Path Pages 332-357 Categories of Infectious Agents Prions – abnormal forms of host protein (prion protein or PrP); cause transmissible spongiform encephalopathies, including kuru (associated w/cannibalism), Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE or mad cow disease), and variant CJD (vCJD; transmitted to humans from BSEinfected cows) o PrP normally found in neurons; disease occurs when PrP undergoes conformational change that confers resistance to proteases o Protease-resistant PrP promotes conversion of normal protease-sensitive PrP to abnormal form o Accumulation of abnormal PrP leads to neuronal damage and distinctive spongiform pathologic changes in brain o Spontaneous or inherited mutations in PrP that make it resistant to proteases observed in sporadic and familial forms of CJD o CJD can be transmitted from person to person iatrogenically, by surgery, organ transplant, or blood transfusion Viruses – nucleic acid genome surrounded by protein coat (capsid) sometimes encased in lipid membrane o Best visualized w/electron microscope o Some viral particles aggregate in cells they infect and form characteristic inclusion bodies (i.e., CMV) CMV-infected cells enlarged and show cytoplasmic inclusions Herpesviruses form large nuclear inclusions surrounded by clear halo Smallpox and rabies viruses form characteristic cytoplasmic inclusions Bacteria – prokaryotes; most bound by cell wall (peptidoglycan linked by peptide bridges) o Gram+ bacteria retains crystal-violet stain o Bacteria colonizing skin include Staphylococcus epidermidis and Propionibacterium acnes (causes acne) o Streptococcus mutans contributes to dental plaque o Obligate intracellular bacteria include Chlamydia (replicate inside membrane-bound vacuoles in epithelial cells) and Rickettsia (replicate inside membrane-bound vacuoles in endothelial cells) Get most or all ATP from host cell Chlamydia trachomatis – most frequent infectious cause of female sterility (scarring and narrowing of fallopian tubes) and blindness (chronic inflammation of conjunctiva that eventually causes scarring and opacification of cornea) Rickettseiae injure endothelial cells in which they grow, causing hemorrhagic vasculitis May injury CNS and cause death (Rocky Mountain spotted fever (RMSF)and epidemic typhus); transmitted by arthropod vectors (lice = epidemic typhus, ticks = RMSF and ehrlichiosis, and mites = scrub typus) o Mycoplasma belong to related genus Ureaplasma – extracellular pathogens w/o cell wall Fungi – eukaryotes that possess thick chitin-containing cell walls and ergosterol-containing cell membranes o Grow as rounded yeast cells or as slender filamentous hyphae o Hyphae may be septate (cell walls separating individual cells) or aseptate o Thermal dimorphism – grow as hyphal forms at room temp and yeast at body temp o Produce sexual sores or more commonly asexual spores (conidia) produced in fruiting bodies arising along hyphal filament o Dermatophytes – fungal species confined to superficial layers of skin; referred to by “tinea” followed by area of body affected (tinea pedis = athlete’s foot) Protozoa – single-celled eukaryotes; replicate intracellularly w/in variety of cells or extracellularly in urogenital system, intestine, or blood o Trichomonas vaginalis – flagellated protozoal parasites; sexually transmitted o Most prevalent intestinal protozoans (Entamoeba histolytica and Giardia lamblia) have 2 forms Motile trophozoites attach to intestinal epithelial wall and may invade Immobile cysts resistant to stomach acids and infectious when ingested o Blood-borne protozoa transmitted by insect vectors (replicate there before being passed to new host) Helminths – parasitic worms; highly differentiated multicellular organisms; complex life cycles o Alternate between sexual reproduction in definitive host and asexual multiplication in intermediary host (vector); humans could harbor adult worms (Ascaris lumbricoides), immature stages (Toxocara canis), or asexual larval forms (Echinococcus species) o Once adult worm infects humans, they don’t multiply but produce eggs or larvae passed in feces o In some infections, disease caused by inflammatory responses to eggs or larvae not adult worms (schistosomiasis) Ectoparasites – insects or arachnids that attach to and live on or in skin o May produce disease directly by damaging human host or indirectly by serving as vectors o Some cause itching and excoriations o At site of bite, mouth parts found associated w/mixed infiltrate of lymphocytes, macrophages, and eosinophils Special Techniques for Diagnosing Infectious Agents Bacterial clumps usually stain blue w/H&E Organisms usually best visualized at advancing edge of lesion rather than at center, particularly if necrosis Acute infections diagnosed serologically by detecting IgM in serum; 4x increase in IgM between early and 4-6 weeks is diagnostic of infection Molecular diagnostics – nucleic acid-based tests; used to quantify RNA for treatment o Routine for diagnosis of gonorrhea, chlamydial infection, TB, and herpes encephalitis Agents of Bioterrorism CDC ranked bioweapons into 3 categories o Category A – highest risk and can be readily disseminated or transmitted from person to person; causes high mortality w/potential for major public health impact, might cause public panic, and might require special action for public health preparedness Smallpox – high transmissibility in any climate or season; case mortality rate 30%; lack of effective antiviral therapy; symptoms appear after 7-17 days Initially high fever, headache, and backache, followed by rash (first appears on mucosa of mouth and pharynx) Vaccination ended in 1972 and vaccination immunity has waned o