typhus. Rocky Mountain spotted fever is a reportable disease that has increased in frequency over the last decade from two cases in 1 million people to eight cases in 1 million people. However, the death rate has decreased to approximately 0.5%.
The Chlamydiaceae are slightly smaller than the Rickettsiaceae but are structurally similar and are transmitted directly between susceptible vertebrates without an intermediate arthropod host. Transmission and replication of Chlamydiaceae occur through a defined life cycle. The infectious form, called an elementary body, attaches to and enters the host cell, where it transforms into a larger reticulate body. This undergoes active replication into multiple elementary bodies, which are then shed into the extracellular environment to initiate another infectious cycle. Chlamydial diseases of humans include sexually transmitted genital infections (Chlamydophila trachomatis), which are the most common of the bacterial sexually transmitted infections (STIs)10; ocular infections and pneumonia of newborns (C. trachomatis); upper and lower respiratory tract infections in children, adolescents, and young adults (Chlamydophila pneumoniae), which generally does not cause severe disease unless there is an underlying pulmonary disorder2; and respiratory disease acquired from infected birds (Chlamydia psittaci).
Organisms within the family Anaplasmataceae (including the reorganized genera Ehrlichia, Anaplasma, Neorickettsia, and Wolbachia) are also obligate intracellular organisms that resemble the Rickettsiaceae in structure and produce a variety of veterinary and human diseases, some of which have a tick vector. These organisms target host mononuclear and polymorphonuclear white blood cells for infection and, similar to the Chlamydiaceae, multiply in the cytoplasm of infected leukocytes within vacuoles called morulae. Unlike the Chlamydiaceae, however, the Anaplasmataceae do not have a defined life cycle and are independent of the host cell for energy production. Ehrlichia sennetsu, which is primarily restricted to Japan, produces a disease called sennetsu fever that resembles IM. Disease caused by this organism differs from other Anaplasmataceae because it is associated with eating raw fish infested with E. sennetsu–infected parasites. The most common infections caused by Anaplasmataceae are human monocytic and granulocytic ehrlichiosis. Human monocytic ehrlichi-osis is a disease caused by Ehrlichia chaffeensis and E. canis that can easily be confused with Rocky Mountain spotted fever.
Clinical disease severity ranges from mild to life threatening. Manifestations include generalized malaise, anorexia and nausea, fever, and headache. Decreases in white blood cells (leukopenia) and platelets (thrombocytopenia) often occur. Severe sequelae include severe respiratory failure, encephalopathy, and acute renal failure. The disease is usually more severe in older adults and people with compromised immune function. Evidence validates  the  importance  of  empirical antibiotic treatment when one suspects ehrlichiosis since a fulminant and life-threatening infection is likely with immu- nocompromised people. Human granulocytic ehrlichiosis, which is caused by two species (Anaplasma phagocytophilum and Ehrlichia ewingii), is also transmitted by ticks. The symptoms are similar to those seen with human monocytotropic ehrlichiosis.
The genus Coxiella contains only one species, C. burnetii. Like its rickettsial counterparts, it is a gram-negative intracellular organism that infects a variety of animals, including cattle, sheep, and goats. In humans, Coxiella infection produces a disease called Q fever, characterized by a nonspecific febrile illness often accompanied by headache, chills, and mild pneumonia-like symptoms. The organism produces a highly resistant sporelike stage that is transmitted to humans when contaminated animal tissue is aerosolized (e.g., during meat processing) or by ingestion of contaminated milk.

The fungi are free-living, eukaryotic  saprophytes  found in every habitat on earth. Some are members of the normal human microflora. Fortunately, few fungi are capable of causing diseases in humans, and most of these are incidental, self-limited infections of skin and subcutaneous tissue. Serious fungal infections are rare and usually initiated through puncture wounds or inhalation. Despite their normally harmless nature, fungi can cause life-threatening opportunistic diseases when host defense capabilities have been disabled.
The fungi can be separated into two groups, yeasts and molds, based on rudimentary differences in their morphology. The yeasts are single-celled organisms, approximately the size of red blood cells, which reproduce by a budding process. The buds separate from the parent cell and mature into identical daughter cells. Molds produce long, hollow, branching filaments called hyphae. Some molds produce cross walls, which segregate the hyphae into compartments, and others do not. A limited number of fungi are capable of growing as yeasts at one temperature and as molds at another. These organisms are called dimorphic fungi and include a number of human pathogens such as the agents of blastomycosis (Blastomyces dermatitidis), histoplasmosis (Histoplasma capsulatum), and coccidioidomycosis (Coccidioides immitis).
