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Infectious diseases

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Infectious diseases

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Infectious diseases

  1. 1. INTRODUCTION Infectious diseases • significantly contribute to the mortality in • Elderly. • Immunosuppressed. • Chronic disease states. • constitute six of the top 10 causes of mortality in developing countries abetted by malnutrition & unsanitary living conditions.
  2. 2. How Microorganisms Cause Disease • Humans harbor a complex ecosystem of microbial flora. • Attenuation of normal host defenses  “healthy” microbial flora to cause pathologic infections. • Non-commensal organisms with a wide range of virulence. • Highly infectious microbes produce disease in healthy individuals.
  3. 3. Routes of Entry of Microbes
  4. 4. Routes of Entry of Microbes Vertical transmission  Infection from mother to fetus or newborn child. • Placental-fetal transmission during pregnancy in which the effects on fetal development will depend on when during gestation the infection occurs (e.g rubella infection during 1st trimester ) • Transmission during birth (e.g., gonococcus & chlamydia). • Postnatal transmission in maternal milk (e.g., CMV, HIV, HBV).
  5. 5. Spread & Dissemination of Microbes Within the Body
  6. 6. Release From the Body & Transmission of Microbes • Person to person via respiratory, fecal-oral, sexual, or transplacental routes. • Animal-to-human transmission can occur through direct contact or ingestion (zoonotic infections) • Insect or arthropod vectors may passively spread infection or serve as required hosts for pathogen replication & development. • Survival during extended periods in dust, food, or water;
  7. 7. Host-Pathogen Interactions Host Defenses Against Infection • Innate & adaptive immune systems are critical to preventing or eradicating infection. • Stalemate between host & microbe results in a state of microbial latency without much pathology. • Subsequent diminution of host immunity can result in aggressive reactivation & disease (e.g. EBV, TB)
  8. 8. Host-Pathogen Interactions Immune Evasion by Microbes • Antigenic variation. • Resistance to antimicrobial peptides (defensins & cathelicidins) by inhibiting peptide binding or by producing proteases to degrade peptides. • Resistance to phagocyte killing by production of proteins that kill phagocytes, prevent their migration, or diminish their oxidative burst. • Evasion of apoptosis & manipulation of host cell metabolism which allows replication, enter latency, or even transform the cell.
  9. 9. Host-Pathogen Interactions Immune Evasion by Microbes • Resistance to cytokine-/chemokine-/complement- mediated host defense. • Evasion of recognition by CD4+ helper T cells & CD8+ cytotoxic T-cells. • Downregulation of T-cell responses by exploitation of immunoregulatory mechanisms. • ‘Lying low’ by establishing a state of latent infection in which few if any viral genes are expressed.
  10. 10. Host-Pathogen Interactions Injurious Effects of Host Immunity • Granulomatous responses can sequester pathogens but can cause secondary tissue damage & fibrosis with mycobacterium tuberculosis infection. • Liver damage following HBV infection is due to the immune destruction of infected hepatocytes. • Antibodies directed against bacterial antigens may cross-react with host molecules (e.g., rheumatic heart disease) or may form immune complexes that lodge in vascular beds (e.g., poststreptococcal glomerulonephritis). • Chronic inflammation & epithelial injury may lead to malignancy (e.g., Helicobacter pylori & gastric cancer).
  11. 11. Infections in People With Immunodeficiencies Genetic immunodeficiencies • Antibody deficiencies – X-linked agammaglobulinemia is associated with Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, rotavirus, & enterovirus infections. • Complement proteins: – Associated with infections due to encapsulated bacteria (e.g., S. pneumoniae for early complement components & Neisseria meningitidis for late [C5 to C9] elements). • Neutrophil function: – Infections from S. aureus, gram-negative bacteria, & fungi. • T-cell deficiencies: – Infections due to intracellular pathogens (e.g.viruses & some parasites); defects in TH1 generation increase the risk of infections by atypical mycobacteria, & defects in TH17 generation are associated with chronic mucocutaneous candidiasis.
  12. 12. Infections in People With Immunodeficiencies Acquired immunodeficiencies: HIV annihilation of T-helper cells is associated with a variety of infections • Most organisms that infect people with AIDS were common pathogens before the era of HIV-AIDS • Uncommon organisms were Kaposi sarcoma herpes virus [KSHV], cryptococcus, & Pneumocystis. • Malnutrition also broadly impairs immune defenses.
  13. 13. Infections in People With Immunodeficiencies Immunosuppression : • Use of immunosuppressive drugs in organ transplantation/bone marrow engraftment renders patients susceptible to virtually all organisms, including common environmental microbes. • Hematopoietic stem cell transplant recipients have profound defects in innate & adaptive immunity during the time that it takes for the donated stem cells to engraft, & become susceptible to infection with almost any organism. • Decline of immune responses can result in reactivation of latent infections (herpes, TB) & severe pathologic manifestations.
  14. 14. Infections in People With Immunodeficiencies Diseases of organs other than the immune system also render patients susceptible to specific organisms. • Lack of splenic function in sickle cell disease increases risk of infection by encapsulated bacteria (S. pneumoniae). • Patients with cystic fibrosis commonly get respiratory infections with Pseudomonas. • Burns destroy skin  exposure to microbes  infection with pathogens (P. aeruginosa).
  15. 15. Host Damage • Infectious disease results from the interaction of microbial virulence characteristics & host immune responses. • Infectious agents cause damage by the following: – Entering cells & directly causing cell death. – Releasing toxins that kill cells at a distance. – Releasing enzymes that degrade tissue components. – Damage blood vessels, causing ischemic necrosis. – Inducing host inflammatory cell responses that directly or indirectly injure tissues.
  16. 16. Mechanisms of Viral Injury • Viruses have tissue tropisms that will dictate which tissues will be injured. • Determinants of viral tropisms include : – Binding to specific cell surface proteins HIV binds to CD4 & the CXCR4 chemokine receptor on T cells. – Cell type-specific proteases may be necessary to enable binding Host protease activation of influenza virus hemagglutinin. – Cell type-specific transcription factors JC virus can proliferate only in oligodendroglia. – Physical barriers, local temperature, & pH Enteroviruses resist gut acid & enzymes.
  17. 17. Mechanisms of Viral Injury Once inside cells, viruses cause injury by : – Direct cytopathic effects • Inhibiting host DNA, RNA, or protein synthesis • Producing degradative enzymes or toxic proteins • Inducing apoptosis • Damaging the plasma membrane (HIV) • Lysing cells (rhinoviruses & influenza viruses) – Inducing an antiviral host immune response – Cytotoxic T cells or natural killer (NK) cells • Transformation of infected cells
  18. 18. Mechanisms of Bacterial Injury Bacterial Virulence • Virulence genes are frequently clustered together in the microbe genome as pathogenicity isl&s. • Plasmids & bacteriophages are mobile genetic elements that can encode & transfer virulence factors between different bacteria (e.g., toxins or antibiotic resistance). • Virulence factor expression may be coordinated by the secretion of peptides that turn on specific genes in the population, a process called quorum sensing. • Communities of bacteria—particularly in association with artificial surfaces (e.g., catheters & artificial joints)—can form ‘biofilms’.
  19. 19. Mechanisms of Bacterial Injury Bacterial Adherence to Host Cells • Bacterial adhesins are surface molecules that bind to specific host cells or matrix – Bacterial adhesins influence tissue tropisms. • Pili are filamentous bacterial surface proteins that can also mediate adhesion & can be targeted by immune responses – Pilus variation is a mechanism used by Neisseria gonorrhoeae to escape immune clearance.
  20. 20. Mechanisms of Bacterial Injury Virulence of Intracellular Bacteria • Intracellular bacteria can kill host cells by rapid replication & lysis (Shigella & Escherichia coli). • Intracellular bacteria may permit continued host cell viability while evading intracellular defenses & proliferating within endosomes (M. tuberculosis) or cytoplasm (Listeria monocytogenes).
