Infectious Diseases PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Infectious Diseases Karen M. Frank Alexander J. McAdam...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Infectious Diseases Karen M. Frank Alexander J. McAdam 8 CHAPTER CONTENTS General Principles of Microbial Latent Infections (Herpesvirus Obligate Intracellular Bacterial Pathogenesis 339 Infections) 353 Infections 381 How Microorganisms Cause Disease 340 Herpes Simplex Virus (HSV) Infections 354 Chlamydial Infections 381 Routes of Entry of Microbes 340 Varicella-Zoster Virus (VZV) Infections 355 Infections Caused by Other Intracellular Spread and Dissemination of Microbes Within Cytomegalovirus (CMV) Infections 356 Bacteria 381 the Body 341 Chronic Productive Infections 357 Fungal Infections 383 Release From the Body and Transmission of Transforming Viral Infections 357 Yeast Infections 383 Microbes 342 Epstein-Barr Virus (EBV) Infections 357 Candidiasis 383 Host-Pathogen Interactions 343 Bacterial Infections 359 Cryptococcosis 385 Immune Evasion by Microbes 343 Gram-Positive Bacterial Infections 359 Pneumocystis Infections 386 Injurious Effects of Host Immunity 344 Staphylococcal Infections 359 Mold Infections 386 Infections in People With Streptococcal and Enterococcal Aspergillosis 387 Immunodeficiencies 344 Infections 360 Mucormycosis (Zygomycosis) 387 Host Damage by Microbes 345 Diphtheria 361 Parasitic Infections 388 Mechanisms of Viral Injury 345 Listeriosis 362 Protozoal Infections 388 Mechanisms of Bacterial Injury 345 Anthrax 362 Malaria 388 Spectrum of Inflammatory Responses to Nocardial Infections 363 Babesiosis 390 Infection 347 Gram-Negative Bacterial Infections 364 Leishmaniasis 391 Suppurative (Purulent) Inflammation 347 Neisserial Infections 364 African Trypanosomiasis 392 Mononuclear and Granulomatous Pertussis 365 Chagas Disease 393 Inflammation 347 Pseudomonal Infections 366 Toxoplasmosis 394 Cytopathic-Cytoproliferative Reaction 348 Plague 366 Metazoal Infections 394 Tissue Necrosis 348 Chancroid (Soft Chancre) 367 Strongyloidiasis 395 Chronic Inflammation and Scarring 349 Granuloma Inguinale 367 Cysticercosis and Hydatid Disease (Tapeworm Viral Infections 349 Mycobacterial Infections 367 Infections) 395 Acute (Transient) Infections 349 Tuberculosis 368 Trichinosis 396 Measles 350 Nontuberculous Mycobacterial Infections 373 Schistosomiasis 397 Mumps 350 Leprosy 374 Lymphatic Filariasis 398 Poliomyelitis 351 Spirochete Infections 375 Onchocerciasis 399 West Nile Virus Infections 351 Syphilis 375 Sexually Transmitted Infections 399 Viral Hemorrhagic Fever 352 Lyme Disease 378 Emerging Infectious Diseases 400 Zika Virus Infections 352 Anaerobic Bacterial Infections 379 Special Techniques for Diagnosing Dengue 353 Abscesses 379 Infectious Agents 401 Novel Coronavirus SARS-CoV-2 (COVID-19) 353 Clostridial Infections 380 death among older adults and in people who are immunosup- GENERAL PRINCIPLES OF MICROBIAL pressed or who suffer from debilitating chronic diseases. PATHOGENESIS In lower-income nations inadequate access to medical care and malnutrition contribute to a heavy burden of infectious Despite the availability of effective vaccines and antibiotics, diseases. In these regions of the world, five of the ten leading infectious diseases remain a major health problem throughout causes of death are infectious diseases. Tragically, most of the world. In the United States and other high-income coun- these deaths occur in children, with respiratory infections, tries, infectious diseases are particularly important causes of infectious diarrhea, and malaria taking the greatest toll. 339 340 CHAPTER 8 Infectious Diseases How Microorganisms Cause Disease Skin Most infectious diseases are caused by pathogenic organisms The intact keratinized epidermis protects against infection that exhibit a wide range of virulence. These organisms are by serving as a mechanical barrier, having a low pH, and acquired from a variety of sources, including people, animals, by producing antimicrobial fatty acids and defensins, small insect vectors, and the environment, but they are not found peptides that are toxic to bacteria. Most skin infections are in the normal microbiota of healthy people. Thus, their initiated by mechanical injury of the epidermis. The injury presence is diagnostic of an infection. Over the past few may range from minor trauma to large wounds, burns, and years, it has become evident that humans and other animals pressure-related ulcers. In the hospital setting, infections harbor a complex ecosystem of microbes (the microbiome) may stem from intravenous catheters in patients or needle that has important roles in health and disease. Most of these sticks in health care workers. Some pathogens penetrate commensal organisms coexist peacefully with their human the skin via an insect (vector) or animal bite; vectors include hosts, occupying microenvironmental niches that might fleas, ticks, mosquitoes, and lice. The larvae of Schistosoma otherwise be filled by potential pathogens, and in doing so can traverse unbroken skin by releasing enzymes that dis- help prevent infectious disease. However, under conditions solve the adhesive proteins that hold keratinocytes together. in which normal host defenses are breached or attenuated Certain fungi (dermatophytes) can cause superficial infections (described later), even commensal microbiota may cause of the intact stratum corneum, hair, and nails. symptomatic infections and can even be fatal. We will start our review of infectious disease at the Gastrointestinal Tract beginning of the process, the establishment of a beachhead Gastrointestinal tract infections may occur when local in the host, and then discuss dissemination and transmission defenses are circumvented by a pathogen, or when they of infection, before turning to specific infections. are so weakened that even normal flora produce disease. Most gastrointestinal pathogens are transmitted by food or Routes of Entry of Microbes drink contaminated with fecal material; when hygiene fails, Microbes can enter the host by breaching epithelial diarrheal disease becomes rampant. The gastrointestinal surfaces, inhalation, ingestion, or sexual transmission tract has several local defenses. Of these, acidic gastric (Table 8.1). In general, respiratory, gastrointestinal, and secretions are particularly important because they are highly genitourinary tract infections in otherwise healthy persons effective at killing certain organisms. Neutralizing the are caused by virulent microorganisms with the ability to stomach acid of healthy volunteers increased the infectivity damage or penetrate the epidermis or mucosal epithelium. of Vibrio cholerae by 10,000-fold. A layer of mucus covers By contrast, skin infections in healthy persons are mainly the gut throughout its length, preventing access of luminal caused by organisms that enter the skin through superficial pathogens to the surface epithelium. Pancreatic enzymes injuries. and bile detergents can destroy organisms with lipid Table 8.1 Routes of Microbial Infection Site Major Local Defense(s) Basis for Failure of Local Defense Pathogens (Examples) Skin Epidermal barrier Mechanical defects (punctures, burns, ulcers) Staphylococcus aureus, Candida albicans, Pseudomonas aeruginosa Needle sticks Human immunodeficiency virus, hepatitis viruses Arthropod and animal bites Yellow fever, plague, Lyme disease, malaria, rabies Direct penetration Schistosoma spp. Gastrointestinal Epithelial barrier Attachment and local proliferation of microbes Vibrio cholerae, Giardia duodenalis tract Attachment and local invasion of microbes Shigella spp., Salmonella spp., Campylobacter spp. Uptake through M cells Poliovirus, Shigella spp., Salmonella spp. Acidic secretions Acid-resistant cysts and eggs Many protozoa and helminths Peristalsis Obstruction, ileus, postsurgical adhesions Mixed aerobic and anaerobic bacteria (Escherichia coli, Bacteroides spp.) Bile and pancreatic enzymes Resistant microbial external coats Hepatitis A, rotavirus, norovirus Normal protective Broad-spectrum antibiotic use Clostridioides difficile microbiota Respiratory Mucociliary clearance Attachment and local proliferation of microbes Influenza viruses tract Ciliary paralysis by toxins Haemophilus influenzae, Mycoplasma pneumoniae, Bordetella pertussis Resident alveolar Resistance to killing by phagocytes Mycobacterium tuberculosis macrophages Urogenital Urination Obstruction, microbial attachment, and local Escherichia coli tract proliferation Normal vaginal microbiota Antibiotic use Candida albicans Intact epidermal/epithelial Microbial attachment and local proliferation Neisseria gonorrhoeae barrier Direct infection/local invasion