Daphne Ang, M'D'

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General Principles of Microbial Pathogenesis

• Daphne Ang, M.D.

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Categories of Infectious Agents

• Prions
• Viruses
• Bacteriophages, Plasmids, Transposons
• Bacteria
• Chlamydiae, Rickettsiae, Mycoplasmas
• Fungi
• Protozoa
• Helminths
• Ectoparasites

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Prions

• Abnormal forms of prion protein (PrP)
• PrP are normally found in neurons
• Abnormal PrP are protease-resistant PrP which
  undergoes conformational change
• Accumulation of abnormal PrP leads to neuronal
  damage spongiform pathologic changes in the
  brain
• Spongiform encephalopathies kuru,
  Creutzfeldt-Jakob disease (CJD), bovine
  spongiform encephalopathy (BSE)/madcow disease

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Viruses

• Obligate intracellular parasites, depend on host
  cells metabolic machinery for their replication
• 20-300nm in size consists of nucleic acid genome
  surrounded by a protein coat (capsid) sometimes
  encased in a lipid membrane
• Classified by their nucleic acid genome (DNA,
  RNA, both), presence of lipid envelope, preferred
  cell type for replication (tropism), type of
  pathology (characteristic inclusion bodies)

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Bacteriophages, Plasmids, Transposons

• Mobile genetic elements that infect bacteria and
  can indirectly cause human diseases by encoding
  bacterial virulence factors (eg. Adhesins,
  toxins, enzymes that confer antibiotic
  resistance)

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Bacteria

• Prokaryotes have a cell membrane but lack
  membrane-bound nuclei other membrane enclosed
  organelles
• Cell wall structures
• Gram (-) thin cell wall sandwiched between two
  phospholipid bilayer membranes
• Gram () thick cell wall surrounding the cell
  membrane that retains crystal-violet stain

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Bacteria

• Classified by Gram staining (positive or
  negative), shape (cocci, rods), form of
  respiration (aerobic, anaerobic)
• Some have flagella (for movement), pili (for
  attachment to host), synthesize their own DNA,
  RNA, protein
• Most are extracellular, but can be intracellular
• Normal people are colonized by bacteria
• Skin (1012) S. epidermidis, Propionibacterium
  acnes
• Mouth (1010) Streptococcus mutans
• Colon (1014) 99 anaerobic, Bacteroides sp.

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Bacteria
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Chlamydiae, Rickettsiae, Mycoplasmas

• Like bacteria but lack certain structures,
  metabolic capabilities
• Chlamydia Rickettsiae obligate intracellular
  organism that replicate in membrane-bound
  vacuoles in epithelial endothelial cells
• Mycoplasma lack cell wall

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Fungi

• Eukaryotes that possess thick chitin-containing
  cell walls, ergosterol-containing cell membranes.
  
• Hyphae (septate or aseptate), budding yeast cells
  
• Some exhibit thermal dimorphism (grow as hyphal
  forms at room temperature but as yeast forms at
  body temperature)
• May produce sexual or asexual spores (conidia)
• May cause superficial (dermatophyte) and deep
  infection
• Superficial skin infection Tinea pedis (athlete
  foot), tinea capitis (scalp ringworm)
• Subcutaneous tissue infection, abscesses,
  granulomas Sporotrichosis, tropical mycoses
• Deep fungal infection Candida, Coccidiodides,
  etc.

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Protozoa

• Single-celled eukaryotes
• Intracellular replication
• Plasmodium in RBC
• Leishmania in macrophages
• Extracellular replication
• Intestinal protozoans Entamoeba histolytica,
  Giardia lamblia
• Blood-borne protozoa Plasmodium, Trypanosoma,
  Leishmania
• Trichomonas vaginalis in vagina and male urethra
• Toxoplasma gondii, acquired from oocyst shedding
  kittens, undercooked meat

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Helminths

• Multicellular organisms, complex life cycle
  (sexual reproduction in definitive host, asexual
  multiplication in intermediary host/vector)
• Adult worm in humans do not replicate (except
  Strongyloides stercoralis), but generate eggs or
  larvae
• Consequences of lack of replication of adult
  worms
• Disease is caused by inflammatory responses to
  eggs or larvae
• Disease is in proportion to the number of
  organisms that have infected the individual