  21. 21. Mechanisms of Bacterial Injury Bacterial Toxins Endotoxins (lipopolysaccharide [LPS]) • It is a cell wall component of gram-negative bacteria composed of a common long-chain fatty acid (lipid A) & a variable carbohydrate chain (O antigen). • Low doses of the lipid A component elicit protective inflammatory cell recruitment & cytokine production. • Higher doses of the lipid A component contribute to septic shock, disseminated intravascular coagulation, & adult respiratory distress syndrome.
  22. 22. Mechanisms of Bacterial Injury Bacterial Toxins Exotoxins damage host tissues by : • Enzymes destroy tissue integrity by digesting structural proteins. • Exotoxins alter intracellular signaling • Exotoxins have a binding (B) subunit that delivers a toxic active (A) component into the cell cytoplasm, where it modifies signaling pathways to cause cell dysfunction or death • e.g. seen in diptheria, anthrax, or cholera.
  23. 23. Mechanisms of Bacterial Injury Bacterial Toxins Neurotoxins that block neurotransmitter release, causing paralysis – e.g., in botulism & tetanus Superantigens stimulate large numbers of T cells by linking Tcell receptors with class II MHC molecules on antigenpresenting cells massive T-cell proliferation & cytokine release – e.g., toxic shock syndrome due to S. aureus.
  24. 24. Mechanisms of Bacterial Injury Bacterial Toxins Endotoxin (lipopolysaccharide [LPS]) • It is a cell wall component of gram-negative bacteria composed of a common long-chain fatty acid (lipid A) & a variable carbohydrate chain (O antigen). • Low doses of the lipid A component elicit protective inflammatory cell recruitment & cytokine production. • Higher doses of the lipid A component contribute to septic shock, disseminated intravascular coagulation, & adult respiratory distress syndrome.
  25. 25. Sexually Transmitted Infections • Groups at greater risk includes adolescents, homosexuals & IV drug users. • STIs in children, unless acquired during birth, suggest sexual abuse. • Transmission requires direct person-to-person contact because the pathogens do not survive in the environment. • Transmission often occurs from asymptomatic persons. • Infection with one STI-associated organism increases the risk for additional STIs. • STI in pregnancy can be spread to the fetus either in utero or at delivery, resulting in severe damage.
  26. 26. Sexually Transmitted Infections
  27. 27. Spectrum of Inflammatory Responses to Infection
  28. 28. Spectrum of Inflammatory Responses to Infection Suppurative (Purulent) Inflammation • usually caused by pyogenic bacteria, mostly extracellular gram-positive cocci & gram- negative rods. • Increased vascular permeability & neutrophil recruitment by bacterial chemoattractants. • • Lesions vary from tiny microabscesses to entire lung lobes. • may resolve without sequelae (pneumococcal pneumonia) or may scar (Klebsiella). Pneumococcal pneumonia with extensive neutrophilic infiltrate.
  29. 29. Spectrum of Inflammatory Responses to Infection • Patterns typical for viruses, intracellular bacteria, spirochetes, intracellular parasites & helminths. • The cell type that predominates depends on the host response to a particular pathogen: – plasma cells in chancres of primary syphilis – lymphocytes in viral infections of the brain – macrophages in Myobacterium avium- intracellulare infections of AIDS patients. • Granulomatous inflammation characterized by accumulation of activated macrophages, occurs with resistant organisms that evoke a strong T-cell response – M. tuberculosis Secondary syphilis in the dermis with perivascular lymphoplasmacytic infiltrate & endothelial proliferation. Mononuclear & Granulomatous Inflammation
  30. 30. Spectrum of Inflammatory Responses to Infection Cytopathic-Cytoproliferative Reaction • usually occurs in viral Infections. • there is cell proliferation & necrosis with sparse inflammation. • Other features include – inclusion bodies (herpes virus) – fused cells (measles viruses) – blisters (herpesviruses) – warty excrescences (papillomaviruses). A herpes virus blister showing glassy intranuclear viral inclusion bodies. Herpes virus blister in mucosa
  31. 31. Spectrum of Inflammatory Responses to Infection Tissue Necrosis • Caused by – rampant viral infections • Fulminant HBV infection – secreted bacterial toxins • Clostridium perfringens – direct protozoan cytolysis of host cells • Entamoeba histolytica • There is severe tissue necrosis in the absence of inflammation. C. perfringens-induced necrosis
  32. 32. Spectrum of Inflammatory Responses to Infection Chronic Inflammation & Scarring • Outcomes range from complete healing to scarring. • Excessive scarring can cause dysfunction. – the “pipestem” fibrosis of the liver or fibrosis of the bladder wall caused by schistosomal eggs • Inflammation can be severe despite a paucity of organisms. – M. tuberculosis Schistosoma haematobium infection of the bladder with numerous calcified eggs & extensive scarring
  33. 33. Special Techniques for Diagnosing Infectious Agents • Routine H&E stained sections. – CMV inclusion bodies, C&ida & Mucor, most protozoans, & all helminths • Special stains that take advantage of particular cell wall characteristics or coats – Gram, acid-fast, silver, mucicarmine, & Giemsa stains. • Cultures of fluids/lesional tissues may be performed to speciate organisms & to determine drug sensitivity. • Antibody titers to specific pathogens. – IgM antibodies suggest an acute infection, whereas IgG antibodies suggest something more remote. • Nucleic acid amplification tests (PCR, transcription-mediated amplification – Diagnosis of M. tuberculosis, Neisseria gonnorrhoeae, & Chlamydia trachomatis. – Quantification of HIV, HBV, & HCV to monitor response to treatment.
  34. 34. Viral Infections
  35. 35. Viral Infections - Acute (Transient) Infections Measles • RNA paramyxovirus transmitted by respiratory droplets. • Initial replication is within upper respiratory epithelial cells local lymphoid tissue  systemically. • Koplik spots - ulcerated oral mucosal lesions near Stensen ducts. • Warthin-Finkeldey cells - multinucleated giant cells with eosinophilic inclusion bodies • Marked lymphoid follicular & germinal center hyperplasia. • Infections - croup, pneumonia, diarrhea, keratitis & encephalitis. • Late Cx - Subacute sclerosing panencephalitis & inclusion body encephalitis Warthin-Finkeldey cells
  36. 36. Viral Infections - Acute (Transient) Infections Mumps • Paramyxovirus spread by respiratory droplets. • Initial replication is lymph nodes draining the upper respiratory tracthematogenous spread to salivary gl&s & other sites - testes, ovary, pancreas, & CNS. • Parotitis  Desquamation, edema, & inflammation in salivary gl& ductal epithelium swelling & pain. • Aseptic meningitis is the most common extrasalivary gl& complication. • Orchitis - swelling contained within the tunica albuginea  compromised vascular supply  infarction.
  37. 37. Viral Infections - Acute (Transient) Infections Poliovirus Infection • Spherical, unencapsulated RNA enterovirus transmitted by the fecal-oral route. • The virus infects via CD155, a surface molecule not present in other species. • Multiplication in intestinal mucosa & lymph nodes  transient viremia & fever; • Systemic viremia/retrograde transport via motor neurons  replication  CNS involvement  muscular paralysis/bulbar poliomyelitis. • Antiviral antibodies control the disease.
  38. 38. Viral Infections - Acute (Transient) Infections West Nile Virus • Arthropod-borne flavivirus (arbovirus)  Dengue & Yellow fever. • Transmitted by mosquitos, birds , blood transfusion, organ transplant, breast milk & transplacentally. • Initial replication occurs in skin dendritic cellslymph nodes for further expansion  subsequent hematogenous spread can lead to CNS neuronal infection. • CNS complications - meningitis, encephalitis, meningoencephalitis. • Immunosuppressed & elderly individuals are at greatest risk. • Rare complications - hepatitis, myocarditis, or pancreatitis.