Herpes viruses, syphilis Local trauma Various sexually transmitted infections (e.g., human papillomavirus)  General principles of microbial pathogenesis 341 envelopes. Antimicrobial defensins are produced by gut in alveoli by surviving within the phagolysosomes of epithelial cells. IgA antibodies, produced in mucosal lym- macrophages. phoid tissues such as Peyer patches and secreted into the Other organisms establish disease when local or systemic gut lumen (Chapter 17), can neutralize potential pathogens. defenses are impaired. The damage to respiratory mucociliary Peristalsis can clear organisms, preventing their local clearance by influenza, mechanical ventilation, smoking or overgrowth. Finally, the normal gut microbiota competitively cystic fibrosis sets the stage for superinfection by bacteria. inhibits colonization and overgrowth by potential pathogens, Many other infectious agents cause respiratory infections such as Clostridioides difficile. Many common gastrointestinal primarily in the setting of systemic immunodeficiency. pathogens are resistant to local defenses. Norovirus (the Examples include fungal infections by Pneumocystis jirovecii scourge of the cruise ship industry) is a nonenveloped virus in acquired immunodeficiency syndrome (AIDS) patients that is resistant to inactivation by acid, bile, and pancreatic and by Aspergillus spp. in patients with neutropenia. enzymes and hence easily spreads in places where people are crowded together. Intestinal protozoa and helminths Urogenital Tract transmitted as cysts or eggs, respectively, have acid-resistant Urine contains small numbers of low-virulence bacteria. outer coats. The urinary tract is protected from infection by regular Pathogens may establish symptomatic gastrointestinal emptying during micturition. Urinary tract pathogens (e.g., disease through several distinct mechanisms: E. coli) almost always gain access via the urethra and must Toxin production. Some organisms contaminating food be able to adhere to urothelium to avoid being washed can produce gastrointestinal disease without necessarily away. Women have more than 10 times as many urinary establishing an infection in the host. An example is tract infections as men because the length of the urethra is Staphylococcus aureus, which elaborates a powerful exo- 5 cm in women versus 20 cm in men, making women more toxin during its growth in contaminated food that is susceptible to entry of bacteria from the rectum. Expulsion responsible for acute food poisoning. of urine from the bladder eliminates microbes. Predictably, Bacterial colonoization and toxin production. Other bacteria obstruction of urinary flow or reflux of urine is a major establish an infection and produce damaging toxins. factor in susceptibility to urinary tract infections. Examples include V. cholerae and enterotoxigenic Esch- From puberty until menopause the vagina is protected erichia coli, which bind to the intestinal epithelium and from pathogens by lactobacilli, which ferment glucose to multiply in the overlying mucous layer. These organisms lactic acid, producing a low pH environment that suppresses elaborate potent exotoxins that are responsible for the growth of pathogens. Antibiotics can kill the lactobacilli symptomatic disease. and allow overgrowth of yeast, causing vaginal candidiasis. Adhesion and mucosal invasion. Shigella spp., Salmonella enterica, Campylobacter jejuni, and Entamoeba histolytica Vertical Transmission invade the intestinal mucosa and lamina propria and Vertical transmission of infectious agents from mother to cause ulceration, inflammation, and hemorrhage that fetus or newborn child is a common mode of transmission manifest clinically as dysentery. Candida albicans invades of certain pathogens and may occur through several different superficially into oral and esophageal squamous mucosa routes. in immunocompromised patients to cause thrush. Placental-fetal transmission is most likely to occur when the mother becomes infected with a pathogen during Respiratory Tract pregnancy. Some resulting infections interfere with fetal A plethora of microorganisms, including viruses, bacteria, development, and the degree and type of damage depend and fungi, are inhaled daily, mainly in dust or aerosol on the age of the fetus at the time of infection. Rubella particles. Microorganisms in large particles are trapped in virus infection during the first trimester can lead to heart the mucociliary blanket that lines the nose and the upper malformations, intellectual disability, cataracts, or deaf- respiratory tract and transported by ciliary action to the ness, but rubella virus infection during the third trimester back of the throat, where they are swallowed and cleared. has little effect. Particles smaller than 5 microns are carried into the alveoli, Transmission during birth is caused by contact with infectious where they are phagocytosed by leukocytes. agents during passage through the birth canal. Examples The microorganisms that infect the healthy respiratory include gonococcal and chlamydial conjunctivitis. tract evade local defenses through several different Postnatal transmission in maternal milk can transmit mechanisms. Some respiratory viruses attach to and enter cytomegalovirus (CMV), human immunodeficiency virus epithelial cells in the lower respiratory tract and pharynx. (HIV), and hepatitis B virus (HBV). For example, influenza viruses have envelope proteins called hemagglutinins that bind to sialic acid on the surface of Spread and Dissemination of Microbes Within the Body epithelial cells. Attachment induces the host cell to endo- Although some disease-causing microorganisms remain cytose the virus, leading to viral entry and replication. Certain localized to the initial site of infection, others have the bacterial respiratory pathogens, including Mycoplasma capacity to invade tissues and spread to distant sites via pneumoniae and Bordetella pertussis, release toxins that enhance the lymphatics, the blood, or the nerves (Fig. 8.1). Pathogens their ability to establish an infection by impairing ciliary can spread within the body in several ways. Some pathogens activity. Another important mechanism of establishing secrete enzymes that break down tissues, allowing the respiratory infection is resistance to killing following organisms to spread contiguously in tissue. Organisms that phagocytosis. Mycobacterium tuberculosis gains a foothold disseminate often travel through the lymphatics to regional 342 CHAPTER 8 Infectious Diseases Portal of entry Infection Release From the Body and Transmission of Microbes (skin, respiratory, Microbes use a variety of exit strategies to ensure their gastrointestinal, genitourinary transmission from one host to the next. Release may be epithelia) accomplished by skin shedding, coughing, sneezing, voiding of urine or feces, during sexual contact, or through insect Spread within Spread through vectors. Some pathogens are released for only brief periods nerves of time or periodically during disease flares, but others may inflammatory cells M. tuberculosis Varicella-zoster be shed for long periods by asymptomatic carrier hosts. in macrophages virus, rabies Pathogens vary in hardiness in the environment. Fragile pathogens persist outside of the body for only short periods Lymphatics of time and must be passed quickly from person to person, often by direct contact. Spread through Most pathogens are transmitted from person to person lymphatics and by respiratory, fecal-oral, or sexual routes. blood Viruses and bacteria spread by the respiratory route are aerosolized in droplets and released into the air. Some respiratory pathogens, including influenza viruses, are Bloodstream spread in large droplets that travel no more than 3 feet Spinal cord and from the source, but others, including M. tuberculosis and brainstem Liver varicella-zoster virus, spread in small particles that can travel longer distances. Most enteric pathogens are spread by the fecal-oral route, Heart that is, by ingestion of stool-contaminated water or food. Water-borne pathogens involved in epidemic outbreaks Hepatitis that are spread in this fashion include hepatitis A and E Salivary gland Yellow fever viruses (HAV and HEV), poliovirus, rotavirus, V. cholera, Shigella spp., C. jejuni, and S. enterica. Some parasitic Poliomyelitis helminths (e.g., hookworms, schistosomes) shed eggs in Endocarditis Mumps stool that hatch as larvae that are capable of penetrating Figure 8.1 Routes of entry and dissemination of microbes. To enter the the skin of the next host. body, microbes penetrate the epithelial or mucosal barriers. Infection may Sexual transmission often entails prolonged intimate or remain