Category B – moderately easy to disseminate, produce moderate morbidity but low mortality, and require specific diagnostic and disease surveillance; many food-borne or water-borne o Category C – emerging pathogens engineered for mass dissemination because of availability, ease of production, and dissemination; potential for high morbidity and mortality Transmission and Dissemination of Microbes In general, respiratory, GI, or GU tract infections that occur in healthy persons caused by relatively virulent microorganisms capable of damaging or penetrating intact epithelial barriers Most skin infections in healthy persons caused by less virulent organisms entering skin through damaged sites Dense keratinized outer layer of skin – natural barrier to infection; low pH (5.5) and presence of fatty acids inhibit growth of microorganisms other than normal flora o Dermatophytes can infect stratum corneum, hair, and nails; few microbes traverse unbroken skin Schistosoma larvae released from freshwater snails penetrate swimmers’ skin by releasing collagenase, elastase, and other enzymes that dissolve ECM Most GI pathogens transmitted by food or drink contaminated w/fecal material o Acid lethal for many GI pathogens (Shigella and Giardia cysts resistant to gastric acid) o Normal defenses in GI tract include: Layer of viscous mucus covering intestinal epithelium Lytic pancreatic enzymes and bile detergents Mucosal antimicrobial peptides (defensins) Normal flora Secreted IgA antibodies (made by plasma cells in MALT) o MALT – lymphoid aggregates covered by single layer of specialized epithelial cells (M cells) important for transport of antigens to MALT and for binding and uptake of numerous gut pathogens, including poliovirus, enteropathic E. coli, V. cholerae, Salmonella typhi, and Shigella flexneri o Host defenses weakened by low gastric acidity, antibiotics that alter normal bacterial flora, or when stalled peristalsis or mechanical obstruction Most enveloped viruses inactivated by bile and digestive enzymes; nonenveloped resistant o Enteropathogenic bacteria diseases In contaminated food, certain staph starins release enterotoxins (food poisoning) V. cholerae and toxigenic E. coli multiply inside mucous layer overlying gut epithelium and release exotoxins that cause gut epithelium to secrete large volumes of fluid (diarrhea) Shigella, Salmonella, and Campylobacter invade and damage intestinal mucosa and lamina propria, causing ulceration, inflammation, and hemorrhage (dysentery) Salmonella typhi passes from damaged mucosa through Peyer patches and mesenteric lymph nodes into bloodstream, resulting in systemic infection o Fungal infection mainly in immunocompromised o In gut, protozoa cysts convert to motile trophozoites and attach to sugars in intestinal epithelia through surface lectins Giardia lamblia attaches to epithelial brush border Cryptosporidia taken up by enterocytes, where they form gametes and spores E. histolytica causes contact-mediated cytolysis through channel-forming pore protein and ulcerates and invades colonic mucosa o Intestinal helminths only cause disease when present in large numbers or in ectopic sites (obstructing gut or invading and damaging bile ducts; deprive host of nutrients in large numbers Larvae of some pass through gut briefly on their way to another organ (Trichinella spiralis larvae cyst in muscle; Echinococcus larvae cyst in liver or lung) Inhaled particles travel directly to alveoli, where they are phagocytosed by alveolar macrophages or neutrophils recruited to lung by cytokines o Pathogens evade defenses by attaching to epithelial cells in lower respiratory tract and pharynx Flu virus possesses hemagglutinin proteins that project from surface of virus and bind sialic acid on surface of epithelial cells; attachment induces host cell to engulf virus, leading to viral entry and replication in host cell Sialic acid interferes w/shedding of newly synthesized viruses from host cell; neuraminidase (cell surface protein) cleaves sialic acid and allows virus to release from host cell; neuraminidase lowers viscosity of mucus and facilitates viral transit in respiratory tract Some anti-flu drugs: sialic acid analogues that inhibit neuraminidase and prevent viral release from host cells o Certain bacterial pathogens impair ciliary activity Haemophilus influenzae and Bordetella pertussis elaborate toxins that paralyze mucosal cilia P. aeruginosa (cause of severe respiratory infection in those w/cystic fibrosis) and M. pneumoniae produce ciliostatic substances Strep pneumoniae and Staph species lack specific adherence factors and gain access after viral infection causes loss of ciliated epithelium (superinfection) o M. tuberculosis gains foothold in normal alveoli because it is able to escape killing w/in phagolysosomes of macrophages Urinary tract almost always invaded from exterior via urethra; successful pathogens adhere to epithelium From puberty to menopause, vagina protected from pathogens by low pH resulting from catabolism of glycogen in normal epithelium by lactobacilli o STDs attach to vaginal or cervical mucosa or enter via local breaks in mucosa during intercourse Microbial spread initially follows tissue planes of least resistance and sites drained by regional lymphatics o Spread to lymph nodes can lead to bacteremia and colonization of distant organs Secondary foci – infectious foci seeded by blood Rubella infection during first trimester can cause congenital heart disease, mental retardation, cataracts, or deafness in infant; little damaged caused during third trimester Transmission of treponemes leads to congenital syphilis only when T. pallidum infects mother late in second trimester but then