  39. 39. Viral Infections - Acute (Transient) Infections Viral Hemorrhagic Fever (Ebola, Marburg & Lassa) • Systemic infection caused by enveloped RNA viruses from four different families (arenaviruses, filoviruses, bunyaviruses, & flaviviruses). • Manifestations range from mild, acute disease (fever, headache, rash, myalgia, neutropenia, & thrombocytopenia) to severe, life- threatening hemodynamic deterioration & shock. • Infect endothelial cells  2º hemorrhagic manifestations to endothelial/platelet dysfunction. • Macrophage & dendritic cell  profound cytokine release.
  40. 40. Viral Infections - Latent Infections (HHV) • Latency is defined as the persistence of viral genomes that do not produce infectious virus infarction. • Reactivation of the latent virus  dissemination +/-tissue injury. • Human herpes virus are large, encapsulated double-stranded DNA viruses. • 3 subgroups are defined by the most common infected cell & the site of latency :- – α-Group infects epithelium & produces latent infections of neurons • HSV-1, HSV-2 & VZV – β-Group infects lymphocytes & can be latent in a variety of cell types. • CMV, HHV-6 & HHV-7. – γ-Group causes latency in lymphoid cells • EBV & KSHV/HHV-8.
  41. 41. Viral Infections - Latent Infections (HHV) Herpes Simplex Viruses • replicates in skin & mucous membranes at the site of initial inoculation (usually oropharynx/genitals), causing vesicular lesions. • epithelial infection  sensory neurons  retrograde axonal transport to the sensory neuron ganglia (latent infection) • During reactivation, virus spreads from regional ganglia back to skin or mucous membranes. • Lesions range from self-limited cold sores & gingivostomatitis (HSV-1) to genital sores (HSV-2) to life threatening disseminated visceral infections (hepatitis & bronchopneumonitis) and encephalitis • Classic lesions include large, pink-purple, virion-containing intranuclear inclusions (Cowdry type A inclusions) and inclusion-bearing multinucleated syncytia.
  42. 42. Viral Infections - Latent Infections (HHV) Herpes Simplex Viruses • HSV-1 is also the major infectious cause of corneal blindness in the US. • Herpes epithelial keratitis reflects virus-induced cytolysis of the superficial corneal epithelium. • Herpes stromal keratitis results in – mononuclear cell infiltrates around keratinocytes and endothelial cells. – Subsequent neovascularization, scarring, and corneal opacification leads to blindness. Herpes epithelial keratitis Herpes stromal keratitis
  43. 43. Viral Infections - Latent Infections (HHV) Varicella-Zoster Virus • transmitted by aerosols, disseminates hematogenously & causes widespread vesicular skin lesions. • Acute VZV infection causes chickenpox & reactivation of latent VZV causes shingles/herpes zoster. • VZV infects mucous membranes, skin, and neurons, establishing a latent infection in sensory ganglia. • causes interstitial pneumonia, encephalitis, transverse myelitis, & necrotizing visceral lesions in immunocompromised hosts.
  44. 44. Viral Infections - Latent Infections (HHV) Varicella-Zoster Virus Shingles occurs when latent VZV in dorsal root ganglia reactivates, infecting sensory nerves that carry viruses to the skin & causing painful vesicular lesions, typically in a dermatomal distribution. Dorsal root ganglion with varicella-zoster virus infection showing ganglion cell necrosis & associated inflammation
  45. 45. Viral Infections - Latent Infections (HHV) Varicella-Zoster Virus • Skin lesions evolve rapidly from macules to vesicles, classically resembling “a dew drop on a rose petal.” • Histologically vesicles contain epithelial cell blisters and intranuclear inclusions. Skin lesion of chickenpox (varicella-zoster virus) with intraepithelial vesicle. 'dew drop on rose petal' appearance.
  46. 46. Viral Infections - Latent Infections (HHV) Cytomegalovirus • transmitted in breast milk, respiratory droplets, blood, and saliva and can have transplacental, venereal, feco-oral, transfusion, or organ transplantation. • mononucleosis-like syndrome (fever, atypical lymphocytosis, lymphadenopathy & hepatosplenomegaly). • cause life-threatening colitis/pneumonitis, hepatitis, chorioretinitis, and meningoencephalitis in AIDS/immunosuppressed patients. • Causes cytomegalic inclusion disease (CID) - intrauterine growth retardation, hemolytic anemia, jaundice, encephalitis, deafness & mental retardation.
  47. 47. Viral Infections - Latent Infections (HHV) Cytomegalovirus • CMV infection causes marked cellular enlargement, with characteristic large intranuclear inclusions surrounded by a clear halo, and smaller basophilic cytoplasmic inclusions. A large cell containing a large basophilic intranuclear “owl’s eye” and intracytoplasmic inclusion bodies.
  48. 48. Viral Infections - Chronic Productive Infections • In some infections the immune system cannot eliminate the virus, thus resulting in persistent viremia. • High mutation rates may be a mechanism to evade the immune system. • e.g. HIV, HBV
  49. 49. Viral Infections - Transforming Viral Infections Epstein-Barr Virus • Occur through close contact, including saliva, blood or venereal transmission. • Begins in nasopharyngeal and oropharyngeal epithelial cells  infection of B cells in underlying lymphoid tissues  virus binds to CD21 (the complement C3d receptor). • Has a productive lytic infection, releasing more virions. • Establishes a latent infection via genes that can induce B-cell proliferation as well as production of heterophile antibodies which can agglutinate sheep or horse erythrocytes.
  50. 50. Viral Infections - Transforming Viral Infections Epstein-Barr Virus • Causes infectious mononucleosis characterized by fever, fatigue, sore throat, lymphocytosis, generalized lymphadenopathy, & splenomegaly; hepatitis & rash. • Symptoms are secondary to the host immune response: – CD8+ cytotoxic T cells (the atypical lymphocytes seen in the – blood) recognize and lyse EBV-infected B cells. – Reactive proliferation of these T cells leads to lymphadenopathy and splenomegaly. • Persistence of EBV in a small population of latently infected cells can result in late reactivation and B-cell proliferation. • In immunocompromised individuals, EBV is associated with B-cell lymphoma & also contributes to some cases of Burkitt lymphoma.
  51. 51. Viral Infections - Transforming Viral Infections Atypical lymphocytes in infectious mononucleosis. Epstein-Barr Virus
  52. 52. Bacterial Infections - Gram-Positive Bacterial Infections Staphylococcal Infections • Organisms are pyogenic (pus-forming) cocci that grow in clusters and are distinctive for local destructiveness. • cause a variety of skin infections (boils, carbuncles, impetigo), osteomyelitis, pneumonia, endocarditis, food poisoning & toxic shock syndrome. • Less virulent ones cause opportunistic infections – Staphylococcus epidermidis in IV drug abusers, patients with catheters/prosthetic heart valves. – Staphylococcus saprophyticus causes UTI
  53. 53. Bacterial Infections - Gram-Positive Bacterial Infections Staphylococcal Infections Virulence factors include the following: – Surface proteins that allow host cell adherence. – Enzymes that degrade host proteins, promoting invasion and tissue destruction. – Toxins that damage host cell membranes (hemolysins) or induce skin sloughing (exfoliative toxins), vomiting (enterotoxins), or shock (superantigens). – Antibiotic resistance is a growing problem with S. aureus – infections. • methicillin-resistant S. aureus (MRSA) can now be a virulent community-acquired infection.
  54. 54. Bacterial Infections - Gram-Positive Bacterial Infections Streptococcal and Enterococcal Infections • Cocci that grow in pairs or chains. • Classified by their pattern of hemolysis on blood agar – β (complete or clear hemolysis) – α (partial or green hemolysis) – γ (no hemolysis, rarely pathogenic) • β-Hemolytic streptococci are grouped by their carbohydrate (Lancefield) antigens: – Group A (Streptococcus pyogenes) causes pharyngitis, scarlet fever, erysipelas, impetigo, rheumatic fever, toxic shock syndrome, necrotizing fasciitis, and glomerulonephritis. – Group B (Streptococcus agalactiae) colonizes the female genital tract and causes chorioamnionitis in pregnancy; neonatal sepsis and meningitis.