localized at the site of entry or spread to other sites in the body. mucosal contact and is responsible for spread of a wide Most common microbes (selected examples are shown) spread through the variety of pathogens, including viruses (e.g., herpes lymphatics or bloodstream (either freely or within inflammatory cells). simplex virus [HSV], HIV, human papillomavirus [HPV]); However, certain viruses and bacterial toxins may also travel through bacteria (Treponema pallidum, Neisseria gonorrhoeae); nerves. (Modified from Mims CA: The Pathogenesis of Infectious Disease, ed 4, San Diego, 1996, Academic Press.) protozoa (Trichomonas vaginalis); and arthropods (Phthiris pubis, lice). There are several additional routes of transmission. Saliva is responsible for transmitting viruses that replicate in the lymph nodes, from which they may reach the bloodstream. salivary glands or the oropharynx, including Epstein-Barr Certain viruses, such as rabies virus, poliovirus, and varicella- virus (EBV). Some important human pathogens are protozoa zoster virus, spread to the central nervous system (CNS) that are spread through blood meals taken by arthropod by infecting peripheral nerves and then traveling along vectors (mosquitoes, ticks, mites). Finally, zoonotic infections axons. However, the most common and efficient mode of are those transmitted from animals to humans, either by microbial dissemination is through the bloodstream, by direct contact (including animal bites), use of animal prod- which the organism can reach all organs. The consequences ucts, or via an invertebrate vector. of blood-borne spread of pathogens vary widely depending on the virulence of the organism, the magnitude of the infection, the pattern of seeding, and host factors such as KEY CONCEPTS immune status. As discussed in Chapter 4, disseminated HOW MICROORGANISMS CAUSE DISEASE pathogens may produce a systemic inflammatory response Transmission of infections can occur by contact (direct and syndrome called sepsis that manifests as fever, low blood indirect), the respiratory route, the fecal-oral route, sexual pressure, and coagulopathies that may progress to organ transmission, vertical transmission, or insect/arthropod vectors. failure and death if unchecked, even in previously healthy A pathogen can establish infection if it possesses virulence individuals. In other instances, the major signs of spread factors that overcome normal host defenses or if the host of the infection are related to seeding of tissues by pathogens. defenses are compromised. These may take the form of a single infectious nidus (an Host defenses against infection include the following: abscess or tuberculoma), multiple small sites of infection Skin: tough keratinized barrier, low pH, fatty acids (e.g., miliary tuberculosis or Candida microabscesses), or Respiratory system: alveolar macrophages, mucociliary clear- infection of the heart and vessels (infectious endocarditis ance by bronchial epithelium, IgA and mycotic aneurysm).  General principles of microbial pathogenesis 343 Table 8.2 Mechanisms of Antigenic Variation GI system: acidic gastric pH, viscous mucus, pancreatic enzymes and bile, defensins, IgA, and normal microbiota Type Example Disease Urogenital tract: repeated flushing and acidic environment High mutation rate Human AIDS created by commensal microbiota immunodeficiency Pathogens can proliferate locally, at the site of initial infection, virus Influenza virus Influenza or spread to other sites by direct extension (invasion) or by transport in the lymphatics, the blood, or nerves. Genetic reassortment Influenza virus Influenza Rotavirus Diarrhea Genetic rearrangement Borrelia burgdorferi Lyme disease Host-Pathogen Interactions (e.g., gene Neisseria gonorrhoeae Gonorrhea recombination, gene Trypanosoma brucei African sleeping The outcome of infection is determined by the virulence conversion, sickness of the microbe and the nature of the host immune response, site-specific inversion) Plasmodium falciparum Malaria which may eliminate the infection or, in some cases, Large diversity of Rhinoviruses Colds exacerbate or cause tissue damage. The host has a large serotypes Streptococcus Pneumonia and and complex armamentarium of defenses against pathogens, pneumoniae meningitis including physical barriers and components of the innate and adaptive immune systems, which were discussed in Chapter 6. Microbes undergo continuous evolution to combat To escape recognition, microbes have strategies that host defenses. Here we discuss some specific features of allow them to “change their coats” by expressing differ- microbes and the host response that are important deter- ent surface antigens (Borrelia spp. and trypanosomes). minants of the outcome of infections. Influenza viruses have a segmented RNA genome that allows for frequent recombination events, permitting Immune Evasion by Microbes antigenic drift (changes in antibody-binding sites of major Most pathogenic microbes have developed one or more viral envelope glycoproteins) and antigenic shift (reassort- strategies to evade host defenses (Fig. 8.2). ment of genomes between two viral strains creating a new Antigenic variation. Antibodies against microbial antigens strain). Other microbes generate numerous genetic vari- block microbial adhesion and uptake into cells, act as ants through mutation (over 95 capsular polysaccharides opsonins to facilitate phagocytosis, and fix complement. in different strains of Streptococcus pneumoniae) (Table 8.2). Resistance to antimicrobial peptides. Pathogens, such as Shigella spp., S. aureus, and Candida spp., use strategies to avoid killing by cationic antimicrobial peptides that include changes in net surface charge and membrane hydrophobicity, which prevent antimicrobial peptide Modulation of surface structure Inhibition of phagocytosis insertion and pore formation, secretion of proteins that to avoid recognition inactivate or degrade the peptides, and pumps that export (e.g., antigenic variability) the peptides. Resistance to killing by phagocytes. The carbohydrate capsule on the surface of many bacteria (S. pneumoniae, Neisseria Inhibition of meningitidis, Haemophilus influenzae) prevents phagocytosis phagosome- of the organisms by neutrophils. S. aureus expresses lysosome fusion protein A, which binds the Fc portion of antibodies and Escape from phagosome inhibits phagocytosis by competitively reducing binding Modulate: of the antibodies to phagocyte Fc receptors. Some patho- Signal transduction gens are resistant to intracellular killing in phagocytes, Gene expression including mycobacteria (which inhibit phagosome- Cell death lysosome fusion), Listeria monocytogenes (which disrupts the phagosome membrane and escapes onto the cytosol), Cryptococcus neoformans, and certain protozoa (e.g., Leishmania spp., Trypanosoma spp., Toxoplasma gondii). Evasion of apoptosis and manipulation of host cell metabolism. Some viruses produce proteins that interfere with apop- tosis of the host cell, buying time to replicate, enter latency, Hide from immune or even transform infected cells. Microbes that replicate Viral cytokines or Inhibition surveillance; intracellularly (viruses, some bacteria, fungi, and protozoa) soluble receptor of antigen viral latency also express factors that modulate autophagy, thus homologs presentation evading degradation. Resistance to cytokine-, chemokine- and complement-mediated Figure 8.2 An overview of mechanisms used by viral and bacterial pathogens to evade innate and adaptive immunity. (Modified with host defense. Some viruses interfere with interferon (IFN) permission from Finlay B, McFadden G: Anti-immunology: evasion of the function by producing soluble homologues of IFN-α/β host immune system by bacterial and viral pathogens, Cell or IFN-γ receptors that function as “decoys” that inhibit 2006;124:767–782.) the actions of secreted IFNs; by producing proteins that 344 CHAPTER 8 Infectious Diseases inhibit the JAK/STAT cytokine receptor signaling and HCV infection is mainly due to the effects of the immune pathway; or by producing proteins that inactivate or response on infected liver cells: in an attempt to clear the inhibit double-stranded RNA–dependent protein kinase virus, host T cells and, possibly, natural killer (NK) cells (protein kinase R [PKR]), through which IFNs inhibit kill the hepatocytes. Antibodies produced against the viral replication. streptococcal M protein can cross-react with cardiac proteins Evasion of recognition by CD8+ cytotoxic T lymphocytes (CTLs) and damage the heart, leading to rheumatic heart disease. and CD4+ helper T cells. T cells recognize microbial antigens Poststreptococcal glomerulonephritis is caused by immune presented