causes severe fetal osteochondritis and periostitis that leads to bony lesions Microbes that cause STIs can spread from pregnant woman to fetus and cause severe damage to child o Perinatally acquired C. trachomatis causes conjunctivitis o Neonatal HSV infection much more likely to cause visceral and CNS disease than infection acquired later in life o Syphilis frequently causes miscarriage o HIV infection may be fatal to children infected prenatally or perinatally How Microorganisms Cause Disease Infectious agents establish infection and damage tissues by o Contacting and entering host cells, directly causing cell death o Releasing toxins that kill cells at a distance, releasing enzymes that degrade tissue components, or damaging blood vessels and causing ischemic necrosis o Inducing host immune responses that cause additional tissue damage Virus tropism determined by expression of host cell receptors for virus, presence of transcription factors that recognize viral enhancer and promoter sequences, anatomic barriers, and local temp, pH, and host defenses o Major determinant is presence of viral receptors on host cells HIV glycoprotein gp120 binds to CD4 on T cells and chemokine receptors (CXCR4, mainly on T cells, and CCR5 on macrophages) o JC virus (causes leukoencephalopathy) restricted to oligodendroglia in CNS because promoter and enhancer DNA sequences upstream from viral genes active in glial cells but not neurons or endothelia Direct cytopathic effects – preventing synthesis of host macromolecules by producing degradative enzymes and toxic proteins or inducing apoptosis o Poliovirus inactivates cap-binding protein essential for translation of host cell mRNAs but leaves translation of poliovirus mRNAs unaffected o HSV produces proteins that inhibit synthesis of cellular DNA and mRNA and other proteins that degrade host DNA o HIV vpr protein is pro-apoptotic o Viral replication can trigger apoptosis of host cells by cell-intrinsic mechanisms (perturbations of ER during virus assembly, which can activate caspases) Viral proteins on surface of host cells may be recognized by immune system; host lymphocytes may attack virusinfected cells; CTLs important for defense against viral infections but also can cause tissue injury Pathogenicity islands – groups/clusters of virulence genes in bacterial genome Quorum sensing – bacteria coordinately regulate gene expression within large population of bacteria; can induce expression of virulence factors as concentration in tissues increases o S. aureus coordinately regulates virulence factors by secreting autoinducer peptides; as bacteria grow to increasing concentrations, level of autoinducer peptide increases, stimuliating toxin production Some bacteria produce autoinducer peptide and others respond to it by secreting toxins Communities of bacteria can form biofilms in which organisms live in viscous layer of extracellular polysaccharides that adhere to host tissues or devices (IV catheters and artificial joints) o Biofilms increase virulence of bacteria by making them inaccessible to immune effector mechanisms and increasing resistance to antimicrobial drugs Adhesins – bacterial surface molecules that bind to host cells or ECM; bind bacteria to host cells; limited in structural type but have broad range of host cell specificity o Strep pyogenes – Gram+ bacteria that adheres to host tissues by virtue of protein F and teichoic acid projecting from bacterial cell wall and binding to fibronectin on surface of host cells and ECM o Pili – stalks composed of conserved repeating subunits; variable amino acids on tips determine binding specificity of bacteria Strains of E. coli that cause UTIs express specific P pilus that binds gal(α1-4)gal moiety expressed on uroepithelial cells Some bacteria coated w/antibodies or complement C3b, resulting in phagocytosis of bacteria by macrophages o M. tuberculosis activates alternative complement pathway, resulting in C3b opsonization; once coated, bacteria binds CR3 complement receptor on macrophages and is endocytosed into cell o Gram- bacteria use system of needle-like structures projecting from bacterial surface: binds cells, forms pores in PM, and injects proteins that mediate rearrangement of cytoskeleton, allowing bacterial entry o Listeria monocytogenes manipulates cell cytoskeleton to spread directly from cell to cell; also produces pore-forming protein (listeriolysin O) and 2 phospholipases that degrade phagosome membrane, allowing bacteria to escape into cytoplasm LPS – composed of long-chain fatty acid anchor (lipid A) connected to core sugar chain; attached to core sugar is variable carb chain (O antigen), which is used diagnostically to serotype and differentiate bacterial strains o Activates immunity by induction of important cytokines and chemokines of immune system as well as increased expression of costimulatory molecules, which enhance T-lymphocyte activation o High levels of LPS play role in septic shock, DIC, and adult respiratory distress syndrome, mainly through induction of excessive levels of cytokines (TNF, IL-1, and IL-12 o LPS binds cell-surface receptor CD14 and complex binds TLR4 (pattern recognition receptor of innate immune system) and transmits signals that lead to cellular response Exotoxins – secreted proteins that cause cellular injury and disease o Enzymes – proteases, hyaluronidases, coagulases, fibrinolysins; S. aureus produces proteases that degrade proteins that hold keratinocytes together, causing epidermis to detach from deeper skin o Toxins that alter intracellular signaling or regulatory pathways; most have active (A) subunit w/enzymatic activity and binding (B) subunit that binds receptors on cell surface