Download - Viral & Bacterial Infections 2
VIRAL INFECTION
VIRAL INFECTIONS
•Measles / Mumps•Poliovirus / West Nile virus•Viral Hemoorrhagic fever
Transient Infection
•Hepatitis B virusChronic
Productive Infections
•Herpes Simplex•Cytomegalovirus•Varicella-Zoster
Chronic Latent Infection
•Epstein-Barr Virus•Human Papilloma virus
Transforming Infections
Transient Viremia
Measles- Rubeola virus
Measles virus is an RNA
virus of the paramyxovirus There is only one strain of
measles virus with Envelope
Measles virus is spread by respiratory droplets
Multiplies within upper respiratory epithelial cells
Spread to LN and multilply in lymphocytes and macrophages.
A transient viremia spreads the measles virus throughout the body
PATHOPHYSIOLOGY
Clinical Manifestation
Rashes – hypersensitivity reaction to viral antigens in skin
croup, pneumonia, diarrhea with protein-losing enteropathy,
keratitis with scarring and blindness
encephalitis, hemorrhages ("black measles")
Antibody-protects against reinfection T cell-mediated immunity controls the
viral infection skin rash ( hypersensitivity reaction to viral antigen )
Pathognomonic Koplik spots Ulcerated mucosal lesions in the oral cavity near the opening of Stensen ducts
LN Follicular Hyperplasia & multi- nucleate giant cells, called Warthin-Finkeldey cells, which have eosinophilic nuclear and cytoplasmic inclusion bodies.
Mumps Transient inflammation of the
parotid glands and, less often, of the testes, pancreas and central nervous system
Mumps viruses are spread by respiratory droplets
Multiply within upper respiratory epithelial cells, salivary glands, and T cells in lymph nodes.
A transient viremia
Spreads the mumps virus to other glands and the central nervous system through the choroid plexus.
Clinical Manifestation
Mumps parotitis, which is bilateral in 70% of cases
Mumps orchitis, swelling local hemorrhages Infarction Sterility due to scars and atrophy of the testis
Pancreas destructive lesion causing parenchymal and fat necrosis & pmns
Mumps encephalitis causes perivenous demyelinization and perivascular mononuclear cuffing.
Poliovirus Unencapsulated RNA virus of
Enterovirus Transmitted by fecal-oral route
3 major strains Infects people but not other animals Briefly shed Do not undergo antigenic variation
EFFECTIVELY PREVENTED BY IMMUNIZATION
Poliovirus
Infect Orophraynx Saliva
Swallowed Multiply intestinal mucosa & LN
Transient viremia & Fever
Most are Asymptomatic but 1:100 Invades the CNS
Special Consideration
1 : 100 infected invades the CNS Due to VIREMIA or RETROGRADE
TRANSPORT VIA AXONS TO MOTOR NEURONS
Motor Neurons of Spinal Cord SPINAL POLIOMYELITIS
Brain Stem BULBAR POLIOMYELITIS
CHRONIC LATENT INFECTIONS- Herpesvirus infections
Features:
Cause Acute Infection Followed by Latent Infection Viruses persist in a Non-Infectious Form
With Periodic Reactivation & Shedding of Infectious Virus
Latency defined Inability to recover Infectious particles
from cells that harbor the virus
Herpesvirus infections
•HSV-1 & 2, VZV•Infect Epithelial cells•Produce Latent Infxn in Neurons
Alpha group
•CMV, HERPES 6, Roseola infantum•Produce Latent infxn in a Variety of cells
Beta group
•EBV, KSH/HHV-8•Produce Latent infxn in Lymphoid tissues,
Gamma group
Pathophysiology of Latency
Viral DNA remains w/in Nucleus of Sensory Neurons
No viral protein are produced Only Latency–Associated viral RNA
transcripts are synthesized ( LATS ) Confer Resistance to Apoptosis Contribute to viral persistence in sensory neurons
Reactivation may occur in presence of host immunity Virus Developed ways to avoid Immune
Recognition
ESCAPE or Elude Immune System
DownModulating MHC class I & II molecules Hide from immune system
Producing Homologues of TNF receptor, IL-10 and MHC class I receptors Actively Suppress immune response
Herpes Simplex Virus
Virions- vesicular lesions ( INFECTIOUS)- skin. Mucous membrane, genitalia
Spread to sensory neurons that innervate the I0
site of replication
Viral nucleocapsid transported along axons to neuronal cell bodies
Virus establish Latent infxn ( NOT INFECTIOUS ) Numerous Recurence (INFECTIOUS )
Herpesvirus Blister - Mucosa
Herpes Virus
Viral type Common Presentation
Infrequent Presentation
HSV -1 Oral-labial herpes ConjunctivitisEncephalitisHerpetic whitlowEsophagitisPneumoniaDisseminated Infection
HSV-2 Genital Herpes Perinatal infxnDisseminated Infection
Cytomegalovirus
Usually produce Asymptomatic infxn except Immunocompromised