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Ectoparasites

• Insects (lice, bedbugs, fleas)
• Arachnids (mites, ticks, spiders)
• Produce disease by directly damaging host (cause
  itching, excoriations) or indirectly by serving
  as the vectors for transmission of infectious
  agents (e.g. deer ticks, Borrelia burgdorferi,
  transmits Lyme disease)

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Transmission and Dissemination of Microbes

• Host Barriers of Infection
• Spread and Dissemination of Microbes
• Release of Microbes from the Body
• Sexually Transmitted Infections

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Host Barriers to Infection

• Innate Immune response
• Exists before infection occurs
• Physical barriers to infection, phagocytic cells,
  NK cells, plasma proteins (complement proteins,
  cytokines, acute phase reactants)
• Adaptive Immune response
• Stimulated by exposure to microbes and increase
  in magnitude, speed effectiveness with
  successive exposures to microbes
• Mediated by T and B lymphocytes

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Host Barriers to Infection

• Skin
• Low pH and presence of fatty acids inhibit growth
  of microorganisms
• Most micoorganisms penetrate through breaks in
  the skin, bites, burns, foot sores, animal bites
• A few penetrates unbroken skin (dermatophytes,
  Schistosoma larvae)
• Gastrointestinal Tract
• Acidic gastric secretion
• Viscous mucous layer covering the gut
• Lytic pancreatic enzymes and bile detergents
• Mucosal anitimicrobial peptides (defensins)
• Normal flora
• Secreted IgA antibodies

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Host Barriers to Infection

• Gastrointestinal Tract (Mechanisms of
  pathogenecity)
• Enteropathogenic bacteria
• S. aureus release enterotoxins food poisioning
  symptoms
• V. cholerae, E. coli multiply in mucous layer
  of gut and release exotoxins watery diarrhea
• Shigella, Salmonella, Campylobacter - invade
  damage intestinal mucosa and lamina propria
  ulceration, inflammation, hemorrhage
• S. Typhi passes from damage mucosa to peyer
  patches to mesenteric lymph nodes into blood
  stream systemic infection
• Fungal infection
• Mainly in immunocompromised patients, eg Candida
• Intestinal protozoa
• Cysts (acid resistant) converts into trophozoites
  in the gut attach to sugars on the intestinal
  epithelia through surface lectins
• Giardia lamblia attaches to epithelial brush
  border
• Cryptosporidia are taken up by enterocytes form
  gametes and spores
• E. histolytica contact-mediated cytolysis
  ulcerates and invades mucosa
• Intestinal helminths
• Ascaris lumbricoides obstructs and damage bile
  ducts
• Hookworms cause Fe deficiency anemia by sucking
  blood from intestinal villi
• Diphyllobothrium latum depletes host of vit B12
• Larvae of helminth parasites passes gut on their
  way to another organ, eg. Trichinella spiralis
  (muscle), Echinococcus (live,r lung)

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Host Barriers to Infection

• Respiratory Tract
• Mucociliary blanket smokers, CF, intubation
• Phagocytosis by alveolar macrophages (lt5um)
  Mycobacterium tuberculosis
• Influenza virus
• Hemagglutinin binds to sialic acid on
  epithelial cells leading to viral entry and
  replication within host cell
• Neuraminidase cleaves sialic acid allows
  virus to release from host cell
• H. influenza, B. pertussis elaborate toxins
  that paralyze mucosal cilia
• S. pneumonia, S. aureus lacks adherence
  factors, gains entry after viral infection
• Urogenital Tract
• Infection via urethra, FgtM (shorter distance of
  urinary bladder and skin)
• Infection of the kidney is via retrograde
  transmission
• Vagina is normally protected from pathogens by
  low pH (catabolism of glycogen in the normal
  epithelium by lactobacilli) antibiotic treatment
  cause increase susceptibility to infection

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Spread and Dissemination of Microbes

• Placental-fetal route of transmission
• Congenital rubella syphilis infection

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Release of Microbes from the Body

• Depending on location of infection
• Skin shedding
• Coughing, sneezing
• Voiding of urine or feces
• Insect vectors
• Human-human transmission
• Repiratory route
• Fecal-oral route
• Sexual route
• Animals to human transmission
• Invertebrate vectors
• Vertebrates

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Sexually Transmitted Infections

• Initial site of infection urethra, vagina,
  cervix, rectum, oral pharynx
• Person-person spread, maybe infectious in the
  absence of symptoms
• To reduce spread report to public health
  authorities
• General features
• Infection of one STI increases the risk for
  additional STIs
• Coinfection of Chlamydia and gonorrhea
• The microbes that cause STIs can be spread from a
  pregnant woman to the fetus and cause severe
  damage to the fetus

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How Microorganisms Cause Disease?