and delivers A subunit into cell cytoplasm Effect of toxins depends on binding specificity of B domain and cellular pathways affected by A A-B toxins made by Bacillus anthracis, V. cholerae, and some strains of E. coli o Neurotoxins produced by Clostridium botulinum and Clostridium tetani – inhibit release of neurotransmitters, resulting in paralysis A domains interact specifically w/proteins involved in secretion of neurotransmitters at synaptic junction; both tetanus and botulism can result in death from respiratory failure due to paralysis of chest and diaphragm muscles o Superantigens – bacterial toxins that stimulate large number of T lymphocytes by binding conserved portions of T-cell receptor, leading to massive T-lymphocyte proliferation and cytokine release High levels of cytokines lead to capillary leak and shock (TSS from S. aureus and S. pyogenes) Granulomatous inflammatory reaction to M. tuberculosis is delayed hypersensitivity response that sequesters bacilli and prevents spread but can also produce tissue damage and fibrosis Following infections w/S. pyogenes, antibodies produced against streptococcal M protein can cross-react w/cardiac proteins and damage heart (rheumatic heart disease) Immune Evasion by Microbes Microbes that grow in lumen of intestine or gallbladder (S. typhi) hide from cell-mediated immune defenses Larger parasites form cysts in host tissues that are covered by dense capsule and are inaccessible to immunity Low fidelity of viral RNA polymerases (HIV and flu) and reassortment of viral genomes (flu virus) create viral antigenic variation Cationic antimicrobial peptides (defensins, cathelicidins, and thrombocidins) provide initial defense against invading mcirobes; avoiding these enables pathogens to avoid killing by neutrophils and macrophages Carb capsule on many bacteria shields bacterial antigens and prevents phagocytosis of organisms by neutrophils Some bacterial pathogens (Salmonella) modify lipid moiety of LPS to reduce TLR activation Protein A molecules of S. aureus bind Fc portion of antibodies and thus inhibit phagocytosis Neisseria, Haemophilus, and Streptococcus all secrete proteases that degrade antibodies Some viruses produce soluble homologues of IFN-α/β or IFN-γ receptors that bind to and inhibit actions of secreted IFNs or produce proteins that inhibit intracellular JAK/STAT signaling downstream of IFN receptors o May inactivate or inhibit ds RNA-dependent protein kinase (PKR; key mediator of antiviral effects of IFN) Several DNA viruses (HSV, CMV, and EBV) bind to or alter localization of MHC class I proteins, impairing peptide presentation to CD8+ T cells o Downregulation of MHC class I molecules encourage NK cell targeting; herpesviruses express MHC class I homologues that act as effective inhibitors of NK cells by engaging killer inhibitory receptors o Can target MHC class II molecules for degradation, impairing antigen presentation to CD4+ T cells o Can infect WBCs and directly compromise function o HIV infects CD4+ T cells, macrophages, and DCs; EBV infects B lymphocytes Infections in Immunosuppressed Hosts Patients w/antibody deficiency (X-linked agammagloulinemia) contract severe bacterial infections and viruses o S. pneumoniae, H. influenzae, S. aureus, rotaviruses, and enteroviruses Patients w/T-cell defects especially susceptible to infections w/intracellular pathogens (viruses and parasites) Patients w/deficiencies in complement proteins particularly susceptible to infections by S. pneumoniae, H. influenzae, and N. meningitides Children w/deficiencies in neutrophil function lead to increased infections w/S. aureus, some Gram-, and fungi Diseases that impair production of WBCs (leukemia) makes patients vulnerable to opportunistic infections Patients receiving bone marrow transplants have profound defects in innate and adaptive immunity during long time it takes for donated bone marrow to engraft; become susceptible to infection w/almost any organism Lack of splenic function in those w/sickle cell disease makes them susceptible to infection w/encapsulated bacteria (S. pneumoniae) which are normally opsonized and phagocytosed by splenic macrophages Burns destroy skin, removing barrier, allowing infection w/P. aeruginosa Malnutrition may impair host defenses Spectrum of Inflammatory Responses to Infection Suppurative (purulent) inflammation – acute; increased vascular permeability and WBC infiltration (neutrophils) o Neutrophils attracted to site of infection by release of chemoattractants from pyogenic (pus-forming) bacteria that evoke release (mostly extracellular Gram+ cocci and Gram- rods) o Massing of neutrophils and liquefactive necrosis of tissue form pus Mononuclear inflammation – diffuse interstitial infiltrates; common feature of chronic inflammatory processes o Develop acutely if viruses, intracellular bacteria, spirochetes, helminths, or intracellular parasites o Presence of lymphocytes reflects cell-mediated immune responses against pathogen or infected cells o Granulomatous inflammation – form of mononuclear inflammation evoked by infectious agents that resist eradication and capable of stimulating strong T-cell mediated immunity Characterized by accumulation of activated macrophages (epithelioid cells) , which may fuse to form giant cells In some cases, central area of caseous necrosis Cytopathic-cytoproliferative reaction – usually produced by viruses; cell necrosis or cellular proliferation, usually w/sparse inflammatory cells o Some viruses replicate in cells and make viral aggregates visible as inclusion bodies or induce cells to fuse and form multinucleated cells (polykaryons) o Focal cell damage in skin may cause epithelial cells to become