  55. 55. Bacterial Infections - Gram-Positive Bacterial Infections Streptococcal and Enterococcal Infections • α-Hemolytic streptococci include S. pneumoniae, a common cause of adult community-acquired pneumonia and meningitis. • Viridans-group includes both α- and γ-hemolytic streptococci that are normal oral flora but are common causes of endocarditis • Streptococcus mutans is the major cause of dental caries (metabolizes sucrose to lactic acid which demineralizes tooth enamel). • Enterococci cause endocarditis and urinary tract infections; many are antibiotic resistant. • Enterococci have an antiphagocytic capsule and produce enzymes that degrade host tissues. • Streptococcal infections are characterized by diffuse interstitial neutrophilic infiltrates with minimal host tissue destruction
  56. 56. Bacterial Infections - Gram-Positive Bacterial Infections Streptococcal and Enterococcal Infections Streptococcal virulence factors include the following: – Capsules that resist phagocytosis (S. pyogenes and S.pneumoniae). – M proteins that inhibit complement activation (S. pyogenes). – Exotoxins that cause fever and rash (S. pyogenes) in scarlet Fever. – Pneumolysin destroys host-cell membranes and damages tissue (S. pneumoniae).
  57. 57. Bacterial Infections - Gram-Positive Bacterial Infections Diphtheria • caused by Corynebacterium diptheriae, a slender gram-positive rod with clubbed ends; it is passed as an aerosol or through skin exudates. • life-threatening disease characterized by an oropharyngeal fibrinosuppurative exudate; C. diphtheriae growth in this membrane elaborates an exotoxin that injures heart, nerves, and other organs. • Toxin is a phage-encoded two-part (A-B) toxin that blocks host protein synthesis. – The B fragment binds to the cell surface and facilitates entry of the A subunit. – the A subunit blocks protein synthesis by adenosine diphosphate (ADP) ribosylation (and inactivation) of elongation factor-2.
  58. 58. Bacterial Infections - Gram-Positive Bacterial Infections Listeriosis • caused by L. monocytogenes - a gram-positive, facultative intracellular bacillus. • causes sepsis and meningitis in elderly & immunosuppressed people and placental infections in pregnant women with consequent neonatal infections. • express leucine-rich proteins called internalins that bind epithelial E-cadherin and promote internalization. • bacillus then uses listeriolysin O and two phospholipases to degrade the phagolysosome membrane and escape into the cytoplasm. • Resting macrophages internalize but do not kill Listeria; macrophages activated by interferon-γ effectively phagocytize and kill the bacterium.
  59. 59. Bacterial Infections - Gram-Positive Bacterial Infections Anthrax • Bacillus anthracis is a spore-forming, gram-positive bacillus prevalent in animals having contact with spore-contaminated soil. • Humans contract anthrax through exposure to contaminated animal products or powdered spores (a biologic weapon). • 3 major anthrax syndromes are known; in all cases, lesions are characterized by necrosis with neutrophil and macrophage exudates: – Cutaneous: Painless, pruritic papules that become edematous vesicles followed by a black eschar. – Inhalation: Rapidly leads to sepsis, shock, and frequently death . – GI: Contracted by eating contaminated meat; causes severe, bloody diarrhea and often death
  60. 60. Bacterial Infections - Gram-Positive Bacterial Infections Anthrax • Toxin is composed of a B subunit involved in toxin endocytosis and A subunits of two different types: – Edema factor converts adenosine triphosphate (ATP) to cAMP, which causes cellular water efflux. – Lethal factor is a protease that causes cell death Bacillus anthracis in the subcapsular sinus of a hilar lymph node of a patient who died of inhalational anthrax
  61. 61. Bacterial Infections - Gram-Positive Bacterial Infections Nocardia • aerobic, gram-positive bacteria growing in branched chains; they also stain with modified acid-fast protocols (Fite- Faraco stain) • are found in soil and cause opportunistic infections in immunocompromised hosts. • Nocardia asteroides causes indolent respiratory infections often with CNS dissemination; • Nocardia brasiliensis infects the skin. • Nocardia elicit suppurative responses, surrounded by granulation tissue and fibrosis.
  62. 62. Bacterial Infections - Gram-Negative Bacterial Infections Neisserial Infections • aerobic, gram-negative diplococci • they usually have stringent in vitro growth. • requirements (e.g., sheep blood-enriched [“chocolate”] agar). • N. meningitidis is an important cause of bacterial meningitis, particularly in children younger than age 2; there are 13 different serotypes. – Bacteria colonize the oropharynx (10% of the population is colonized at any one time) and are spread by respiratory droplets. – Meningitis occurs when people encounter serotypes to which they are not previously immune (e.g., in military barracks or college dormitories). • Neisseria gonorrhoeae is the second most common sexually transmitted bacterial infection in the US
  63. 63. Bacterial Infections - Gram-Positive Bacterial Infections Neisserial Infections • Neisseria gonorrhoeae is the second most common sexually transmitted bacterial infection in the US (after Chlamydia). – In males it causes symptomatic urethritis; in women it is often asymptomatic and can lead to pelvic inflammatory disease, infertility, and ectopic pregnancy. – Disseminated adult infections cause septic arthritis & hemorrhagic rash. – Neonatal infections cause blindness and, rarely, sepsis. • Virulence factors include a capsule that inhibits opsonization & antigenic variation to escape the immune response: – Adhesive pili undergo genetic recombination. – Outer membrane adhesive OPA proteins (so-called because they make colonies opaque) undergo 5-nucleotide frameshifts. – Host defects in complement lead to more severe infections.
  64. 64. Bacterial Infections - Gram-Positive Bacterial Infections Pertussis • caused by Bordetella pertussis, a gram-negative coccobacillus • it is a highly communicable illness characterized by paroxysms of violent coughing (whooping cough). • Coordinated expression of virulence factors is regulated by the Bordetella virulence gene (bvg) locus: – Hemagglutinin binds to respiratory epithelium carbohydrates and macrophage Mac-1 integrins. – Pertussis toxin ADP ribosylates and inactivates guanine nucleotide-binding proteins; G proteins cannot transduce signals, and bronchial epithelium cilia are paralyzed. • Infection causes laryngotracheobronchitis with mucosal erosion & mucopurulent exudates associated with striking peripheral lymphocytosis.
  65. 65. Bacterial Infections - Gram-Positive Bacterial Infections Pseudomonas Infection • caused by Pseudomonas aeruginosa, an opportunistic aerobic, gram-negative bacillus. • frequently seen in patients with cystic fibrosis, burns, or neutropenia and is a common hospital-acquired infection. • It also causes corneal keratitis in contact wearers and external otitis (swimmer’s ear) in normal hosts. • Pseudomonas pneumonia can cause extensive tissue necrosis by vascular invasion with subsequent thrombosis. • Skin infections give rise to well-demarcated necrotic and hemorrhagic skin lesions, ecthyma gangrenosum.
  66. 66. Bacterial Infections - Gram-Positive Bacterial Infections Pseudomonas Infection • Virulence factors include the following: – Pili and adherence proteins that bind to epithelial cells & lung mucin. – Endotoxin that cause gram-negative sepsis and disseminated – intravascular coagulation. – Exotoxin A that inhibits protein synthesis by the same mechanism as diphtheria toxin. – Phospholipase C that lyses red cells and degrades surfactant & an elastase that degrades IgG and extracellular matrix (ECM). – Iron-containing compounds that are toxic to endothelium. – In patients with cystic fibrosis the organism secretes an exopolysaccharide (alginate) that forms a slimy biofilm that protects bacteria from antibodies, complement, phagocytes & antibiotics.