by MHC molecules, class I for CTLs and class complexes formed between antistreptococcal antibodies and II for CD4+ cells (see Chapter 6). Several DNA viruses streptococcal antigens that deposit in the renal glomeruli, (e.g., HSV, CMV, EBV) bind to or alter localization of producing inflammation. A cycle of inflammation and MHC class I proteins, impairing peptide presentation to epithelial injury contributes to the pathogenesis of inflam- CD8+ T cells. Herpesviruses also can target MHC class matory bowel disease, with microbes playing a role (Chapter II molecules for degradation, impairing antigen presenta- 17). Viruses (HBV, HCV) and bacteria (Helicobacter pylori) tion to CD4+ T-helper cells. that are not known to carry or activate oncogenes are associ- Another strategy exploits immunoregulatory mechanisms ated with cancers, presumably because these microbes trigger to downregulate antimicrobial T cell responses. Loss of T cell chronic inflammation, which provides fertile ground for potency over time, termed T-cell exhaustion, is a feature the development of cancer (Chapter 7). of chronic infections by HIV, hepatitis C virus (HCV), and HBV. Programmed cell death protein 1 (PD-1) is an Infections in People With Immunodeficiencies immune checkpoint cell surface receptor, and the PD-1 Inherited or acquired defects in innate and adaptive pathway, which normally functions to maintain T-cell immunity often impair the immune system, rendering tolerance to self antigens, is an important mediator of the affected individual susceptible to infections (Chapter T-cell exhaustion during chronic viral infection. Tumors 6). Organisms that cause disease in immunodeficient exploit the same mechanisms to suppress destructive individuals but not in people with intact immune systems immune responses (Chapter 7). Anti–PD-1 immunotherapy are called opportunistic. Worldwide, the most devastating is approved for the treatment of cancers and is being immunodeficiency is that caused by infection with HIV, the explored as a possible adjunctive therapy for chronic cause of AIDS. Other causes of acquired immunodeficiencies infections that are resistant to antimicrobial therapy. include infiltrative processes that suppress bone marrow Another way of avoiding the immune system is to “lie function (such as leukemia), immunosuppressive drugs low” by establishing a state of latent infection in which used to treat patients with autoimmune diseases and organ few, if any, viral genes are expressed, until later reactiva- transplant recipients, as well as drugs used to treat cancer, tion. Examples include latent infections of neurons by and hematopoietic stem cell transplantation. Opportunistic HSV and varicella-zoster virus, and of B lymphocytes organisms (e.g., Aspergillus spp. and Pseudomonas spp.) cause by EBV. significant disease in these patients. Decline of immune Pathogens can infect immune cells and interfere with responses can result in reactivation of latent infection (e.g., their function (e.g., HIV, which infects and destroys CD4+ herpesviruses and M. tuberculosis). Age-related decline in T cells). immune function may increase infections in the elderly. Nonimmune diseases or injuries also increase susceptibility KEY CONCEP TS to infection: Pseudomonas aeruginosa and Burkholderia cepacia in cystic fibrosis due to a defective transmembrane conductance IMMUNE EVASION BY MICROBES regulator, S. pneumoniae in people with sickle cell disease After bypassing host tissue barriers, infectious microorganisms due to loss of splenic macrophages, and P. aeruginosa in must also evade host innate and adaptive immunity to successfully burns due to barrier disruption. Finally, malnutrition can proliferate and be transmitted to the next host. Strategies include impair immune defenses. the following: In addition to common immunodeficiencies, rare inherited Antigenic variation (primary) immunodeficiency diseases illuminate important Inactivating antibodies or complement aspects of specific components of host defense, as well as Resisting phagocytosis (e.g., by producing a capsule) the unique vulnerabilities of certain pathogens. Suppressing the host adaptive immune response (e.g., by interfer- Antibody deficiencies, as seen in patients with X-linked ing with cytokines or inhibiting MHC expression and antigen agammaglobulinemia, lead to increased susceptibility to presentation) infections by extracellular bacteria, including S. pneu- Establishing latency, during which viruses survive in a silent moniae, H. influenzae, and S. aureus, as well as a few viruses state in infected cells (rotavirus and enteroviruses). Infecting and disabling or killing immune cells Complement defects involving the early components of the complement cascade lead to susceptibility to infections by encapsulated bacteria, such as S. pneumoniae, whereas Injurious Effects of Host Immunity deficiencies of the late membrane attack complex com- The host immune response to microbes can be a major ponents (C5 to C9) are associated with infections due to cause of tissue injury. The granulomatous inflammatory Neisseria spp. reaction to M. tuberculosis sequesters the bacilli and prevents Defects in neutrophil function, as in chronic granulomatous their spread, but it also can produce tissue damage and disease, lead to increased susceptibility to infections with fibrosis. Similarly, damage to hepatocytes following HBV S. aureus, some gram-negative bacteria, and fungi.  General principles of microbial pathogenesis 345 Defects in Toll-like receptor (TLR) signaling pathways have Virus varied effects. Mutations in MyD88 or IRAK4, which are Receptor signaling proteins downstream of several TLRs, predis- pose to pyogenic bacterial infections (S. pneumoniae), and impaired TLR3 responses are associated with childhood HSV encephalitis. Entry, uncoating T-cell defects lead to susceptibility to intracellular patho- gens, particularly viruses and some parasites. Inherited Viral genome mutations that impair the generation of T-helper 1 (Th1) replication, cells (such as mutations in IL-12 or IFN-γ receptors, or mRNA synthesis the transcription factor STAT1) are associated with atypi- Metabolic cal mycobacterial infections, discussed later. By contrast, derangements Viral protein defects that impair the generation of Th17 cells (mutations synthesis in STAT3) are associated with chronic mucocutaneous Cell lysis or Reduced candidiasis. host cell fusion VIRAL DNA, RNA, PROTEINS protein Neoplastic Host Damage by Microbes synthesis transformation Infectious agents establish infection and damage tissues by Viral Virus Viral a few mechanisms: inclusions assembly antigens They can contact or enter host cells and cause cell death directly, or cause changes in cellular metabolism and proliferation that can eventually lead to transformation. They may release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis. They can induce host immune responses that, though directed against the invader, cause additional tissue damage. Mechanisms of Viral Injury Host T cell–mediated injury Viruses can directly damage host cells by entering them and Figure 8.3 Mechanisms by which viruses cause injury to cells. replicating at the cell’s expense. The predilection for viruses to infect certain cells and not others is called tropism. A major determinant of tissue tropism is the presence of viral unaffected. Viruses can induce cell death by activating receptors on host cells. Viruses bind to proteins found on so-called death receptors (in the tumor necrosis factor [TNF] the surface of host cells that normally function as receptors receptor family) on the plasma membrane and by trig- for host factors. This is presumably one way in which viruses gering the intracellular apoptotic machinery. Large evolve to infect, survive within cells, and spread. For amounts of viral proteins are synthesized in infected cells, example, HIV glycoprotein gp120 binds to CD4 on T cells including unfolded or misfolded proteins that activate and to the chemokine receptors CXCR4 (mainly on T cells) the ER stress response; this, too, activates pro-apoptotic and CCR5 (mainly on macrophages) (Chapter 6), and EBV pathways. Finally, some viruses encode proteins that are binds to complement receptor 2 (also known as CR2 or CD21) pro-apoptotic, such as the HIV viral protein R (Vpr). on B cells. Other tropisms are explained by cell-lineage–spe- Antiviral immune responses. Host lymphocytes can recog- cific factors. JC virus infection, which causes leukoencepha- nize and destroy virus-infected cells, but, as mentioned lopathy (Chapter 28), is restricted to oligodendroglial cells earlier, CTLs also can be responsible for tissue injury. in the CNS because JC viral genes