• They can contact or enter host cells and directly
  cause cell death.
• They may release toxins that kill cells at a
  distance, release enzymes that degrade tissue
  components, or damage blood vessels and cause
  ischemic necrosis.
• They can induce host cellular responses that,
  although directed against the invader, cause
  additional tissue damage, usually by
  immune-mediated mechanisms.

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Mechanisms of Viral Injury

• Directly damage host cells by entering them and
  replicating at the hosts expense
• Tissue Tropism
• host cell receptors for the virus
• CXCR4 (on T cells), CCR5 (macrophages) HIV
  gp120
• transcription factors that recognize viral
  enhancer and promoter sequences
• JC virus restricted to oligodendroglia
  promoter/enhancer DNA sequences upstream from the
  viral genes are only active in glial cells
• anatomic barriers, local temperature, pH, and
  host defenses
• Enteroviruses replicate in intestine because they
  are resistant to acids, bile, digestive enzymes
• Rhinovirus replicate in URT because they survive
  in lower temperature

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Mechanisms of Viral Injury
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Mechanisms of Bacterial Injury

• Bacterial adherence to host cells
• Ability to invade cells and tissue (virulence)
• Ability to deliver toxins

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Mechanisms of Bacterial Injury

• Bacterial adherence to host cells
• Adhesins
• Bacterial surface molecules that bind bacteria to
  host cells
• Fibrillae (Gram() bacteria are composed of
• Lipoteichoic acids
• Hydrophobic, bind to fibronectin surface of
  buccal epithelial cells
• M protein
• Prevents phagocytosis by host macrophages
• Non-fibrillar adhesins (protein F)
• Binds to fibronectin, helps evade immune response
  by entering epithelial cells
• Fimbriae/pili
• Filamentous proteins on surface of G(-) bacteria
• Determines the binding specificity of bacteria
• E coli (P pilus) binds to gal moiety expressed on
  uroepithelial cells

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Mechanisms of Bacterial Injury

• Virulence of Intracellular Bacteria
• Intracellular growth allows the bacteria to
  escape certain immune response (antibodies),
  facilitates spread of the bacteria
• Entrance to host
• M.tb activates alternative complement pathway
  C3b (opsonization) which allows them to be
  endocytosed into the macrophages
• G(-) bacteria has projections that form pores in
  host cell and injects proteins that mediate
  cytoskeleton rearrangement facilitating bacterial
  entry
• Inside the Cell
• M.tb blocks fusion of lysosome with the phagosome
  
• L. monocytogenes produces a pore-forming protein
  (listeriolysin O) phospholipase to degrade
  phagosome membrane, allowing escape into the
  cytoplasm
• Shigella E. coli inhibit protein synthesis,
  rapidly replicates and lyse the host cell within
  6 hours

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Mechanisms of Bacterial Injury

• Bacterial Toxins
• Endotoxin LPS, large component of G(-) bacteria
  
• Long-chain fatty acid anchor (lipid A)
• Carbohydrate antigen (O antigen) used for
  serotyping
• Activates cytokine that enhance T-lymphocyte
  activation
• Also cause septic shock, DIC, ARDS through TNF,
  IL-1, IL-12
• Enterotoxin released protein that cause
  cellular injury
• Enzymes (proteases, hyaluronidases, coagulases,
  fibrinolysins)
• S. aureus proteases cleaves proteins that
  separates epidermal cells
• A-B toxins (V. cholerae, B. anthracis, E. coli)
• B toxin for binding
• A toxin for enzymatic effect
• Neurotoxins (C. botulinum and tetani)
• Inhibit release of neurotransmitter resulting in
  paralysis
• Superantigens (S. aureus, S. pyogenes)
• Binds to conserved portions of T-cell receptor
  that stimulates a large number of T lymphocytes
  increased cytokines capillary lead and shock