Found in All Secretions include Milk Can carry the usual dormant virus for life Transmission
1. Transplacental 4. Venereal Route2. Cervical or Birth Canal 5. Organ transplant 3. Breast Milk 6. Blood transfusion4. Saliva (children-day care)
Diseases:
Congenital CMV- acquired in Utero 95% asymptomatic Mother w/ primary infection CID develops Classic cytomegalic inclusion disease CID
Similar to erythroblastosis fetalis
Diseases:
Perinatal Infections Passage birth canal/breast milk Majority asymptomatic due to ( +) Ig from
mother Many continue excrete CMV in urine/saliva x
years Pneumonitis Later in life Hearing loss noted
CMV- mononucleosis like illness Fever, atypical lymphos, mild hepatitis,
Lymphadenopathy CMV in Immunocompromised
Disseminated CMV- lungs, GIT, Retina
Varicella – Zoster Virus
Acute Infection – Chickenpox Infects mucous membrane, skin, neurons
Reactivation – Herpes zoster / shingles
Self-limiting Latent infxn in Sensory Ganglia
Transmitted by Aerosols Disseminates Hematogenously Cause widespread vesicular skin
lesions
Varicella-Zoster Virus
Infect Dorsal Root Ganglia• neurons• Satellite cells
around neurons
Recur many years after
• Shingles• Recurs ONLY
ONCE- Immunocom-promised
Latent infxn in Sensory Ganglia
CHRONIC PRODUCTIVE INFECTIONS
HIV AND HBV
Features of Chronic Productive Infections
High Mutation Rate
Immune system unable to Eliminate virus
Viral replication continue Persistent Viremia
Hepatitis B Virus- Hepa dna
Percutaneous/ Perinatal / Sexual
HBV- PATHOGENESIS
HBV integrate in host genome Cause Hepatic injury is due to immune
response not cytopathic effect of virus Cytotoxic T lymphocytes eliminate
infected cells Evasion of immune system
Inhibiting IFN-beta downregulation of viral gene expression
High mutation rate
HBV- PATHOGENESIS
Chronic Infxn 5-10% Adults Up to 90 % Perinatally infected Children
Carrier State Occur when CTL response is Dormant
Transforming Viruses
TRANSFORMING INFECTION
EBV ,HPV, HBV, HTLV-1
Epstein – Barr Virus
Close human contact - Saliva during kissing.
Epstein – Barr Virus
Infectious Mononucleosis
Fever, Atypical Lymphos Nodes – EnlargeSplenomegaly
Sore throat
Nasopharyngeal Carcinoma
Burkitts Lymphoma
Atypical lymphocytes- Reactive T lymphocytes
IMMUNE RESPONSE TO EBV
T cell response
• More important in the control of polyclonal B-cell
• Proliferation of Cytotoxic CD8+ T cells and natural killer cells.
B cell response• Heterophil Antibodies• Produced by Non infected B
cells
Immune response Brakes
viral shedding
Limiting the number of
infected B cells rather than eliminating
themLatent EBV
remains in a few B cells as
well as in oropharyngeal epithelial cells
Uncontrlled Proliferation of Infected B cells
Burkitt lymphoma and nasopharyngeal
carcinoma
Ac quired Defects in Cellular Immunity
Some
Human Papilloma Virus
Non-enveloped D ouble stranded
D NA
Transmitted - Skin or Genital Contact
Proliferative Lesions of Squamous Epithelium
Some associated with SCC
Major Cause of Cervical Cancer
HPV
HPV initially Infect Basal cells in epithelium
Mature virions are produced w ithin the Granular layer of skin
Shed from stratum corneum
K oilocytosis – perinuclear halo
Malignant TransformationHPV E 6 stimulates Ubi q uitination and Degradation of p 5
3
And HPV E 7 binds Rb
AndDysregulate cell cycle
And
Promote cellular Transformation and Malignancy
BACTERIAL INFECTION
Gram Positive Bacteria
Staphylococcus aureus Infection
Skin Lesions Abscesses Sepsis Osteomyelitis
Pneumonia Endocarditis Food Poisoning Toxic Shock
Syndrome
Other Staph species
Opportunistic infection Prosthetic valves Catheter D rug addicts
Polysaccharide capsule – attach artificial materials
UTI in young women
Staph epidermidis Staph saprophyticus
Pathogenesis- Staph aureus
Clumping Factor Binds fibrinogen, Fibronectin, Use as bridge Adhere host Endothelial cells
Enzymes - Lipase Degrade skin lipids
Protein A Binds the Fc portion of
immunoglobulins – Escape Ab-mediated killing
Pathogenesis- Staph aureus
Superantigens Stimulate 2 0 % of Lymphos Release of large
amounts of TNF, IL-1 Septic Shock
Toxins –Damage host cell Membrane damaging toxins
Exfoliative ToxinsSuperficial epidermis split away from deeper skin
Exfoliation at the site Bulbous impetigo
Disseminated exfoliation Staph Scalded Syndrome
staph food poisoning
S. aureus enterotoxins
Stimulating emetic receptors in the
abdominal viscera
Vomiting &Diarrhea occur 1- 6
hours after ingestion.