require glial-specific host Transformation of infected cells. Oncogenic viruses can transcription factors for their expression. stimulate cell growth and survival by a variety of mecha- Physical barriers can contribute to tissue tropism. For nisms, including expression of virus-encoded oncogenes, example, enteroviruses replicate in the intestine in part expression of viral proteins that inactivate key tumor because they can resist inactivation by acids, bile, and suppressors, and insertional mutagenesis, in which digestive enzymes. Rhinoviruses infect host cells within the expression of host genes is altered by the insertion of upper respiratory tract because they replicate optimally at viral genes into host genes or flanking sequences (see the lower temperatures found in sites exposed to the ambient Chapter 7). atmosphere. Once viruses are inside host cells, they can damage or Mechanisms of Bacterial Injury kill the cells by a number of mechanisms (Fig. 8.3): Bacterial Virulence. Bacterial damage to host tissues Direct cytopathic effects. Some viruses kill cells by prevent- depends on the ability of the bacteria to adhere to host ing synthesis of critical host macromolecules (e.g., host cells, to invade cells and tissues, and to deliver toxins. cell DNA, RNA, or proteins), or by producing degradative Pathogenic bacteria have virulence genes that encode proteins enzymes and toxic proteins. Poliovirus inactivates cap- responsible for these properties. An example of the impor- binding protein, which is essential for translation of host tance of such genes can be found in the various strains of cell mRNAs but leaves translation of poliovirus mRNAs S. enterica. All S. enterica strains that infect humans are so 346 CHAPTER 8 Infectious Diseases closely related that they form a single species, meaning that conserved repeating protein subunits, and the variable they share many housekeeping genes. Differences in a rela- tip fibrillum determines the tissue-binding specificity of tively small number of virulence genes determine whether the bacteria. The precise tissue-tropism of E. coli that an isolate of S. enterica causes life-threatening typhoid fever cause urinary tract infections is determined by the tip or self-limited enteritis. Virulence genes are frequently found fibrillum expressed by the bacteria. Adhesion to bladder grouped together in clusters called pathogenicity islands. epithelium is mediated by tip fibrillum that binds Mobile genetic elements such as plasmids and bacterio- d-mannosylated receptors, and adhesion to the renal phages can transmit functionally important genes to bacteria, epithelium depends on binding of tip fibrillum to including genes that influence pathogenicity and drug galabiose-containing glycosphingolipids. Pili can be resistance. Genes for toxins are sometimes found in plasmids targets of the host antibody response and, in turn, some but are more often found in the genomes of bacteriophages, bacteria such as N. gonorrhoeae vary their pili to escape including the genes that encode the toxins responsible for from the host immune system. the pathogenesis of the infections cholera, diphtheria, and botulism. Genes for acquired antibiotic resistance traits are Intracellular Bacteria. Bacteria have evolved a variety of more frequently found on plasmids, which can spread not mechanisms for entering host cells. Some bacteria use only within bacterial species but also among more distantly receptors that are important in the host immune response related organisms. For example, a plasmid with genes for to gain entry into macrophages. M. tuberculosis uses host vancomycin resistance can spread not only among Enterococ- receptors for opsonins (antibodies and C3b) as well as poorly cus spp., but also to more distantly related (and virulent) defined nonopsonic receptors on macrophages. Some gram- S. aureus. negative bacteria use a type III secretion system to enter Many bacteria coordinately regulate gene expression epithelial cells. This consists of needlelike structures project- within a large population by a process called quorum sensing. ing from the bacterial surface that bind to host cells. These Quorum sensing allows bacteria to turn on gene expression proteins then form pores in the host cell membrane and and express specific traits only when the organism grows inject bacterial proteins that mediate the rearrangement of to reach a high concentration. To do this, bacteria secrete the host cell cytoskeleton in a fashion that facilitates bacterial small autoinducer molecules which, when present at high entry. levels, induce expression of genes for toxin production (S. After bacteria enter the host cell, their fate (and that of aureus), competence for genetic transformation (S. pneu- the infected cell) varies greatly depending on the organism. moniae), or generation of biofilms (P. aeruginosa). Autoinduc- Shigella spp. and E. coli inhibit host protein synthesis, replicate ers can be N-acyl-homoserine lactones in gram-negative rapidly, and lyse the host cell within hours. Most bacteria bacteria, or peptides in gram-positive bacteria. Coordinated are killed within macrophages when the phagosome fuses expression of virulence factors within bacterial populations with an acidic lysosome to form a phagolysosome, where may allow bacteria growing in discrete host sites, such as ingested microbes are destroyed, but certain bacteria elude an abscess or consolidated pneumonia, to overcome host this host defense. M. tuberculosis blocks fusion of the lysosome defenses. Interestingly, with quorum sensing, different with the phagosome, allowing it to proliferate unchecked bacterial colonies within the same population may express within the macrophage. Other bacteria avoid destruction different genes. Thus, unicellular bacteria acquire some of in macrophages by leaving the phagosome and entering the more complex properties of multicellular organisms, in the cytoplasm. L. monocytogenes produces a pore-forming which different cells perform different functions. protein called listeriolysin O and two phospholipases that Communities of bacteria form biofilms in which the degrade the phagosome membrane, allowing the bacterium organisms live within a viscous layer of extracellular polysac- to escape into the cytoplasm, protected from the killing charides that adhere to host tissues or devices such as mechanisms of macrophages. In the cytoplasm, L. monocy- intravascular catheters and artificial joints. In addition to togenes modifies the host cell actin cytoskeleton to promote enhancing adherence to host tissues, biofilms increase the direct spreading of the organism to neighboring cells. The virulence of bacteria by protecting the microbes from immune growth of bacteria inside cells can allow them to escape effector mechanisms and increasing their resistance to from certain effector mechanisms of the immune response antimicrobial drugs. Biofilm formation seems to be particu- (e.g., antibodies and complement), and can also facilitate larly important in the persistence and relapse of bacterial the spread of the bacteria. An example of the latter is the endocarditis, artificial joint infections, and respiratory migration of infected macrophages carrying M. tuberculosis infections in people with cystic fibrosis. from the lung to draining lymph nodes and other more distant sites. Bacterial Adherence to Host Cells. Bacteria use various surface structures to attach to host cells and tissues. Bacterial Toxins. Any bacterial substance that contributes Adhesins are bacterial surface proteins that bind the to illness can be considered a toxin. Toxins are classified as organisms to host cells or extracellular matrix. Adhesins endotoxin, which is a component of the gram-negative have a broad range of host cell specificity. For example, bacterial cell, and exotoxins, which are proteins that are Streptococcus pyogenes adheres to host tissues using the secreted by many kinds of bacteria. adhesins protein F and teichoic acid, which project from Bacterial endotoxin is a lipopolysaccharide (LPS) in the bacterial cell wall and bind to fibronectin on the surface the outer membrane of gram-negative bacteria that both of host cells and in the extracellular matrix. stimulates host immune responses and injures the host. Pili are filamentous structures on the surface of bacteria Lipid A, the part of LPS that anchors the molecule in the that act as adhesins. The stalks of pili are composed of host cell membrane, has the endotoxin activity of LPS. LPS  General principles of microbial pathogenesis 347 binds to the cell-surface receptor CD14, and the complex Pathogens can induce immune responses that cause tissue of LPS/CD14 then binds to