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Immune Evasion By Microbes

• (1) remaining inaccessible to the host immune
  system
• (2) varying or shedding antigens
• (3) resisting innate immune defenses
  (phagocytosis, complement system)
• Resistance to cationic antimicrobial peptides
  (defensins, cathelicidins, thrombocidins)
  important initial defense
• Carbohydrate capsule (H.influenza, S. pneumonia,
  N. meningitidis) prevents phagocytosis
• Replication within phagocytes (Mycobacteria,
  Listeria, Legionella, C. neoformans, Leishmania,
  Toxoplasma etc)
• (4) preventing T-cell activation or impairing
  effective T-cell antimicrobial response

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Spectrum of Inflammatory Responses to Infection

• Suppurative (Polymorphonuclear) Inflammation
• Characterized by leukocytic infiltrate,
  neutrophils
• mostly evoked by G() cocci G(-) rods
• Mononuclear and Granulomatous Inflammation
• Diffuse mononuclear infiltrate (lymphocytes,
  plasma cells)
• Common feature of chronic inflammatory processes
• Response to viruses, intracellular
  bacteria/parasites, spirochetes, helminths
• Granulomatous inflammation (M. tb, H. capsulatum,
  Schistosoma)
• Accumulation of activated macrophages
  (epithelioid cells) which may form giant cells
• Cytopathic-Cytoproliferative Inflammation
• Produced by viruses, characterized by cell
  necrosis or proliferation with sparse inflmmatory
  cells
• Inclusion bodies (viral aggregates within cells)
  e.g. CMV, herpes
• Necrotizing Inflammation
• C. perfringens
• Extensive tissue destruction and necrosis
  (gangrenous necrosis)
• Chronic Inflammation and Scarring
• Final common pathyway of many infection, may lead
  to healing or scarring

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Acute Inflammation
Granulomatous Inflammation
Viral Cytopathic change
Chronic Inflammation
Necrotizing Inflammation
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Viral Infection
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Measles (Rubeola)

• ssRNA virus Paramyxovirus
• Transmission respiratory droplet ? virus
  multiplies in respiratory epithelium ? lymphoid
  tissue, replicates in mononuclear cells ? spreads
  by blood throughout body
• Cough, coryza, conjunctivitis, photophobia
• Koplik spots (pathognomonic) ? maculopapular rash
  from the ears down ? Giant cell Warthin-Finkeldy
  cells (eosinophilic nuclear and cytoplasmic
  inclusion bodies)
• Rare complication subacute sclerosing
  panencephalitis (chronic CNS degeneration)
• Live vaccine (single strain)

Paramyxovirus Mumps, Measles, RSV, Parainfluenza
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Measles
Measles giant cells with glassy eosinophilic
intranuclear inclusion
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Mumps

• ssRNA virus, Paramyxovirus family
• Transmission respiratory droplets ? lymph,
  replicates in lymphocytes ? spread through blood
  to glands
• Parotitis
• Pancreatitis
• Orchitis in adult males (sterility caused by
  scars and atrophy of the testis after resolution
  of viral infection)
• Meningoencephalitis (perivenous demyelination and
  perivascular mononuclear cuffing)
• Live vaccine reduced the incidence of mumps by
  99 in USA

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Mumps
Parotitis
Orchitis
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Poliovirus

• Spherical unencapsulated RNA virus, Enterovirus
• Transmission fecal-oral route infects or
  pharynx ? secreted to saliva ? swallowed and
  multiplies in intestinal mucosa and l.n. ?
  usually asymptomatic few percentage with fever
  and poliomyelitis (viral damage of anterior motor
  neurons/flaccid paralysis of lower limbs)
• Three strains all of which is included in the
  vaccine
• Sabin (live/oral/best gut immunity)
• Salk (killed/injectable)

Enterovirus Coxsackievirus A, B Hepatitis A
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West Nile Virus

• Encapsulated ssRNA Flavivirus arthropod borne
  virus
• Africa, Middle East, Europe, SEA, Australia
• Asymptomatic, headache, myalgia, maculopapular
  rash (half of cases), acute flaccid paralysis
• Pathogenesis not clear
• Rare complication hepatitis, myocarditis,
  pancreatitis

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Viral Hemorrhagic Fevers

• Fever and hemorrhage, caused by enveloped
  viruses arenaviruses, filoviruses,
  bunyaviruses, flaviviruses
• Transmission (not well understood) insect
  bite/inhalation ? endothelial cell infection ?
  platelet and endothelial dysfunction ? hemorrhage
  and necrosis in multiple organs (liver necrosis,
  DIC)