  67. 67. Bacterial Infections - Gram-Positive Bacterial Infections Plague • Yersinia is a gram-negative, facultative intracellular bacterium with three clinically important species: – Yersinia pestis causes plague; it is transmitted from rodents to humans by aerosols or fleabites. – Yersinia enterocolitica and Yersinia pseudotuberculosis cause fecaloral transmitted ileitis and mesenteric lymphadenitis. • Yersinia proliferate in lymphoid tissues. • Causes massive lymph node enlargement (buboes), pneumonia, and sepsis, with massive bacterial proliferation, tissue necrosis, and neutrophilic infiltrates.
  68. 68. Bacterial Infections - Gram-Positive Bacterial Infections Plague Virulence factors include the following: • Yersinia toxins (called Yops) that are injected into host phagocytes by a syringe- like mechanism; the toxins block phagocytosis and cytokine production. • A biofilm that obstructs the flea GI tract, forcing it to regurgitate before feeding and thus ensuring infection.
  69. 69. Bacterial Infections - Gram-Positive Bacterial Infections Plague Virulence factors include the following: • Yersinia toxins (called Yops) that are injected into host phagocytes by a syringe- like mechanism; the toxins block phagocytosis and cytokine production. • A biofilm that obstructs the flea GI tract, forcing it to regurgitate before feeding and thus ensuring infection.
  70. 70. Bacterial Infections - Gram-Positive Bacterial Infections Chancroid and Granuloma Inguinale • Chancroid (soft chancre) is an acute, venereal, ulcerative genital infection caused by Haemophilus ducrey which is most common in Africa & Southeast Asia; the ulcerations probably serve as important cofactors in HIV transmission. • Granuloma inguinale is a sexually transmitted disease caused by Klebsiella granulomatis, a minute, encapsulated coccobacillus. • Infection begins as a papule on the genitalia or extragenital sites • (oral mucosa or pharynx) that ulcerates & granulates to form a • soft, painless mass, with prominent epithelial hyperplasia at the • borders. • • Left untreated, the lesion may scar and cause urethral, vulvar, or • anal strictures; it is also associated with lymphatic scarring and • lymphedema of the external genitalia.
  71. 71. Bacterial Infections - Gram-Positive Bacterial Infections Chancroid and Granuloma Inguinale • Chancroid (soft chancre) is an acute, venereal, ulcerative genital infection caused by Haemophilus ducrey which is most common in Africa & Southeast Asia; the ulcerations probably serve as important cofactors in HIV transmission. • Granuloma inguinale is a sexually transmitted disease caused by Klebsiella granulomatis, a minute, encapsulated coccobacillus. • Infection begins as a papule on the genitalia or extragenital sites (oral mucosa or pharynx) that ulcerates & granulates to form a soft, painless mass, with prominent epithelial hyperplasia at the borders. • Left untreated, the lesion may scar and cause urethral, vulvar, or anal strictures; it is also associated with lymphatic scarring and lymphedema of the external genitalia.
  72. 72. Bacterial Infections - Mycobacteria Tuberculosis • caused by M. tuberculosis & transmitted person to person as an aerosol and increasingly is multidrug resistant. • Infection represents only the presence of organisms and in most cases does not cause clinical disease. • Virulence is based on the properties of its cell wall. • Host recognition of tuberculosis organisms involves multiple innate pathogen-associated molecular patterns (lipoproetins & glycolipids) triggering Toll-like receptors (TLR)-2 and -9. • Outcomes of infection depend on host immunity.
  73. 73. Bacterial Infections - Mycobacteria Tuberculosis • Infection leads to the induction of a TH1-mediated delayed hypersensitivity response that activates macrophages. – Promote endocytosis and killing via nitric oxide (NO) and/or autophagy. – Promote cytocidal activity through tumor necrosis factor & defensin production. – Surround microbes with granulomatous inflammation. • Caseating granulomas are characteristic; central necrosis is surrounded by lymphocytes and activated macrophages. • T-cell immunity to mycobacteria can be detected by a tuberculin skin test which signifies only prior T-cell sensitization to mycobacterial antigens and does not discriminate infection and disease.
  74. 74. Bacterial Infections - Mycobacteria Tuberculosis • Granulomas formed in response to infection typically involve the lung apex and draining lymph node  Ghon complex. • Eventual control of the infection leaves behind only a small residua  a tiny fibrocalcific nodule at the site where viable organisms may remain within granulomas, dormant for decades. • 5% of primary infections are symptomatic, with lobar consolidation, hilar adenopathy & pleural effusions. – Rarely, hematogenous spread leads to tuberculous meningitis – & systemic miliary tuberculosis. – >50% of patients with severe immune deficiency will have extrapulmonary involvement.
  75. 75. Microscopy
  76. 76. Bacterial Infections - Mycobacteria Tuberculosis • Secondary tuberculosis occurs in a previously exposed host, classically involving the lung apices. • If immunity wanes, the infection can reactivate to produce communicable disease with substantial morbidity & mortality. • Classically, because of prior T-cell sensitization, there is more tissue damage with apical pulmonary cavitation & increased systemic manifestations with low-grade fever, night sweats & weight loss. • HIV is associated with an increased risk of tuberculosis, due to diminished T-cell immunity. • Diagnosis of tuberculosis can be made : – Identifying acid-fast bacilli in sputum or tissue – Culture from sputum or tissue (allows drug sensitivity testing) – Polymerase chain reaction (highly sensitive)
  77. 77. Cavitary Tuberculosis
  78. 78. Bacterial Infections - Mycobacteria Mycobacterium Avium Complex • These common environmental bacteria cause widely disseminated infections in immunocompromised hosts characterized by abundant acid-fast organisms within macrophages.
  79. 79. Bacterial Infections - Mycobacteria Leprosy • slowly progressive infection caused by Mycobacterium leprae affecting skin & peripheral nerves with resultant deformities. • Inhaled M. leprae are phagocytized by pulmonary macrophages & disseminated hematogenously; however, they replicate only in cooler tissues of the periphery. • Virulence is based on the properties of its cell wall. • 2 patterns of disease depending on the host immune response: – Tuberculoid leprosy – Lepromatous (anergic) leprosy
  80. 80. Bacterial Infections - Mycobacteria Leprosy • Tuberculoid leprosy – Associated with a TH1 response (IFN-γ), with extensive granulomatous inflammation with few bacilli. – Clinically there are insidious, dry, scaly skin lesions lacking sensation, with asymmetric peripheral nerve involvement. – Local anesthesia with skin and muscle atrophy increases the risk of trauma with chronic ulcers, and autoamputation of digits.
  81. 81. Bacterial Infections - Mycobacteria Leprosy • Lepromatous (anergic) leprosy – Associated with a relatively ineffective TH2 response, with large collections of lipid-laden macrophages overstuffed with bacilli. – Clinically there are disfiguring cutaneous thickening and nodules, with nervous system damage due to mycobacterial invasion into perineural macrophages and Schwann cells. – The testes are usually extensively involved leading to sterility.
  82. 82. Bacterial Infections - Spirochetes Syphilis • caused by Treponema pallidum, transmitted venereally or transplacentally (congenital syphilis). • A TH1 delayed-type hypersensitivity response with macrophage activation appears important in reining in the infection, but can also be the cause of disease manifestations. • Primary syphilis occurs about 3 weeks after contact: – A firm, nontender, raised, red lesion (chancre) forms on the penis, cervix, vaginal wall, or anus; this will heal even without therapy. – Treponemes are plentiful (visualizable with silver or immunofluorescent stains) at the chancre surface; there is an exudate composed of plasma cells, macrophages & lymphocytes, with a proliferative endarteritis. – Treponemes spread lymphohematogenously throughout the body even before the chancre appears.
  83. 83. • Chancre contains an intense infiltrate of plasma cells, with scattered macrophages and lymphocytes
  84. 84. Bacterial Infections - Spirochetes Syphilis • Secondary syphilis occurs 2 to 10 weeks later in 75% of untreated patients, due to spread and proliferation of spirochetes in skin (including palms and soles) and mucocutaneous tissues (especially mouth). – Superficial lesions with erosions are painless and contain infectious spirochetes. Mucocutaneous lesions show plasma cell infiltrates and obliterative endarteritis. – Lymphadenopathy, mild fever, malaise, and weight loss are common.