TLR4. Other molecules in the damage. Absence of an immune response may reduce damage outer structures of gram-positive bacteria can have effects induced by some infections; conversely, immune compromise similar to LPS, including lipoteichoic acid, which binds to can allow uncontrolled expansion of microorganisms that can TLR2. The response to lipid A or lipotechoic acid is beneficial directly cause injury. to the host in that it activates protective immunity in several ways. It induces the production of important cytokines and chemoattractants (chemokines) by immune cells and increases Spectrum of Inflammatory Responses to Infection the expression of costimulatory molecules, which enhance T-lymphocyte activation. However, high levels of endotoxin In contrast to the vast molecular diversity of microbes, the play a pathogenic role in septic shock, disseminated intra- morphologic patterns of tissue responses to microbes are vascular coagulation (DIC), and adult respiratory distress limited, as are the mechanisms directing these responses. syndrome, mainly through induction of excessive levels of Therefore, many pathogens produce similar reaction patterns, cytokines such as TNF, IL-6, and IL-12. and few features are unique or pathognomonic for a par- Exotoxins are secreted bacterial proteins that cause ticular microorganism. Moreover, sometimes the immune cellular injury and disease. They can be classified into broad status of the host determines the histologic features of the categories by their mechanism of action. These are briefly inflammatory response to microbes. Thus, pyogenic bacteria, described next and discussed in more detail in the specific which normally evoke vigorous leukocyte responses, may sections about each type of bacteria. cause rapid tissue necrosis with little leukocyte exudation Enzymes. Bacteria secrete a variety of enzymes (proteases, in a profoundly neutropenic host. Similarly, in a patient hyaluronidases, coagulases, fibrinolysins) that act on who is not immunocompromised, M. tuberculosis causes substrates in host tissues or on host cells. These enzymes well-formed granulomas with few mycobacteria present, have roles in tissue destruction and abscess formation. whereas in an AIDS patient the same mycobacteria multiply For example, exfoliative toxins produced by S. aureus profusely in macrophages, which fail to coalesce into cause staphylococcal scalded skin syndrome by degrading granulomas. proteins that hold keratinocytes together, causing the There are five major histologic patterns of tissue reaction epidermis to detach from the deeper skin. in infections (Table 8.3). Toxins that alter intracellular signaling or regulatory pathways. Most of these toxins have an active (A) subunit with Suppurative (Purulent) Inflammation enzymatic activity and a binding (B) subunit that binds This pattern is characterized by increased vascular perme- to receptors on the cell surface and delivers the A subunit ability and leukocytic infiltration, predominantly of neu- into the cell cytoplasm. The effects of these toxins are trophils (see Fig. 3.15). The neutrophils are attracted to the diverse and depend on the binding specificity of the B site of infection by release of chemoattractants from the domain and the cellular pathways affected by the A “pyogenic” (pus-forming) bacteria that evoke this response, domain. A-B toxins are made by many bacteria including mostly extracellular gram-positive cocci and gram-negative Bacillus anthracis, V. cholerae, and some strains of E. coli. rods. Masses of dying and dead neutrophils and liquefactive Neurotoxins are A-B toxins produced by Clostridium botu- necrosis of the tissue form pus. The sizes of purulent lesions linum and Clostridium tetani that inhibit release of neu- range from tiny microabscesses formed in multiple organs rotransmitters, resulting in paralysis. These toxins do during bacterial sepsis secondary to a colonized heart valve, not kill neurons; instead, the A domains interact specifi- to diffuse involvement of entire lobes of the lung in pneu- cally with proteins involved in secretion of neurotransmit- monia. How destructive the lesions are depends on their ters at the synaptic junction. Both tetanus and botulism location and the organism involved. For example, S. can result in death from respiratory failure due to paralysis pneumoniae usually spare alveolar walls and cause lobar of the chest and diaphragm muscles. pneumonia that resolves completely, whereas S. aureus and Superantigens are bacterial toxins that stimulate a large Klebsiella pneumoniae destroy alveolar walls and form number of T lymphocytes by binding to conserved abscesses that heal with scar formation. Bacterial pharyngitis portions of the T-cell receptor, leading to massive (S. pyogenes) can resolve without sequelae, whereas untreated T-lymphocyte proliferation and cytokine release. The acute bacterial inflammation of a joint can destroy the joint high levels of cytokines can lead to systemic inflammatory in a few days. response syndrome. Mononuclear and Granulomatous Inflammation Diffuse, predominantly mononuclear, interstitial infiltrates KEY CONCEPTS are a common feature of all chronic inflammatory processes, HOST DAMAGE but when they develop acutely, they often are a response Diseases caused by microbes involve interplay between microbial to viruses, intracellular bacteria, or intracellular parasites. virulence factors and host responses. In addition, spirochetes and helminths provoke chronic Infectious agents cause death or dysfunction by directly interact- inflammatory responses. Which mononuclear cell predomi- ing with the host cells. nates within the inflammatory lesion depends on the host Injury may be due to local or systemic release of microbial immune response to the organism. For example, plasma products including endotoxin (LPS), exotoxins, or cells are abundant in the primary and secondary lesions of superantigens. syphilis (Fig. 8.4), whereas lymphocytes predominate in HBV infection or viral infections of the brain. The presence 348 CHAPTER 8 Infectious Diseases Table 8.3 Spectrum of Inflammatory Responses to Infection Type of Response Pathogenesis Examples Suppurative (Purulent) Increased vascular permeability Pneumonia (Staphylococcus aureus) Infection Leukocyte infiltration (neutrophils) Abscesses (Staphylococcus spp., anaerobic and other Chemoattractants from bacteria bacteria) Formation of “pus” Mononuclear and Mononuclear cell infiltrates (monocytes, macrophages, Syphilis granulomatous plasma cells, lymphocytes) inflammation Cell-mediated immune response to pathogens Tuberculosis (“persistent antigen”) Formation of granulomata Cytopathic-cytoproliferative Viral transformation of cells Cervical cancer (human papillomavirus) reactions Necrosis or proliferation (including multinucleation) Chicken pox, shingles Linked to neoplasia Herpes Tissue necrosis Toxin- or lysis-mediated destruction Gangrene (Clostridium perfringens) Lack of inflammatory cells Hepatitis (hepatitis B virus) Rapidly progressive processes Chronic inflammation/ Repetitive injury leads to fibrosis Chronic hepatitis with cirrhosis (hepatitis B and C scarring Loss of normal parenchyma viruses) No reaction Severe immune compromise Mycobacterium avium in untreated AIDS (T-cell deficiency) Mucormycosis in bone marrow transplant patients (neutropenia) of these lymphocytes reflects cell-mediated immune responses Cytopathic-Cytoproliferative Reaction against the pathogen or pathogen-infected cells. At the other These reactions are usually produced by viruses. The lesions extreme, macrophages may become filled with organisms, are characterized by cell necrosis or cellular proliferation, as occurs in M. avium complex infections in AIDS patients, usually with sparse inflammatory cells. Some viruses rep- who cannot mount an effective immune response to the licate within cells and make viral aggregates that are visible organisms. as inclusion bodies (e.g., herpesviruses or adenovirus) or Granulomatous inflammation is a distinctive form of induce cells to fuse and form multinucleated cells called mononuclear inflammation usually evoked by infectious polykaryons (e.g., measles virus or herpesviruses). Focal cell agents that resist eradication and are capable of stimulating damage in the skin may cause epithelial cells to become strong T cell–mediated immunity (e.g., M. tuberculosis, detached, forming blisters (Fig. 8.5). Some viruses can cause Histoplasma capsulatum, schistosome eggs). Granulomatous epithelial cells to proliferate (e.g., venereal warts caused by inflammation is characterized by accumulation and aggrega- HPV or the umbilicated papules of molluscum contagiosum tion of activated macrophages called “epithelioid” cells, caused by poxviruses). Finally, viruses can contribute to some of which may fuse to form giant cells. Granulomas the development of malignant neoplasms (Chapter 7). may contain a central area of caseous necrosis (see Chapter 3 and discussion of tuberculosis later in this chapter). Tissue Necrosis Clostridium perfringens and other organisms such as Coryne- bacterium diphtheriae that secrete powerful toxins cause such rapid and severe necrosis (gangrenous necrosis) that tissue Figure 8.4 Secondary syphilis in the dermis with perivascular lymphoplasmacytic infiltrate and endothelial proliferation. Figure 8.5 Herpesvirus blister in mucosa. See Fig. 8.9 for viral inclusions.  