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Herpes Simplex Virus 1 and 2
KSHV/HHV-8 Kaposi sarcoma
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Herpes Infection
Gingivostomatitis
Glassy intranuclear inclusion
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Cytomegalovirus

• CMV binds to EGRF not known if the virus uses
  this receptor to gain entry
• Produces enlargement of infected cells ? large
  intranuclear inclusion surrounded by a clear halo
  owls eye
• Dx morphologic alterations in tissue section,
  viral culture, rising antiviral antibody titer,
  detection of CMV antigens, qualitative or
  quantitation PCR based detection of CMV DNA

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Cytomegalovirus
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Varicella-Zoster Virus

• Asynchronous rash, chickenpox latent in dorsal
  root ganglia ? shingles, herpes zoster in adults
  (severe nerve pain)
• Associated with Reyes syndrome (Children with
  chickenpox treated with Aspirin)
• Transmission similar to HSV , latent in dorsal
  root ganglia, most frequent in trigeminal ganglia
  (recurs only once, in elderly and
  immunocompromised)

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HZV Infection
Inraepithelial vesicle ? Vesicular skin lesion
and Shingles in dermatome innervated by the
trigeminal ganglia ?
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Hepatitis B Virus

• Cause acute and chronic liver disease
• DNA virus (Hepadnavirus)
• Transmitted percutaneously (IV drug use, blood
  transfusion), perinatally or sexually
• Cellular injury occurs due to immune response to
  infected liver cells
• CTL response is a major determinant of whether a
  person clears the virus or becomes a chronic
  carrier
• Chronic hepatitis lymphocytic inflammation,
  apoptotic hepatocytes, cirrhosis, increased risk
  of hepatocellular CA

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Epstein-Barr Virus

• Selectively infects B cells by binding to CD21
  (CR2) present on B cells
• Infectious Mononucleosis, Kissing disease)
• Benign, self-limited lymphoproliferative disorder
• Fatigue, fever, sore throat, lymphadenopathy,
  splenomegaly
• Atypical reactive T lymphocytes (Downey Type II
  cells)
• Antigens produced EA, VCA, EBNA, MA
• Also causes Burkitt Lymphoma, nasopharyngeal
  cancer, thymus carcinoma

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Human Papillomavirus

• Nonenveloped DNA virus Papovavirus
• Transmission skin or genital contact ?
  perinuclear vacuolization of epithelial cells
  koilocytosis
• HPV E6 stimulates ubiquitination, degradation of
  p53 HPV E7 binds to Rb releasing E2F tf ?
  cellular transformation and malignancy
• HPV 6 11 anogenital and laryngeal papillomas
  (warts
• HPV 16 18 CIN/Cervical CA

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Some Medically Important Bacteria
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Staphylococcal Infection

• Gram () cocci in clusters
• S. aureus
• Transmission hand contact, sneezing, surgical
  wounds, foods (canned meats, custard pastries,
  potato salad)
• Pathogenesis exotoxins (Protein A, TSST-1,
  Enterotoxins A-E, Exfoliatins, Cytolysin)
• S. epidermidis
• Opportunistic infections in catheterized
  patients, patients with prosthetic heart valves,
  drug addicts
• S. saprophyticus
• Common cause of UTI in women

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Staphylococcal Infection
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Streptococcal Infection

• G() cocci in pairs

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Streptococcus - Erysipelas
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Diphtheria

• G() rods with clubbed ends, Corynebacterium
  diphtheriae
• Diphtheria toxin (A-B) inhibits protein
  synthesis by adding ADP-ribose to EF-2 tf
• Pseudomembrane formation in oropharynx ?
  obstruction
• Fatty myocardial change, polyneuritis
• Immunization doesnt prevent colonization but
  protects from the lethal effects of the toxin

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Listeriosis

• G() facultative intracellular bacterium,
  Listeria monocytogenes
• Transmission food borne, transplacental spread
• Diseases
• Listeriosis generally asymptomatic, in pregnant
  woman (fever, chills, septicemia, abortion,
  stillbirth)
• Neonates Sepsis, meningitis, granulomatosis
  infantiseptica (disseminated granulomas with
  central necrosis)
• Immunocompromised sepsis and meningitis