detached, forming blisters o Some viruses cause epithelial cells to proliferate (papules or warts) Tissue necrosis – Clostridium perfringens and other organsims secrete powerful toxins that cause rapid and severe necrosis (gangrenous necrosis) that tissue damage is dominant feature o Few inflammatory cells present; lesions resemble infarcts w/disruption or loss of basophilic nuclear staining and preservation of cellular outlines o E. histolytica causes colonic ulcers and liver abscesses characterized by extensive tissue destruction w/liquefactive necrosis (w/o inflammatory infiltrate) o Viruses can cause widespread severe necrosis of host cells associated w/inflammation (total destruction of temporal lobes of brain by herpesvirus or liver by HBV Chronic HBV infection may cause cirrhosis (dense fibrous septae surround nodules of regenerating hepatocytes) Viral Infections Measles (rubeola) virus – can produce severe disease in people w/defects in cellular immunity o ss RNA virus of paramyxovirus family (includes mumps, respiratory syncytial virus (LRI in infants), parainfluenza virus (croup), and human metapneumovirus) o Only one serotype of measles virus; 2 cell-surface receptors (CD46 (complement-regulatory protein that inactivates C3 convertases) and SLAM (T-cell activation)) CD46 expressed on all nucleated cells SLAM expressed on cells of immune system Both receptors bind viral hemagglutinin protein o Transmitted by respiratory droplets; initially multiplies in upper resp. epithelia then spreads to lymphoid o o o Replicates in epithelial cells, endothelial cells, monocytes, macrophages, DCs, and lymphocytes Replication of virus in lymphatic tissue followed by viremia and systemic dissemination May cause croup, pneumonia, diarrhea w/protein-losing enteropathy, keratitis w/scarring and blindness, encephalitis, and hemorrhagic rashes (black measles; malnourished children w/poor meds) o Most children develop T cell-mediated immunity to measles virus that controls viral infection and produces measles rash (hypersensitivity reaction to measles-infected cells in skin) Rash less frequent in immunodeficient (cell-mediated) but occurs in agammaglbulinemics o Antibody-mediated immunity to measles virus protects against reinfection o Measles can cause transient immunosuppression, resulting in secondary bacterial and viral infection o Subacute sclerosing panencephalitis and measles inclusion body encephalitis rare late complications o Blotchy reddish brown rash produced by dilated skin vessels, edema, and moderate nonspecific mononuclear perivascular infiltrate o Ulcerated mucosal lesions in oral cavity near opening of Stensen ducts (Koplik spots) marked by necrosis, neutrophilic exudate, and neovascularization o Lymphoid organs have marked follicular hyperplasia, large germinal centers, and randomly distributed multinucleate giant cells (Warthin-Finkeldey cells) which have eosinophilic nuclear and cytoplasmic inclusion bodies; also found in lungs and sputum Mumps virus – 2 types of surface glycoproteins: one w/hemagglutinin and neuraminidase activities; other w/cell fusion and cytolytic activities o Enter upper respiratory tract through inhalation of droplets, spread to draining lymph nodes where they replicate in lymphocytes (preferentially activated T cells), and spread through blood to salivary glands o Infects salivary ductal epithelial cells, resulting in desquamation of involved cells, edema, and inflammation that leads to classic salivary gland pain and swelling of mumps o Can spread to CNS, testis, ovary, and pancreas o Aseptic meningitis – most common extrasalivary gland complication o Mumps parotitis – glands enlarged, have doughy consistency, are moist, glistening, and reddish brown Gland interstitium edematous and diffusely infiltrated by macrophages, lymphocytes, and plasma cells, which compress acini and ducts Neutrophils and necrotic debris fill ductal lumen and cause focal damage to ductal epithelium o Mumps orchitis – edema, mononuclear cell infiltration, and focal hemorrhages Because testis tightly contained in tunica albuginea, parenchymal swelling compromises blood supply and cause areas of infarction Sterility caused by scars and atrophy of testis after resolution of viral infection o Pancreas – lesions destructive, causing parenchymal and fat necrosis and neutrophil-rich inflammation o Mumps encephalitis causes perivenous demyelination and perivascular mononuclear cuffing Polio virus – spherical unencapsulated RNA virus of enterovirus genus o 3 major strains, all in Salk formalin-fixed vaccine (killed) and Sabin oral, attenuated (live) vaccine o Infects people (not animals), only briefly shed, doesn’t undergo antigenic variation, and effectively prevented by immunization o Transmitted by fecal-oral route; first infects oropharynx, is secreted in saliva, and is swallowed o Multiplies in intestinal mucosa and lymph nodes, causing transient viremia and fever o Uses human CD155 to gain entry into cells (doesn’t bind to cells in other species) o In 1/100 patients, virus invades CNS and replicates in motor neurons of spinal cord (spinal poliomyelitis) or brain stem (bulbar poliomyelitis) Secondary to viremia or retrograde transport of virus along axons of motor neurons o Antiviral antibodies control disease in most cases West Nile virus – arthropod-borne virus (arbovirus) of flavivirus group (includes dengue fever and yellow fever) o Wild birds develop prolonged viremia (major reservoir for virus) o Can be transmitted by blood transfusion, transplanted organs, breast milk, and transplacentally o After inoculation by mosquito, virus replicates in skin DCs, which migrate to lymph nodes, where virus replicates