The appearance of a fungal colony tends to reflect its cellular composition. Colonies of yeast are generally smooth with a waxy or creamy texture. Molds tend to produce cottony or powdery colonies composed of mats of hyphae collectively called a mycelium. The mycelium can penetrate the growth surface or project above the colony like the roots and branches of a tree. Yeasts and molds produce a rigid cell wall layer that is chemically unrelated to the peptidoglycan of bacteria and is therefore not susceptible to the effects of penicillin-like antibiotics.
Most fungi are capable of sexual or asexual reproduction. The former process involves the fusion of zygotes with the production of a recombinant zygospore. Asexual reproduction involves  the  formation  of  highly  resistant  spores  called conidia or sporangiospores, which are borne by specialized structures that arise from the hyphae. Molds are identified inthe laboratory by the characteristic microscopic appearance of the asexual fruiting structures and spores.
Like the bacterial pathogens of humans, fungi can produce disease in the human host only if they can grow at the temperature of the infected body site. For example, a number of fungal pathogens called dermatophytes are incapable of growing at core body temperature (37°C), and the infection is limited to the cooler cutaneous surfaces. Diseases caused by these organisms, including ringworm, athlete’s foot, and jock itch, are collectively called superficial mycoses. Systemic mycoses are serious fungal infections of deep tissues and, by definition, are caused by organisms capable of growth at 37°C. Yeasts such as Candida albicans are commensal flora of the skin, mucous membranes, and gastrointestinal tract and are capable of growth at a wider range of temperatures. Intact immune mechanisms and competition for nutrients provided by the bacterial flora normally keep colonizing fungi in check. Alterations in either of these components by disease states or antibiotic therapy can upset the balance, permitting fungal overgrowth and setting the stage for opportunistic infections.

In a strict sense, any organism that derives benefits from its biologic relationship with another organism is a parasite. In the study of clinical microbiology, however, the term parasite has evolved to designate members of the animal kingdom that infect and cause disease in other animals, and includes protozoa, helminths, and arthropods.
The protozoa are unicellular animals with a complete complement of eukaryotic cellular machinery, including a well-defined nucleus and organelles. Reproduction may be sexual or asexual, and life cycles may be simple or complicated, with several maturation stages requiring more than one host for completion. Most are saprophytes, but a few have adapted to the accommodations of the human environment and produce a variety of diseases, including malaria, amebic dysentery, and giardiasis.2 Protozoan infections can be passed directly from host to host such as through sexual contact, indirectly through contaminated water or food, or by way of an arthropod vector. Direct or indirect transmission results from the ingestion of highly resistant cysts or spores that are shed in the feces of an infected host. When the cysts reach the intestine, they mature into vegetative forms called trophozoites, which are capable of asexual reproduction or cyst formation. Most trophozoites are motile by means of flagella, cilia, or ameboid motion.
The helminths are a collection of wormlike parasites that include the nematodes or roundworms, cestodes or tapeworms, and trematodes or flukes. The helminths reproduce sexually within the definitive host, and some require an intermediate host for the development and maturation of offspring. Humans can serve as the definitive or intermediate host and, in certain diseases such as trichinosis, as both. Transmission of helminth diseases occurs primarily through the ingestion of fertilized eggs (ova) or the penetration of infectious larval stages through the skin directly or with the aid of an arthropod vector. Helminth infections can involve many organ systems and sites, including the liver and lung, urinary and intestinal tracts, circulatory and central nervous systems, and muscle. Although most helminth diseases have been eradicated from the United States, they are still a major health concern of developing nations.
The parasitic arthropods of humans and animals include the vectors of infectious diseases (e.g., ticks, mosquitoes, biting flies) and the ectoparasites. The ectoparasites infest external body surfaces and cause localized tissue damage or inflammation secondary to the bite or burrowing action of the arthropod. The most prominent human ectoparasites are mites (scabies), chiggers, lice (head, body, and pubic), and fleas. Transmission of ectoparasites occurs directly by contact with immature or mature forms of the arthropod or its eggs found on the infested host or the host’s clothing, bedding, or grooming articles such as combs and brushes. Many of the ectoparasites are vectors of other infectious diseases, including endemic typhus and bubonic plague (fleas) and epidemic typhus (lice).