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Anthrax

• Spore forming, box-car shaped, G() rod, Bacillus
  anthracis
• Transmission inhalation of spores from animal
  hair and wool
• Anthrax toxin
• A subunit edema factor (EF), lethal factor (LF)
• B component mediates entry
• Diseases
• Cutaneous anthrax papule ? vesicle ? ruptures,
  central necrosis (eschar) with erythematous
  border, painful lymphadenopathy, fever
• Inhalational anthracis/Pneumonia cough, fever,
  facial edema, dyspnea, diaphoresis, cyanosis,
  shock with mediastinal hemorrhagic lymphadenitis
  (release of toxins in lymph nodes)
• Gastrointestinal (eating contaminated meat)
  abdominal pain, nv, severe bloody diarrhea

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Anthrax
Bacillus sp.
Cutaneous Anthrax
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Nocardia

• Aerobic G() rods in branched chains
• Transmission air borne, traumatic implantation
• Immunosuppressed and cancer patients are
  predisposed
• Diseases
• Cavitary bronchopulmonary nocardiosis
• Cough, fever, dyspnea
• May spread hematogenously to brain (abscess)
• Cutaneous/Subcutaneous nocardiosis
• Cellulitis and abscess

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Neisserial Infection

• G(-) diplococci
• Virulence factors (more impt in gonorrhea) Ag
  variation
• Pili adherence to mucosal surface
• Opacity proteins (OPA) - binding and promotes
  entry into cell
• N. meningitidis
• Transmission respiratory droplets, spread via
  meninges to bloodstream
• Meningitis
• N. gonorrhea
• Transmission sexual contact, birth
• Urethritis, Endocervicitis, PID, Arthritis,
  Proctitis,
• Infants Ophthalmia

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Whooping Cough

• G(-) cocobacillus, Bordetella pertussis
• Paroxysms of violent coughing followed by loud
  inspiratory whoop
• Pathogenesis respiratory droplet ? colonizes
  bronchial epithelium, invades macrophages ?
  releases hemmaglutinin adhesin and exotoxin ?
  paralyzes cilia
• Vaccine has effectively prevented this disease

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Pseudomonas Infection

• Opportunistic, aerobic, G(-) rod, Pseudomonas
  aeruginosa
• Transmission water aerosoles, respirators,
  humidifiers, sink drains, raw vegetables
• Diseases
• Necrotizing inflammation (whitish necrotic
  centers and red, hemorrhagic peripheral areas)
• Deadly pathogen of CF (bronchial obstruction by
  mucus plugging), burns (ecthyma gangrenosum),
  neutropenia, DIC
• Corneal keratitis in contact lenses wearers,
  external otitis (swimmers ear and in DM)

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Pseudomonas Infection
Necrotizing inflammation and Ecthyma gangrenosum
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Mycobacteria

• Acid fast rods with waxy cell wall
• Cell wall contains high concentration of lipids,
  long chain fatty acid called Mycolic acid
• Cell wall makes it resistant to dessication and
  many chemicals but is sensitive to UV

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Mycobacterium tuberculosis

• Transmission respiratory droplets
• Predisposing Factors poverty, HIV infection,
  immunosuppression
• Pathogenesis
• Sulfatides in cell envelope inhibits
  phagosome-lysosomal fusion allowing intracellular
  survival
• Cord factor inhibits leukocyte migration,
  disrupts mitochondrial respiration oxidative
  phophorylation
• Tuberculin and mycolic acid ? delayed
  hypersensitivity and cell mediated immunity
  (granulomas and caseation)
• Damage is done by immune system

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PTB
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PTB
Granuloma
Acid fast bacilli
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Clinical Features of PTB
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Secondary PTB
Ghon focus and complex
Miliary TB
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Mycobacterium Avium-Intracellulare Complex

• M. kansasii, M. scrofulaceum, M.
  avium-intracellulare
• Found in waters, soil, dust, domestic animals
• Non-contagious, problem in AIDS (CD4 count lt60
  cells/mm3)
• Hallmark widely disseminated in mononuclear
  systems, abundant AFB within macrophages ?
  lymphadenopathy, hepatosplenomegaly

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Mycobacterium leprae/Leprosy