further, enters bloodstream, and can cross BBB In CNS, virus infects neurons o Chemokines direct WBCs to CNS for viral clearance CCR5 essential host factor to resist neuroinvasive infection CCR5Δ32 allele (deletion in coding sequence that results in complete loss of function in homozygous individual) associated w/symptomatic and lethal West Nile virus Loss of CCR5 receptor is protective against HIV-1 infection (HIV uses this to infect hosts) o Infection usually asymptomatic; 20% get mild short-lived febrile illness w/headache and myalgia Maculopapular rash seen in half of cases o CNS complications not frequent (1/150); mortality of 10% in meningoencephalitis (long-term cognitive and neurologic impairment in many survivors) o Perivascular and leptomeningeal chronic inflammation, microglial nodules, and neuronophagia (predom. In temporal lobes and brain stem) observed in brains of those who died from West Nile virus o Rare complications include hepatitis, myocarditis, and pancreatitis Viral hemorrhagic fevers (VHFs) – systemic infections caused by enveloped RNA viruses in arenavirus, filovirus, bunyavirus, and flavivirus families o All depend on animal or insect host for survival and transmission o Some viruses (Ebola, Marburg, Lassa) can pass person to person o Potential biologic weapons because of infectious properties, morbidity, and mortality, and absence of therapy and vaccines o Hemorrhagic manifestations due to thrombocytopenia or severe platelet or endothelial dysfunction Typically increased vascular permeability May be necrosis and hemorrhage in many organs, particularly liver o Most disease manifestations related to activation of innate immune responses o Viral infection of macrophages and DCs leads to release of mediators that modify vascular function and have procoagulant activity Herpesvirus infections – chronic latent infections o α-group viruses – HSV-1, HSV-2, and VZV; infect epithelial cells and produce latent infection in neurons o β-group viruses – lymphotrophic; CMV, human herpesvirus-6 (causes exanthema subitum (roseola infantum, 6th disease; benign rash in infants), and human herpesvirus-7 (no known disease association)) Infect and produce latent infection in variety of cell types o γ-group viruses – EBV, KSHV/HHV-8 (cause of Kaposi sarcoma); produce latent infection mainly in lymphoid cells o herpesvirus simiae is Old World monkey virus that resembles HSV-1; can cause fatal neurologic disease in animal handlers, usually resulting from animal bite HSV-1 and HSV-2 differ serologically; genetically similar and cause similar set of primary and recurrent infections o Produce acute and latent infection; replicate in skin and mucous membranes at site of entrance, where they produce infectious virions and cause vesicular lesions of epidermis o Viruses spread to sensory neurons that innervate primary sites of replication o Viral nucleocapsids transported along axons to neuronal cell bodies, where establish latent infection During latency, viral DNA remains in nucleus of neuron; only LATs synthesized (no viral proteins) Some LATs miRNAs that confer resistance to apoptosis o Reactivation may occur repeatedly w/ or w/o symptoms; results in spread of virus from neurons to skin or mucous membranes Reactivation occurs in presence of host immunity because viruses avoid immune recognition Evade CTLs by inhibiting MHC class I recognition pathway Elude humoral immune defenses by producing receptors for Fc domain of Ig and inhibitors of complement o Corneal epithelial disease immune mediated; HSV-1 is major cause of corneal blindness o HSV-1 major cause of fatal sporadic encephalitis; when virus spreads to brain (temporal lobes and orbital gyri of frontal lobes) o Neonates and those w/compromised cellular immunity can suffer disseminated herpesvirus infections o Infected cells contain large pink to purple intranuclear inclusions (Cowdry type A) that consist of intact and disrupted virions w/stained host cell chromatin pushed to edges of nucleus Due to cell fusion, can produce inclusion-bearing multinucleated syncytia o Intraepithelial vesicles (blisters) formed by intracellular edema and ballooning degeneration of epidermal cells; frequently burst and crust over; some may result in superficial ulcerations o Gingivostomatitis – usually encountered in children; caused by HSV-1; vesicular eruption extending from tongue to retropharynx causing cervical lymphadenopathy Swollen erythematous HSV lesions of fingers or palm (herpetic whitlow) occur in infants and occasionally health care workers o Genital herpes more often caused by HSV-2 than HSV-1; vesicles that are rapidly converted into superficial ulcerations rimmed by inflammatory infiltrate Transmitted to neonates during passage through birth canal of infected mothers; more commonly fulminates w/generalized lymphadenopathy, splenomegaly, and necrotic foci throughout lungs, liver, adrenals, and CNS o Herpes epithelial keratitis – virus-induced cytolysis of superficial epithelium o Herpes stromal keratitis characterized by infiltrates of mononuclear cells around keratinocytes and endothelial cells, leading to neovascularization, scarring, opacification of cornea, and eventual blindness Immunological reaction to HSV infection o Disseminated skin and visceral herpes infections usually in hospitalized patients w/some form of underlying cancer or immunosuppression Kaposi varicelliform eruption – generalized vesiculating involvement of skin Eczema herpeticum – confluend, pustular, or hemorrhagic blisters, often w/bacterial superinfection and viral dissemination to internal viscera Herpes esophagitis frequently complicated by superinfection w/bacteria or fungi Herpes bronchopneumonia – can be introduced by intubation of patient w/active oral lesions; often necrotizing Hepes hepatitis may cause liver failure Varicella-Zoster virus (VZV) – causes chickenpox and shingles (herpes zoster) o Infects mucous membranes, skin, and neurons; causes self-limited primary infection in immunocompentent individuals; establishes latent infection in sensory ganglia o Transmitted in epidemic fashion by aerosols, disseminates hematogenously, and causes widespread vesicular skin lesions o Infects neurons and/or satellite cells around neurons in DRG and recurs years after primary (shingles) o Shingles localized and painful in dermatomes innervated by (most often) trigeminal ganglia o Most people don’t have recurrence; usually recurs in immunocompetent (once) or immunosuppressed or elderly (multiple) o Diagnosed by viral culture or detection of viral antigens in cells scraped from superficial lesions o Chickenpox rash occurs 2 weeks after respiratory infection; lesions appear in multiple waves centrifugally from torso to head and extremities; each lesion progresses rapidly from macule to vesicle Lesions resemble dewdrop on rose petal Vesicles contain intranuclear inclusions in epithelial cells After a few days, most vesicles rupture, crust over, and heal by regeneration Bacterial superinfection of vesicles ruptured by trauma may lead to destruction of basal epidermal layer and residual scarring o Shingles occurs when latent virus in DRG reactivated and infects sensory nerves that carry it to one or more dermatomes Virus infects keratinocytes and causes vesicular lesions associated w/intense itching, burning, or sharp pain because of simultaneous radiculoneuritis Rarely geniculate nucleus involved, causing facial paralysis (Ramsay Hunt syndrome) Sensory ganglia contain dense, predominantly mononuclear infiltrate w/herpetic intranuclear inclusions in neurons and supporting cells Can cause interstitial pneumonia, encephalitis, transverse myelitis, and necrotizing visceral lesions, particularly in immunosuppressed people Cytomegalovirus – disease manifestations depend on age of host and immune status o Latently infects monocytes and bone marrow progenitors o o o o o o o o o o Can be reactivated when cellular immunity depressed; causes asymptomatic or mono-like infection in healthy individuals but devastating systemic infections in neonates and immunocompromised Gigantism of both cell and nucleus; in nucleus is large inclusion surrounded by clear halo (owl’s eye) Transmission occurs by Transplacental transmission from newly acquired or primary infection in mother w/o protective antibodies (congenital CMV) 95% of cases asymptomatic Cytomegalic inclusion disease from mother w/o protective antibodies; resembles erythroblastosis fetalis; suffer intrauterine growth retardation, be profoundly ill, and manifest jaundice, hepatosplenomegaly, anemia, bleeding due to thrombocytopenia, and encephalitis Fatal cases have microcephaly and foci of calcification Those who survive have mental retardation, hearing loss, and neurologic impairments May be interstitial pneumonitis, hepatitis, or hematologic disorder; most recover w/o problem (few develop mental retardation later) Neonatal transmission through cervical or vaginal secretions at birth or later through breast milk from mother w/active infection (perinatal CMV) Diagnosis made by shell-virus culture of urine or oral secretions Asymptomatic in majority of cases; uncommonly develop interstitial pneumonitis, failure to thrive, skin rash, or hepatitis Acquired maternal antibodies against CMV Many continue to excrete CMV in urine or saliva for months to years Subtle effects on hearing and intelligence later in life reported in some Transmission through saliva during preschool years from kid to kid or kid to parents Transmission by venereal route; dominant mode after age 15; may be via respiratory secretions and fecal-oral route Iatrogenic transmission through organ transplants or blood tranfusions Acute infection induces transient but severe immunosuppression Can infect DCs and impaire their maturation and ability to stimulate T cells Can elude immune responses by downmodulating MHC class I and II molecules and producing homologues of TNF receptor, IL-10, and MHC class I molecules Can both activate and evade NK cells by inducing ligands for activating receptors and class I-like proteins that engage inhibitory receptors Prominent intranuclear basophilic inclusions spanning half the nuclear diameter surrounded by clear halo; also smaller basophilic inclusions in cytoplasm In glandular organs, parenchymal epithelial cells affected; neurons affected in brain; alveolar macrophages and epithelial and endothelial cells affected in lungs; tubular epithelial and glomerular endothelial cells affected in kidneys Affected cells enlarged and show cellular and nuclear pleomorphism Disseminated CMV causes focal necrosis w/minimal inflammation in virtually any organ CMV mono – nearly always asymptomatic; most common clinical manifestation in immunocompetent hosts beyond neonatal period is mono-like illness (fever, atypical lymphocytosis, lymphadenopathy, and hepatomegaly accompanied by abnormal LFT results); diagnosis by serology Excretion of virus may occur in body fluids for months to years Once infected, a person is seropositive for life, whether they have virus active or not; virus latent in lymphocytes Most common opportunistic viral pathogen in AIDS Disseminated CMV infections primarily affect lungs (pneumonitis) and GI tract (colitis) In pulmonary infection, interstitial mononuclear infiltrate w/foci of necrosis develops, accompanied by typical enlarged cells w/inclusions Pneumonitis can progress to