Viral infections 349 Acute (Transient) Infections The viruses that cause transient infections are structurally heterogeneous, but all elicit effective immune responses that eliminate the pathogens, limiting the durations of these infections. However, specific viruses exhibit widely differing degrees of genetic diversity, a variable that has an important impact on the susceptibility of the host to reinfection by viruses of the same type. The mumps virus, for example, has only one genetic subtype and infects people only once, whereas other viruses, such as influenza viruses, can repeat- edly infect the same individual because new genetic variants arise periodically in nature. Immunity to some viruses, Figure 8.6 Schistosoma haematobium infection of the bladder with numerous calcified eggs and extensive scarring. Table 8.4 Selected Human Viruses and Viral Diseases damage is the dominant feature. The parasite E. histolytica Organ causes colonic ulcers and liver abscesses characterized System Species Disease by extensive tissue destruction with liquefactive necrosis Respiratory Adenovirus Upper and lower and little inflammatory infiltrate. Some viruses can cause respiratory tract infections, widespread and severe necrosis of host cells associated with conjunctivitis, inflammation, as exemplified by total destruction of the diarrhea temporal lobes of the brain by HSV or the liver by HBV. Rhinovirus Upper respiratory tract infection Chronic Inflammation and Scarring Influenza viruses A, B Influenza Many infections elicit chronic inflammation, which can Respiratory syncytial Bronchiolitis, virus pneumonia lead either to complete healing or to extensive scarring. For example, chronic HBV infection may cause cirrhosis of Digestive Mumps virus Mumps, pancreatitis, the liver, in which dense fibrous septae surround nodules orchitis Rotavirus Childhood of regenerating hepatocytes with complete loss of normal gastroenteritis liver architecture and consequent changes in blood flow. Norovirus Gastroenteritis Sometimes the exuberant scarring response is the major cause Hepatitis A virus Acute viral hepatitis of dysfunction (e.g., the “pipestem” fibrosis of the liver or Hepatitis B virus Acute or chronic fibrosis of the bladder wall caused by schistosomal eggs [Fig. hepatitis 8.6] or the constrictive fibrous pericarditis in tuberculosis). Hepatitis D virus With hepatitis B virus, acute or These patterns of tissue reaction are useful guidelines chronic hepatitis for analyzing microscopic features of infectious processes, Hepatitis C virus Acute or chronic but they rarely appear in pure form because different types hepatitis of host reactions often occur at the same time. For example, Hepatitis E virus Acute viral hepatitis the lung of an AIDS patient may be infected with CMV, Systemic with Measles virus Measles (rubeola) which causes cytolytic changes, and at the same time by skin eruptions Rubella virus German measles Pneumocystis spp., which causes interstitial inflammation. (rubella) Similar patterns of inflammation also can be seen in tissue Varicella-zoster virus Chickenpox, shingles responses to physical or chemical agents and in inflammatory Herpes simplex virus 1 Oral herpes (“cold sore”) diseases of unknown cause (Chapter 3). Herpes simplex virus 2 Genital herpes Systemic with Cytomegalovirus Cytomegalic inclusion This concludes our discussion of the general principles hematologic disease of the pathogenesis and pathology of infectious disease. disorders Epstein-Barr virus Infectious We now turn to specific infections caused by viruses, bacteria, mononucleosis fungi, and parasites, and focus on their pathogenic mecha- Human Acquired nisms and pathologic effects rather than details of clinical immunodeficiency immunodeficiency features, which are available in clinical textbooks. Infections viruses 1 and 2 syndrome that typically involve a specific organ are discussed in other Arboviral and Dengue viruses 1 to 4 Dengue hemorrhagic chapters. hemorrhagic fever fevers Yellow fever virus Yellow fever Skin/genital warts Human papillomavirus Condyloma; cervical VIRAL INFECTIONS carcinoma Central nervous Poliovirus Poliomyelitis Viruses are the cause of many clinically important acute system JC virus Progressive multifocal and chronic infections, which may affect virtually every leukoencephalopathy (opportunistic) organ system (Table 8.4). 350 CHAPTER 8 Infectious Diseases particularly respiratory and gastrointestinal viruses, wanes immunocompromised individuals) are rare late complications with time, and this too allows the same virus to infect the of measles. The pathogenesis of subacute sclerosing pan- host repeatedly. encephalitis is not well understood, but a replication-defective variant of measles may be involved in this persistent viral Measles infection. Measles is an acute viral infection that affects multiple Antibody-mediated immunity to measles virus protects organs and causes a wide range of disease, from mild, against reinfection. Measles also can cause transient but self-limited infections to severe systemic manifestations. profound immunosuppression, resulting in secondary A major initiative by several governments and international bacterial and viral infections, which are responsible for much bodies, including the World Health Organization (WHO), of measles-related morbidity and mortality. Delayed-type to increase vaccination for measles reduced the number of hypersensitivity responses are reduced following measles measles-related deaths by 84% from 2000 to 2016, however infection, indicating a reduction in lymphocyte responses. there were still almost 90,000 deaths worldwide. Because This may be associated with an inhibition of the ability of of poor nutrition and lack of access to medical care, children infected dendritic cells to stimulate lymphocytes. in lower-income countries are 10 to 1000 times more likely to die of measles than are children in higher-income coun- tries. Measles can produce severe disease in people with MORPHOLOGY defects in cellular immunity (e.g., people infected with HIV The blotchy, reddish brown rash of measles virus infection on or people with a hematologic malignancy). In higher-income the face, trunk, and proximal extremities is produced by dilated nations, epidemics of measles occur when the virus is skin vessels, edema, and a mononuclear perivascular infiltrate. introduced by individual(s) traveling from an area of endemic Ulcerated mucosal lesions in the oral cavity near the opening of disease, and then spreads, primarily to unvaccinated the Stensen ducts (the pathognomonic Koplik spots) are marked individuals. In recent years, such outbreaks have occurred by necrosis, neutrophilic exudate, and neovascularization. The several times each year in the United States. The diagnosis lymphoid organs typically have marked follicular hyperplasia, large may be made clinically, by serology, or by detection of viral germinal centers, and randomly distributed multinucleate giant RNA in respiratory secretions or urine. cells, called Warthin-Finkeldey cells, which have eosinophilic nuclear and cytoplasmic inclusion bodies (Fig. 8.7). These are pathogno- Pathogenesis monic of measles and are also found in the lung and sputum. The Measles virus is a single-stranded RNA virus of the Para- milder forms of measles pneumonia show the same peribronchial myxoviridae family, which includes mumps, respiratory and interstitial mononuclear cell infiltration that is seen in other syncytial virus, parainfluenza virus (a cause of croup), and nonlethal viral infections. human metapneumovirus. There is only one serotype of measles virus. Measles virus is very efficiently transmitted by the airborne route via aerosolized respiratory secretions. Mumps Three cell-surface receptors have been identified for measles Mumps is an acute systemic viral infection usually associ- hemagglutinin protein. Signaling lymphocytic activation ated with pain and swelling of the salivary glands. Like molecule family member 1 (SLAMF1) is