• Acid fast obligate intracellular, M. leprae
• Transmission aerosols from lesions in the upper
  respiratory tract ? taken up by alveolar
  macrophages ? blood ? grow in cool tissue of skin
  and extremities
• 2 patterns of disease
• Tuberculoid leprosy dry scaly skin lesions that
  lack sensation, large asymmetric peripheral nerve
  involvement ? nerve degeneration causes skin
  ulceration, autoamputation, contractures,
  paralyses
• Lepromatous leprosy symmetric skin thickening
  and nodules

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Leprosy/Hansen Disease
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Syphilis

• spirochete, Treponema pallidum
• Transmission sexual contact, transplacental
• Chronic venereal disease, divided into three
  stages

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Syphilis
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Lyme Disease

• Gram (-), larger spirochete, Borrelia burgdorferi
• Transmission
• Ixodes (deer ticks, nymphs) mainly in Northeast
  (Connecticut), Midwest (Wisconsin), West Coast
  (California) ? organism invades skin ?
  bloodstream ? heart, joints, CNS
• Lyme Disease
• Initial Symptoms
• Erythema (chronicum) migrans annular skin
  lesion with erythematous edge and central
  clearing bulls eye
• Malaise HA, fatigue, fever, chills,
  musculoskeletal pain, lymphadenopathy
• 1-several weeks
• Neurologic HA, meningitis, Bells palsy
• Cardiac arrhythmias, myocarditis, pricarditis
• Months - years
• Arthralgias, arthritis

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Clostridial Infection

• Spore-forming G() bacilli, anaerobic
• C. perfringens secretes 14 toxins (? toxin
  destroys cell membrane
• Botulinum toxin cleaves synaptobrevin ? blocks
  release of Ach at NMJ ? flaccid paralysis
• Tetanus toxin blocks ?aminobutyric acid from
  motor neuron ? spastic paralysis
• C. difficile produces enterotoxin A stimulates
  chemokine production and cytotoxin B cytopathic
  effect

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Pseudomembranous Colitis
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Chlamydial Infection

• Obligate intracellular bacteria, Chlamydia
  trachomatis, exist in two forms elementary body
  (infectious) and reticulate body (active)
• Transmission sexual contact, at birth, hand-to
  eye contact
• Various disease are associated with different
  serotypes
• Serotypes D-K Urethritis, cervicitis, PID,
  Inclusion conjunctivitis, Pneumonia in infants
• Serotypes L1,2,3 Lymphogranuloma venereum
  (chronic ulcerative disease), swollen lymph nodes
  ? genital elephantiasis, fistulas
• Serotypes A,B,Ba, C Follicular conjunctivitis ?
  conjunctival scarring and inturned eyelashes ?
  corneal scarring and blindness

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Rickettsial Infection

• Obligate intracellular bacteria
• Pathogenesis infects endothelial cells (lungs
  and brain) leading to vascular leakage

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Fungal Infection/Mycoses

• Fungi are eukaryotes that grow by
• Budding (yeasts)
• Filamentous extension/hyphae (molds)
• Dimorphic (yeast at body temp mold form at room
  temp)

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Candidiasis

• Forms true hyphae, pseudohyphae, germ tube
• Oral thrush, esophagitis, gastritis, septicemia
  in IC, AIDS patients
• Endocarditis in IV drug users
• Cutaneous infection in obesity, infants
• Yeast vaginitis in diabetic women

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Cryptococcosis

• Encapsulated yeasts (C. neoformans) from soil
  enriched with pigeon droppings
• Causes opportunistic infection (meningitis) in
  AIDS, lymphoma/leukemia, SLE patients

83
Aspergillosis

• Monomorphic, septated, filamentous fungus with
  dichotomous branching (A. fumigatus)
• Diseases
• Fungus ball
• Allergic bronchopulmonary aspergillosis
• Invasive aspergillosis (severe neutropenia, CF,
  burns)

84
Zygomycosis (Mucormycosis)

• Nonseptated filamentous fungi, branches in 90
  angle
• Disease
• Rhinocerebral infection, paranasal swelling,
  hemorrhagic exudates from nose and eyes, mental
  lethargy
• Occurs in ketoacidotic diabetic patients and
  leukemic patients