full-blown acute respiratory distress syndrome Intestinal necrosis and ulceration can develop, leading to formation of pseudomembranes and debilitating diarrhea HBV – member of hepadnavirus family; DNA virus transmitted percutaneously (IV drug use or transfusion), perinatally, or sexually o Infects hepatocytes; cellular injury occurs mainly from immune response to infected liver cells, not cytopathic effects of virus o Effectiveness of CTL response is determinant of whether person clears virus or becomes chronic carrier o When infected hepatocytes destroyed by CTLs, replicating virus eliminated and infection cleared o If rate of infection of hepatocytes outpaces ability of CTLs to eliminate infected cells, chronic infection established (happens in 5% of adults and up to 90% of children perinatally) Chronic hepatitis has lymphatic inflammation, apoptotic hepatocytes (CTL-mediated killing) and progressive destruction of liver parenchyma Long-term viral replication and recurrent immune-mediated liver injury can lead to cirrhosis of liver and increased risk for hepatocellular carcinoma o In some infected individuals, hepatocytes infected, but CTL response dormant, resulting in carrier state w/o progressive liver damage EBV – lymphoproliferative disorder associated w/development of lymphomas and nasopharyngeal carcinoma o Atypical activated T lymphocytes = mononucleosis cells o Some develop hepatitis, meningoencephalitis, and pneumonitis o Transmitted by close human contact, frequently saliva o Envelope glycoprotein binds to CD21 (CR2), the receptor for C3d component of complement (on B cells) o Infection begins in nasopharyngeal and oropharyngeal lymphoid tissues (tonsils) Gains access to submucosal lymphoid tissues by transient infection of epithelium or transcytosis into submucosa; infection of B cells may be B cells have productive infection w/lysis of infected cells and release of virions which may infect other B cells (minority) In most B cells, EBV establishes latent infection o People w/X-linked agammaglobulinemia (lack B cells) don’t become latently infected or shed virus) o During latent infection, small number of EBV genes expressed; involved in establishing latency EBNA1 – binds EBV genome to chromosomes, mediating episomal persistence and maintenance LMP1 binds to TNF receptor-associated factors and activates signaling pathways that mimic Bcell activation by CD40 (normal B-cell response) EBNA2 stimulates transcription of host cell genes, including genes that drive cell cycle entry Activated B cells disseminate in circulation and secrete antibodies (including anti-sheep RBC antibodies used for diagnosis of infectious mono) Heterophile antibodies bind to antigens that differ from antigens that induced them o Symptoms appear on initiation of host immune response; cellular immunity mediated by CTLs and NKs Atypical lymphocytes in blood mainly EBV-specific CD8+ CTLs, also include CD16+ NK cells Reactive proliferation of T cells centered in lymphoid tissues (lymphadenopathy and splenomegaly) o Early in course of infection, IgM antibodies formed against viral capsid antignes; later IgG antibodies formed that persist for life o Fully developed humoral and cellular responses to EBV act as brakes on viral shedding, resulting in elimination of B cells expressing full complement of EBV latency-associated genes EBV persists throughout life in small population of resting B cells in which expression of EBV genes limited to EBNA1 and LMP2 Cells in latent pool can reactivate expression of EBNA2 and LMP1, causing them to proliferate Cellular immunodeficient: proliferation can progress through EBV-associated B-cell lymphomas Can contribute to development of some cases of Burkitt lymphoma (chromosomal translocation involving c-myc oncogene is critical oncogenic event o Peripheral blood shows absolute lymphocytosis (more than 60% of WBCs lymphocytes) Atypical lymphocytes have abundant cytoplasm containing multiple clear vacuolations; an oval, indented, or folded nucleus; and scattered cytoplasmic azurophilic granules Most atypical lymphocytes are CD8+; sufficiently distinctive to strongly suggest Dx o Lymph nodes enlarged throughout body, principally posterior cervical, axillary, and groin o o o o o o o o Expansion of paracortical areas by activated T cells (immunoblasts) Occasionally, EBV-infected B cells resemble Reed-Sternberg cells (malignant cells in Hodgkin lymphoma) B-cell areas (follicles) may be hyperplastic (usually mild) Spleen enlarged; usually soft and flesh w/hyperemic cut surface Expansion of white pulp follicles and red pulp sinusoids due to presence of activated T cells Vulnerable to rupture because rapid increase in size produces tense fragile splenic capsule Liver involved to some degree, but hepatomegaly mild to moderate Atypical lymphocytes in portal areas and sinusoids; scattered isolated cells or foci of parenchymal necrosis Diagnosis depends on characteristic atypical lymphocytes in peripheral blood, positive heterophile antibody reaction (monospot), and specific antibodies for EBV antigens (viral capsid antigens, early antigens, or Epstein-Barr nuclear antigen) Most common complication is marked hepatic dysfunction w/jaundice, elevated hepatic enzyme levels, disturbed appetite, and rarely liver failure In those w/X-linked lymphoproliferation syndrome (Duncan disease; disorder caused by defect in SH2D1A gene primarily expressed in CTLs and NKs) SH2D1A also called SAP; participates in signaling pathway critical for effective cellular response to EBV-infected B cells Patients normal until acutely infected w/EBV; failure to control infection leads to chronic infectious mono, agammaglobulinemia, and B-cell lymphoma