  85. 85. Bacterial Infections - Spirochetes Syphilis • Tertiary syphilis occurs in one third of untreated patients, after a long latent period (>5 years). – Cardiovascular syphilis (>80% of tertiary syphilis) results in aortitis (due to endarteritis of the aortic vasa vasorum) with aortic root and arch aneurysms and aortic valve insufficiency. – Neurosyphilis can be symptomatic (meningovascular disease, tabes dorsalis, or diffuse brain parenchymal disease, so-called general paresis) or asymptomatic (cerebrospinal fluid [CSF] abnormalities only, with pleocytosis, increased protein, and decreased glucose). – “Benign” tertiary syphilis is associated with necrotic, rubbery masses (gummas due to delayed-type hypersensitivity to the organisms), which form in various sites (bone, skin, oral mucosa).
  86. 86. • Gummas have centers of coagulated, necrotic material and margins composed of plump, palisading macrophages and fibroblasts surrounded by large numbers of mononuclear leukocytes, chiefly plasma cells. Trichrome stain of liver shows a gumma (scar), stained blue, caused by tertiary syphilis (the hepatic lesion is also known as hepar lobatum
  87. 87. Bacterial Infections - Spirochetes Syphilis • Congenital syphilis usually occurs when the mother has primary or secondary syphilis. – Intrauterine or perinatal death will occur in 50% of untreated cases. – Early (infantile) congenital syphilis includes nasal discharge, a bullous rash with skin sloughing, hepatomegaly, and skeletal abnormalities (nose and lower legs are most distinctive). Diffuse lung or liver fibrosis can also occur. – Late (tardive) manifestations include notched central incisors, deafness, and interstitial keratitis with blindness (Hutchinson triad).
  88. 88. Bacterial Infections - Spirochetes Syphilis • Congenital syphilis usually occurs when the mother has primary or secondary syphilis. – Intrauterine or perinatal death will occur in 50% of untreated cases. – Early (infantile) congenital syphilis includes nasal discharge, a bullous rash with skin sloughing, hepatomegaly, and skeletal abnormalities (nose and lower legs are most distinctive). Diffuse lung or liver fibrosis can also occur. – Late (tardive) manifestations include notched central incisors, deafness, and interstitial keratitis with blindness (Hutchinson triad).
  89. 89. Bacterial Infections - Spirochetes Syphilis Serologic tests • Treponemal antibody tests measure antibodies reactive with T.Pallidum. • Non-treponemal tests (venereal disease research laboratory [VDRL], rapid plasma reagin [RPR]) measure antibody to cardiolipin, a phospholipid in treponemes and normal tissues. • Both tests become positive approximately 6 weeks after infection but are only moderately sensitive (70% to 85%) for primary syphilis; they are >95% sensitive for secondary syphilis. – Nontreponemal test may become negative with time or treatment, but treponemal antibody tests remain positive and are very sensitive for tertiary and latent syphilis.
  90. 90. Bacterial Infections - Spirochetes Lyme Disease • Caused by Borrelia burgdorferi transmitted from rodents by Ixodes ticks. • B. burgdorferi evades antibody-mediated immunity through antigenic variation. • The bacterium does not make toxins; rather the pathology associated with infection is due to host immune responses. • A distinctive feature of Lyme arthritis is an arteritis resembling that is seen in lupus erythematosus.
  91. 91. Bacterial Infections - Spirochetes Lyme Disease 3 stages. • Stage 1 (weeks): Spirochetes multiply at the site of the tick bite, causing an expanding erythema, often with a pale center (erythema chronicum migrans), fever, and lymphadenopathy. • Stage 2 (weeks to months): Spirochetes spread hematogenously, causing secondary skin lesions, lymphadenopathy, migratory joint and muscle pain, cardiac arrhythmias, and meningitis. • Stage 3 (years): • Chronic and occasionally destructive arthritis; less commonly there is encephalitis and polyneuropathy.
  92. 92. Bacterial Infections - Anaerobic Bacteria • These organisms normally reside in niches with low oxygen tension – intestine, vagina, oral recesses • They cause disease when they disproportionately expand – Clostridium difficile colitis following antibiotic treatment or when introduced into sterile sites. • Environmental anaerobes also cause disease. – tetanus, botulism
  93. 93. Bacterial Infections - Abscesses Caused by Anaerobes • In head and neck abscesses, Prevotella and Porphyromonas are the usual anaerobes, whereas S. aureus and S. pyogenes are typical facultative aerobes. • In abdominal abscesses, Bacteroides fragilis, Peptostreptococcus & Clostridium species are the common anaerobes, typically admixed with facultative E. coli. • In genital tract abscesses in women, the anaerobes include Prevotella species, often mixed with facultative E. coli or S. agalactiae. • Anaerobic abscesses are typically foul smelling and poorly circumscribed but otherwise pathologically resemble other pyogenic infections.
  94. 94. Bacterial Infections - Clostridial Infections Gram-positive bacillus anaerobes that produce spores in the soil. • C. perfringens and Clostridium septicum cause cellulitis and muscle necrosis in wounds (gas gangrene), food poisoning, and small bowel infection in ischemic or neutropenic patients. – C. perfringens secretes 14 toxins, the most important being α-toxin which including phospholipase C that degrades erythrocyte, muscle, and platelet cell membranes & sphingomyelinase that causes nerve sheath damage. – C. perfringens enterotoxin lyses GI epithelial cells & disrupts tight junctions, causing diarrhea. – Gas gangrene exhibits marked edema and enzymatic necrosis of involved tissues; fermentation gas bubbles, hemolysis, & thrombosis with minimal inflammation are also characteristic.
  95. 95. Bacterial Infections - Clostridial Infections • Clostridium tetani in wounds (or the umbilical stump of newborns) releases a neurotoxin (tetanospasmin) that causes tetanus convulsive contractions of skeletal musclesby blocking release of γ-aminobutyric acid, a neurotransmitter that inhibits motor neuron activity. • Clostridium botulinum grows in canned foods & it releases a neurotoxin that causes flaccid paralysis of respiratory and skeletal muscles (botulism) by blocking acetylcholine release. – Botulism toxin (Botox) is used in cosmetic surgery for its ability to paralyze strategically selected facial muscles.
  96. 96. Bacterial Infections - Clostridial Infections • C. difficile overgrows other intestinal flora in antibiotic-treated patients and releases two glucosyl transferase toxins, causing pseudomembranous colitis. – Toxin A stimulates chemokine production to recruit leukocytes. – Toxin B (used for diagnosing C. difficile infections) causes cytopathic effects in cultured cells.
  97. 97. Bacterial Infections - Obligate Intracellular Bacteria Chlamydial Infections C. trachomatis exists in two forms: • A metabolically inactive but infectious sporelike elementary body (EB). The EB is internalized by receptor-mediated endocytosis. • Inside host cell endosomes the EB differentiates into the metabolically active reticulate body (RB); the RB replicates to form new EB for release.
  98. 98. Bacterial Infections - Obligate Intracellular Bacteria Chlamydial Infections Specific C. trachomatis diseases are caused by particular serotypes: • Trachoma, an ocular infection of children caused by serotypes A, B & C. • Urogenital infections and conjunctivitis caused by serotypes D to K.
  99. 99. Bacterial Infections - Obligate Intracellular Bacteria Chlamydial Infections Lymphogranuloma venereum • Serotypes L1, L2, and L3 is a sporadic genital infection in the United States and Western Europe. • It is endemic in parts of Asia, Africa, the Caribbean & South America. • 2-6weeks after infection, organism growth and host immune response in draining lymph nodes lead to painful adenopathy. • Lesions contain a mixed granulomatous and neutrophilic response with irregular foci of necrosis (stellate abscesses); • Chlamydial inclusions can be seen in epithelial or inflammatory cells.