85
Malaria

• Protozoa (unicellular eukaryotic organisms),
  intracellular parasite, Plasmodium sp.
• Trasmitted by female Anopheles mosquitoes
• P. ovale, vivax, malariae cause low parasitemia,
  mild anemia and rarely splenic rupture and
  nephrotic syndrome
• P. falciparum causes high levels of parasitemia,
  severe anemia, cerebral symptoms, renal failure,
  pulmonary edema, death
• Paroxysms of chills, fever spike, rigors when the
  infected RBC are lysed, releasing merozoites

86
Life Cycle of Malaria
87
Babesiosis

• Malaria-like protozoan, Babesia microti
• Transmitted by deer tick Ixodes (co-infection
  with Borrelia)
• Primarily a cattle disease disease is severe in
  splenectomized patients
• Fever, hemolytic anemia, shock
• PBS Maltese cross - diagnostic

88
Leishmaniasis
Chronic inflammatory disease of the skin , mucus
membranes, viscera Obligate intracellular
protozoan Leishmania, transmitted by sandfly
bite L. Donovani (visceral, lymphadenopathy,
hepatosplenomegaly, pancytopenia, fever, weight
loss, kala-azar hyperpigmentation of skin) L.
braziliensis (mucocutaneous ulcerating lesions
in larynx, nasal septum, anus, vulva) Cutaneous
(single ulcer)
89
Trypanosome infection

• In blood trypomastigotes with flagellum and
  undulating membrane
• In tissue amastigotes
• Fevers, lymphadenopathy, splenomegaly,
  progressive brain dysfunction (sleeping sickness)

90
Metazoan/Helminths

• Multicellular, eukaryotic organisms
• Transmission uncooked meat, direct invasion
  through skin/insect bites

91
Strongyloidiasis

• Stongyloides stercoralis (Threadworm)
• Filariform larva penetrates intact skin ?
  travels to lungs, trachea ? swallowed ? female
  worms reside in SI mucosa and produce eggs
  (asexual reproduction) ? passed out in stool
• Autoinfection leads to indefinite infections
  unless treated
• Early pneumonitis, abdominal pain, diarrhea
• Later malabsorption, ulcers, bloody stools
• Eosinophil-rich infiltrate in the lamina propria
  and mucosal edema, may be invasive

92
Lymphatic Filariasis

• Wuchereria bancrofti (filarial worm)
• Transmitted by mosquitoes ? develop within
  lymphatic channels into adult male and females
  mate ? release microfilariae into bloodstrem
• Diseases
• Asymptomatic
• Chronic lymphadenitis (elephantiasis) swelling of
  the dependent limbs and scrotum
• Elephantoid skin shows dilation of dermal
  lymphatics with widespread lymphocytic
  infiltrates and focal cholesterol deposits,
  thickened epidermis
• Adult worms are surrounded by intense
  eosinophilia with hemorrhage and fibrin
• Pulmonary eosinophilia (IgE mediated)

93
Onchocerciasis

• Onchocera volvulus
• Transmitted by black fly ? parasites mate in the
  dermis where they become surrounded by mixed
  infiltrate ? subcutaneous nodule (Onchocercoma)
• River blindness chronic pruritic dermatitis
  caused by large numbers of microfilariae in the
  skin and eye chambers

94
Trichinosis

• Trichinella spiralis
• Viable encysted larvae in meat ? develop into
  adults in the gut and mate ? release larvae which
  penetrates into the tissue
• Trichinosis larvae becomes intracellular
  parasites in skeletal muscle ? they modify muslce
  cell nurse cell loss of striations, gains a
  collagenous capsule
• Fever, myalgia, splinter hemorrhages, periorbital
  edema, eosinophilia

95
Schistosomiasis
Portal system
Passed through intestinal wall, shed in feces
96
Schistosomiasis
Schistosoma has separate male and female, have
operculated eggs which contaminate water,
perpetuating the life cycle and which are also
used to diagnose infections First intermediate
hosts are snails
97
Cestodes (Tapeworms)

• Consist of 3 basic portions the head/scolex,
  neck section which produces the proglottids
• Hermaphroditic, each proglottid developing both
  male and female reproductive organs, mature eggs
  developing in the most distal proglottids
• Adhere to the mucosa via the scolex
• Have no GIT, they absorb nutrients from the
  hosts GI tract
• Are diagnosed by finding eggs or proglottids in
  the feces
• Have complex life cycles involving
  extraintestinal larval forms in intermediate
  hosts

98
Cestodes
99
Cysticercosis/Hydatid cyst