expressed on measles virus, mumps virus is a member of the Paramyxo- activated lymphocytes, dendritic cells, and monocytes, and viridae family. Mumps virus has two types of surface it serves as the initial receptor for viral infection. Nectin-4 glycoproteins, one with hemagglutinin and neuraminidase is found on the basal surface of epithelial cells and is thought activities and the other with cell fusion and cytolytic activi- to be important for replication of the virus within the ties. Mumps viruses enter the upper respiratory tract through respiratory tract, before spread of the virus in respiratory inhalation of or contact with respiratory droplets, spread secretions. CD46 was the first cell-surface receptor identified to draining lymph nodes where they replicate in lymphocytes for measles virus, but it has been found to be used only by culture-adapted virus (including the vaccine strain), and not wild-type virus. Measles can replicate in a variety of cell types, including epithelial cells and leukocytes. The virus initially multiplies within the respiratory tract and then spreads to local lymphoid tissues. Replication of the virus in lymphatic tissue is followed by viremia and dissemination to many tissues, including the conjunctiva, skin, respiratory tract, urinary tract, small blood vessels, lymphatic system, and CNS. Most children develop T cell–mediated immunity to measles virus that helps control the viral infection and produces the measles rash. Hence, the rash is less frequent in people with deficien- cies in cell-mediated immunity. In addition, in malnourished children with poor medical care, measles virus may cause croup, pneumonia, diarrhea and protein-losing enteropathy, keratitis leading to scarring and blindness, encephalitis, and hemorrhagic rashes. Subacute sclerosing panencephalitis Figure 8.7 Measles giant cells in the lung. Note the glassy eosinophilic (Chapter 28) and measles inclusion body encephalitis (in intranuclear inclusions.  Viral infections 351 (preferentially in activated T cells), and then spread through Poliovirus, like other enteroviruses, is transmitted by the the blood to the salivary and other glands. Mumps virus fecal-oral route. The virus infects human cells by binding infects salivary gland ductal epithelial cells, resulting in to CD155, a molecule expressed on a variety of cell types, desquamation of involved cells, edema, and inflammation including epithelial cells, lymphocytes, and neurons. The that leads to the classic salivary gland pain and swelling. virus is ingested and replicates in the mucosa of the pharynx Mumps virus also can spread to other sites, including the and gut, including tonsils and Peyer patches in the ileum. CNS, testis, ovary, and pancreas. Aseptic meningitis is the Poliovirus then spreads through lymphatics to lymph nodes most common extrasalivary gland complication of mumps, and eventually the blood, producing transient viremia and occurring in up to 15% of cases. In the United States, out- fever. Although most poliovirus infections are asymptomatic, breaks of mumps have occurred in populations with close in about 1 in 100 infected persons poliovirus invades the contact (e.g., university or high-school settings) in recent CNS and replicates in motor neurons of the spinal cord years, resulting in approximately 6000 cases per year. It is (spinal poliomyelitis) or brainstem (bulbar poliomyelitis). important to note that this is still more than 99% fewer cases Antiviral antibodies control the disease in most cases; it is than occurred annually in the United States before use of not known why they fail to contain the virus in some the mumps vaccine. The diagnosis is usually made clinically, individuals. Viral spread to the nervous system may be but serology or detection of viral RNA in saliva can be used through the blood or by retrograde transport of the virus for definitive diagnosis. along axons of motor neurons. Rare cases of poliomyelitis that occur after vaccination are caused by mutations in the attenuated viruses to revert to wild-type, virulent, forms. MORPHOLOGY The diagnosis can be made by viral culture or detection of Mumps parotitis is bilateral in 70% of cases. The affected glands viral RNA in throat secretions or, more often, stool, or by are enlarged, have a doughy consistency, and are moist, glistening, serology. The neurologic features and neuropathology of and reddish-brown on cross-section. On microscopic examination, poliovirus infection are described in Chapter 28. the gland interstitium is edematous and diffusely infiltrated by macrophages, lymphocytes, and plasma cells, which compress acini West Nile Virus Infections and ducts. Neutrophils and necrotic debris may fill the duct lumen West Nile Virus causes an acute systemic infection that has and cause focal damage to the lining epithelium. two very different presentations: a mild, self-limited infec- In mumps orchitis, testicular swelling may be marked, caused tion or neuroinvasive disease associated with long-term by edema, mononuclear cell infiltration, and focal hemorrhages. neurologic sequelae. West Nile virus is an arthropod-borne Because the testis is tightly contained within the tunica albuginea, virus (arbovirus) of the flavivirus group, which also includes parenchymal swelling may compromise the blood supply and cause viruses that cause dengue fever and yellow fever. West Nile areas of infarction. The testicular damage can lead to scarring, virus has a broad geographic distribution in the Old World, atrophy, and, if severe, sterility. including Africa, the Middle East, Europe, Southeast Asia, Infection and damage of acinar cells in the pancreas may release and Australia. It was first detected in the United States in digestive enzymes, causing parenchymal and fat necrosis and 1999 during an outbreak in New York City and has since neutrophil-rich inflammation. Mumps encephalitis is associated spread across the United States; in 2017, a least one case with perivenous demyelination and perivascular mononuclear was reported in 47 states. West Nile virus is transmitted by cuffing. mosquitoes to birds and to mammals. Infected birds develop prolonged viremia and are the major reservoir for the virus. Humans are incidental hosts. Most affected patients acquire Poliomyelitis the infection from a mosquito bite; less commonly, human- Poliovirus causes an acute systemic viral infection, leading to-human transmission occurs by blood transfusion, organ to a wide range of manifestations, from mild, self-limited transplantation, breastfeeding, or transplacental spread. infections to paralysis of limb muscles and respiratory After inoculation by a mosquito, West Nile virus replicates muscles. Poliovirus is a spherical, unencapsulated RNA virus in skin dendritic cells, which then migrate to lymph nodes. of the enterovirus genus. Other enteroviruses cause childhood Here, the virus replicates further, enters the bloodstream, diarrhea as well as rashes (coxsackievirus A), conjunctivitis and, in some individuals, crosses the blood-brain barrier (enterovirus 70), viral meningitis (coxsackieviruses and and infects neurons in the CNS. echovirus), and myopericarditis (coxsackievirus B). There West Nile virus infection is usually asymptomatic, but are three serotypes of poliovirus, but it is likely that most in 20% of infected individuals it gives rise to a fever, infections are caused by type 1. The inactivated (injected) headache, myalgia, fatigue, anorexia, and nausea. A macu- poliovirus vaccine protects against all three serotypes, and lopapular rash is seen in approximately one-half of cases. the attenuated (oral) poliovirus vaccine is available in various CNS complications (meningitis, encephalitis, meningoen- combinations of one, two, or all three serotypes, although only cephalitis) occur in about 1 in 150 clinically apparent formulations containing one or two serotypes are currently in infections. Meningoencephalitis has a mortality rate of about use. Use of these vaccines has nearly eradicated polio, because 10% and results in long-term cognitive and neurologic poliovirus infects only humans, shows limited genetic varia- impairment in many survivors. Immunosuppressed persons tion, and is effectively neutralized by antibodies generated and older adults appear to be at the greatest risk for severe by immunization. According to global polio surveillance disease. Rare complications include hepatitis, myocarditis, data, in 2017, a total of only 22 polio cases were reported; and pancreatitis. The diagnosis is usually made by serology, however, additional cases were reported in 2018 and 2019 but viral culture and polymerase chain reaction (PCR)-based caused by the natural infection an