  100. 100. Bacterial Infections - Obligate Intracellular Bacteria Chlamydial Infections Lymphogranuloma venereum • Serotypes L1, L2, and L3 is a sporadic genital infection in the United States and Western Europe. • It is endemic in parts of Asia, Africa, the Caribbean & South America. • 2-6weeks after infection, organism growth and host immune response in draining lymph nodes lead to painful adenopathy. • Lesions contain a mixed granulomatous and neutrophilic response with irregular foci of necrosis (stellate abscesses); • Chlamydial inclusions can be seen in epithelial or inflammatory cells.
  101. 101. Bacterial Infections - Obligate Intracellular Bacteria Rickettsial Infections • caused by gram-negative bacilli transmitted by arthropod vectors. • primarily infect endothelial cells, causing endothelial swelling, thrombosis, and vessel wall necrosis. • Vascular thrombosis and increased permeability cause hypovolemic shock, pulmonary edema, and CNS manifestations. • NK cell and cytotoxic T-cell responses are necessary to contain and eradicate infections.
  102. 102. Bacterial Infections - Obligate Intracellular Bacteria Rickettsial Infections • Epidemic typhus (Rickettsia prowazekiiis) transmitted by body lice. – Lesions range from a rash with small hemorrhages to skin necrosis and gangrene with internal organ hemorrhages. – CNS typhus nodules show microglial proliferations with T-cell & macrophage infiltration. • Rocky Mountain spotted fever (Rickettsia rickettsii) transmitted by dog ticks. – A hemorrhagic rash extends over the entire body, including the palms of the hands & soles of the feet. – Vascular lesions in the CNS may involve larger vessels & produce microinfarcts. – Non-cardiogenic pulmonary edema is the major cause of death.
  103. 103. Bacterial Infections - Obligate Intracellular Bacteria Rickettsial Infections • Ehrlichiosis is transmitted by ticks. • The bacteria predominantly infects neutrophils (Anaplasma phagocytophilum and Ehrlichia ewingii) or macrophages (Ehrlichia chaffeensis) with characteristic intracytoplasmic inclusions (morulae). • Infection is characterized by fever, headache, and malaise, progressing to respiratory insufficiency, renal failure & shock.
  104. 104. Fungal Infections • Superficial and cutaneous mycoses: – Common, limited to superficial keratinized layers of skin, hair, and nails. • Subcutaneous mycoses: – Involve skin, subcutaneous tissues, and lymphatics and rarely disseminate • Endemic mycoses: – Caused by dimorphic fungi, capable of causing serious systemic illness in healthy individuals • Opportunistic mycoses: – Can cause life-threatening infections in immunocompromised hosts or in patients with vascular catheters or prosthetic devices
  105. 105. Fungal Infections - Yeast Candidiasis • Candida species are part of the normal flora of the skin, mouth, and GI tract – they occur as yeast and pseudohyphal forms. • Candida causes superficial infections in healthy individuals; disseminated visceral infections in neutropenic patients occur when skin or mucosal barriers are breached. • Candida virulence factors include the following: – Adhesins that mediate binding to host cells. – Enzymes that contribute to invasiveness. – Catalases that aid intracellular survival by resisting phagocyte oxidative killing. – Adenosine that blocks neutrophil degranulation and oxygen radical production. – Ability to grow as biofilms on devices, thereby frustrating immune responses and antifungal agents.
  106. 106. Fungal Infections - Yeast Candidiasis • Innate and T-cell responses are important for protection: – Neutrophil and macrophage phagocytosis and oxidative killing are the first- line defense; these are induced as a TH17 response after Candida β-1,3- glucan engages Dectin-1 on dendritic cells and promotes interleukin (IL)-6 and IL-23 production. – Yeast forms induce a protective TH1 response; filamentous forms tend to induce a nonprotective TH2 response. • Superficial infections of the mouth and vagina are most common, producing superficial curdy white patches. • Chronic mucocutaneous candidiasis occurs in persons with AIDS, with defective T-cell immunity, or with polyendocrine deficiencies (hypoparathyroidism, hypoadrenalism, and hypothyroidism). • Severe, invasive candidiasis occurs via bloodborne dissemination in neutropenic persons; typically, microabscesses (with fungi in the center) are surrounded by areas of tissue necrosis.
  107. 107. Fungal Infections - Yeast Cryptococcosis • encapsulated yeast. – in tissues the capsule stains bright red with mucicarmine – in CSF it is negatively stained with India ink. • Virulence factors include the following: – A capsular polysaccharide (glucuronoxylomannan) inhibits phagocytosis, leukocyte migration, and inflammatory cell recruitment. – Regular alteration in the size and structure of the capsule polysaccharide allows immune evasion. – Laccase, an enzyme that induces formation of a melaninlike pigment with antioxidant properties. – Enzymes that degrade fibronectin and basement membrane proteins and aids in tissue invasion. Mucicarmine stain of cryptococci (staining red) in a Virchow- Robin perivascular space of the brain (soap-bubble lesion).
  108. 108. Bacterial Infections - Fungal Infections Cryptococcosis • In healthy individuals C. neoformans can form solitary pulmonary granulomata (with reactivation if immunity wanes) and rarely causes meningoencephalitis. • It presents as an opportunistic infection in patients with AIDS, leukemia or lymphoid malignancies, lupus, sarcoidosis, or organ transplants, or those receiving high-dose corticosteroids. – In such patients the major lesions involve the CNS, occurring as gray matter cysts (“soap bubble lesions”), occasionally with no inflammatory response.
  109. 109. Fungal Infections - Molds Aspergillosis • Ubiquitous mold transmitted by airborne conidia. • It grows as septated hyphae branching at acute angles occasionally with spore-producing fruiting bodies. • It causes allergy (allergic bronchopulmonary aspergillosis) in healthy individuals and severe sinusitis, pneumonia, and invasive disease in immunocompromised hosts. • Neutrophils and macrophages are the major host defenses, killing by phagocytosis and reactive oxygen species. • Macrophages recognize Aspergillus through TLR2 and Dectin-1. Neutropenia is a major risk factor. • Preexisting pulmonary lesions caused by tuberculosis, bronchiectasis, old infarcts, or abscesses can develop secondary Aspergillus colonization (aspergillomas) without tissue invasion.
  110. 110. Fungal Infections - Molds Aspergillosis • Virulence factors include the following: – Adhesion to albumin, surfactant, and a variety of ECM proteins. – Antioxidant defenses, including melanin pigment, mannitol, catalases & superoxide dismutase. – Phospholipases, proteases, and toxins, including aflatoxin (synthesized by fungus growing on peanuts), a cause of liver cancer in Africa. • Invasive aspergillosis in immunosuppressed hosts usually presents as necrotizing pneumonia (forming “target lesions”) but often develops widespread hematogenous dissemination. • Aspergillus tends to invade blood vessels with resulting thrombosis; consequently, areas of hemorrhage and infarction are superimposed on necrotizing inflammation.
  111. 111. Fungal Infections - Molds Zygomycosis (Mucormycosis) • opportunistic infection in neutropenic patients and diabetics. – Mucor, Absidia, Rhizopus, and Cunninghamella • Non-septated fungi with right-angle branching. • The primary site of infection (nasal sinuses, lungs, or GI tract) depends on whether the spores are inhaled or ingested. • Macrophages recognize Mucor via TLR2, yielding a proinflammatory cascade of IL-6 and tumor necrosis factor (TNF) • Neutrophils can kill hyphae after germination. • Increased free iron increases Mucor growth. • Diabetes increases the probability of infection by increasing the availability of free iron through ketoacidosis. • In diabetics, fungus may spread from nasal sinuses to the orbit or brain. • These fungi commonly invade arterial walls and cause necrosis.
  112. 112. Meningeal blood vessels with angioinvasive Mucor species. Note the irregular width and near right-angle branching of the hyphae.
  113. 113. Parasitic Infections
  114. 114. Parasitic Infections - Protozoa Malaria • Plasmodium falciparum causes severe malaria • Plasmodium vivax, ovale, and malariae species cause less severe disease. • From the mosquito salivary gland, sporozoites in the bloodstream invade via the hepatocyte receptor for thrombospondin and properdin. • Parasites multiply rapidly causing hepatocyte rupture & release of merozoites (asexual, haploid). • Merozoites bind to sialic acid residues on erythrocyt glycophorin and are internalized. • In erythrocytes, parasites hydrolyze red blood cell hemoglobin to generate characteristic hemozoin pigment and undergo development. • Trophozoites (single chromatin mass) divide to form schizonts (multiple chromatin masses) that form new merozoites. • Merozoites released by red cell lysis cause another round of erythrocyte infection. • A small fraction of the parasites within red blood cells develop into sexual forms (gametocytes) that infect mosquitoes when they feed.
  115. 115. Parasitic Infections - Protozoa Malaria • Infected erythrocytes to clump together or adhere to small vessel endothelium (via “knobs” on erythrocyte surfaces that bind to endothelial cells), causing vascular occlusion  ischemia  cerebral malaria. • Induce high levels of cytokines, such as TNF and interferon-γ that suppress red cell production, cause fever, and stimulate nitric oxide production by release of glycosylphosphatidylinositol (GPI)-linked proteins (including merozoite surface antigens) from infected erythrocytes. • Use antigenic variation to continuously modify surface proteins.
  116. 116. Parasitic Infections - Protozoa Malaria Resistance to Plasmodium occurs through the following: • Heritable erythrocyte traits (common in areas of the world where malaria is endemic): – Sickle cell trait (HbS), hemoglobin C (HbC), loss of globin genes (α- or β-thalassemia) and erythrocyte glucose-6-phosphatase deficiency all lessen malaria severity by reducing parasite proliferation and increasing erythrocyte clearance by macrophages. – Absence of Duffy blood group antigen prevents Plasmodium vivax binding to erythrocytes. • Antibody and T cell–mediated repertoires that develop after chronic infection.
  117. 117. Parasitic Infections - Protozoa Babesiosis • caused by malaria-like protozoans transmitted from white-footed mice to humans by Ixodes ticks. • Babesia cause fever and, through erythrocyte parasitization, hemolytic anemia. • • Babesia resemble malaria schizonts but lack hemozoin pigment, are more pleomorphic, and form characteristic tetrads. Erythrocytes with Babesia, including the distinctive Maltese cross form.
  118. 118. Parasitic Infections - Protozoa Leishmaniasis • Chronic inflammatory disease of skin, mucous membranes, and viscera caused by Leishmania species, obligate intracellular parasites transmitted by sandfly bites. • The life cycle involves two forms: – Promastigotes develop and live extracellularly in the sandfly vector. – Amastigotes multiply intracellularly in the macrophages of mammalian hosts. • When sandflies bite infected hosts, infected macrophages are ingested; amastigotes differentiate into promastigotes in the insect digestive tract and migrate to the salivary gland. • Subsequent bite of a second host delivers the promastigotes; these are phagocytized by macrophages and undergo transformation in phagolysosomes into amastigotes that then proliferate.
  119. 119. Parasitic Infections - Protozoa Leishmaniasis • Disease manifestations vary with the species and host responses. • A patient developing cutaneous disease or mucocutaneous disease, or visceral disease depends on which organism is in play. • Virulence factors include the following: – Lipophosphoglycan on promastigotes • activates complement  C3b deposition on the parasite surface and increasing phagocytosis • inhibits complement action (by preventing membrane attack complex assembly). – gp63 on promastigotes • binds fibronectin to promote promastigote adhesion to macrophages • cleaves complement and lysosomal antimicrobial enzymes to frustrate killing. – A proton pump in amastigotes reduces macrophage phagolysosome acidity.
  120. 120. Parasitic Infections - Protozoa Trypanosomiasis • caused by extracellular parasites transmitted by tse tse flies • disease of intermittent fevers,lymphadenopathy, progressive brain dysfunction (sleeping sickness), cachexia & death. • Lymph nodes and spleen enlarge as a result of hyperplasia & infiltration by lymphocytes, plasma cells, and parasite-laden macrophages. • When parasites breach the blood-brain barrier, they induce a leptomeningitis and a demyelinating panencephalitis.
  121. 121. Giemsa stain of a tissue macrophage with Leishmania donovani
  122. 122. Parasitic Infections - Metazoa Strongyloidiasis • Larvae from soil directly penetrate the skin of humans  to lungs trachea & are swallowed. • Adult female worms produce eggs asexually in the mucosa of the small intestine; passed larvae contaminate soil to complete the cycle. • Diarrhea & malabsorption in immunocompetent hosts. • larvae are present in the duodenal crypts with an underlying eosinophil-rich infiltrate. • Invade colonic mucosa & reinitiate infection in immunocompetent hosts. • Such uncontrolled autoinfection results in massive larval burdens with widespread invasion—occasionally complicated by sepsis caused by bacteria carried into the bloodstream by parasites.
  123. 123. Parasitic Infections - Metazoa Tapeworms (Cestodes): Cysticercosis • caused by larval development after the ingestion of eggs • Taenia solium causes cysticercosis. • transmitted to humans in two ways with distinct outcomes: – Larval cysts (cysticerci) ingested in pork attach to the intestinal wall where they mature and produce egg-laden proglottids (segments) that are passed in stool. – If intermediate hosts (pigs or humans) ingest eggs in feces contaminated food or water, hatching larvae penetrate the gut wall, and disseminate to encyst in many organs, including the brain (causing severe neurologic manifestations).
  124. 124. Parasitic Infections - Metazoa Tapeworms (Cestodes): Hydatid disease • caused by ingestion of Echinococcus granulosus eggs in food contaminated with dog or fox feces. • Eggs hatch in the duodenum and invade the liver, lungs, or bones, where they form cysts. • Humans are accidental hosts for E. granulosus and E.multilocularis; these are normally passed only between the definitive (dog or fox) and intermediate (sheep and rodents) hosts.
  125. 125. Parasitic Infections - Metazoa Schistosomiasis • Caused by – Schistosoma mansoni (Latin America, Africa, and the Middle East) – Schistosoma haematobium (Africa) – Schistosoma japonicum/Schistosoma mekongi (East Asia) • Larvae penetrate human skin, migrate through the vasculature & settle in the pelvic (S. haematobium) or portal (all others) venous systems. • Females produce eggs that may disseminate and are shed in urine or stool. • Eosinophil-rich granuloma formation & fibrosis. • Urinary schistosmiasis is associated with urinary bladder squamous cell carcinoma.
  126. 126. Parasitic Infections - Metazoa Lymphatic Filariasis • caused by two nematodes : – Wuchereria bancrofti (90% of cases) – Brugia malayi • Larvae are contracted from infected mosquitoes. • Larvae develop into adults in lymphatic channels; those mate & release microfilariae that enter the bloodstream and can then infect secondary mosquitoes. • Damage to lymphatics is mediated by TH1-mediated inflammation. • Recurrent lymphadenitis. • Chronic lymphadenitis with swelling of the dependent limb or scrotum (elephantiasis). • Tropical pulmonary eosinophilia.
  127. 127. Emerging Infectious Diseases
  128. 128. Agents of Bioterrorism • These pathogens pose the greatest danger due to efficient disease transmission, significant morbidity and mortality, relative ease of production and distribution, difficulty in defending against or the ability to provoke alarm and fear in the general public.
  129. 129. Agents of Bioterrorism • Category A agents pose the greatest risk; readily disseminated and/or transmitted from person to person, can cause high mortality, and are likely to be societally disruptive. – Smallpox • Category B agents are relatively easy to disseminate (often they are foodborne or waterborne) but have lower morbidity & mortality. – Brucella, Vibrio cholerae, and ricin toxins. • Category C agents include emerging pathogens that have the potential for being engineered for mass dissemination, with high morbidity and mortality. – Hantavirus and Nipah virus.

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