Diseases Causesd by Staphy.
STREPTOCOCCAL INFECTION
Beta Hemolytic Strep
Group A Strep. Pyogenes• Pharyngitis , Post Streptococcal Glomerulonephritis & Rheumatic fever
• Erysipelas ,• Scarlet fever• Toxic shock syndrome,
Strep Pharingitis Epiglottal swelling & abscess Cervical LN Strep Pyogenes
Major antecedent of Poststrep Glomerulonephritis
Ag-Ab complex deposit in glomerulusPoststrep Rheumatic fever
Antistreptococcal M protein antibodies & T cells that cross react with cardiac myosin
STREP PYOGENES:VIRULENCE FACTORS
Capsules M proteins – prevents phagocytosis C5a peptidase – Degrade
chemotactic C5 Antistreptococcal M protein – Ab that
cross react w/ cardiac Myosin ( RHD)
Other Streptococcal Infection Strep. Pneumoniae
Common cause of CAP & Adult Meningitis Lobar Pneumonia
Otitis media, Sinusitis Often preceded by viral infection that
injure ciliated epithelium Has capsule- prevent phagocytosis Pneumolysin
Inserts on target cell membrane Lysis Activates Classical pathway Reducing
complement available for Opsinization
Beta Hemolytic Strep
Group B Strep Agalactiae•Female Genital Tract •Neonatal Sepsis, Meningitis
• Chorioamnionitis
Other Streptococcal Infection Strep. Mutans
Major cause of Dental Caries Sucrose Lactic acid Demineralization of
Tooth enamel Secrete HMW Glucans Promote Bacterial
Aggregation Plaque formation
Salmonella
Neisserial infxn
Whooping cough
Pseudomonas
Chancroid
Granuloma inguinale
Gram negative bacteria
Salmonella Typhi
Enteric fever Transmitted
From person to person Food or Contaminated water
GB colonization may be associated with Gallstones Chronic Carrier State
Pathogenesis
Survive gastric acid In the SI Taken by M cells Engulf by macrophages in the underlying
LN Reactive LN hyperplasia Disseminate by blood & Lymphatic
Unlike S. enteriditidis
Clinical manifestation of Typhoid Fever
•Typhoid fever is a protracted disease with bacteremia, fever, and chills
First week
•Widespread reticuloendothelial involvement•rash, abdominal pain, and prostration•ROSE SPOTS in the abdomen – red maculopapular
Second week
•Ulceration of Peyer patches•Intestinal bleeding and shock during the third week.
Third week
Pathogenesis- Salmonella Invade intestinal epithelial cells as
well as tissue macrophages.
Controlled by invasion genes
induced by the low oxygen tension
found in the gut. Genes encode proteins
: 1. Adhesion
2. Recruitment of host cytoskeletal proteins that internalize the
bacterium.
Intramacrophage growth is important in pathogenicity,
Seems Mediated by bacterial genes that are induced by the acid pH within the
macrophage phagolysosome
Typhoid fever
Blood Culture >90% in the Febrile State
Relapse may occur Systemic dissemination
Encephalopathy Meningitis Seizures Endocarditis Myocarditis Pneumonia Cholecystitis Osteomyeltis
Neisseria Infections
2 Clinically significant species N. meningitidis N. gonorrhea
Neisseria meningitidis
13 serotypes Common Colonizes Oropharynx Spread by respiratory route Only small fraction develop Cause
Bacterial Meningitis Children less than 2 years old
Pathophysiology- N. meningitidis -
Neisseria gonorrhea
Surface pili that form barrier against phagocytosis
Encapsulated gm(-) diplococci STI – Men - Urethritis, Pharyngitis, Proctitis
Urethral strictures, chronic infection of Male genitals
STI – Women - Salpingitis Tubo-ovarian abscess Scar Sterility or Ectopic pregnancy
Perinatal Ophthalmic infxn
Neisseria gonorrhea
Surface pili that form barrier
against phagocytosis
Pili also contain IgA protease that
facilitates attachment
Attach to mucous membranes of
urethra, endocervix, fallopian tube
Internalization based on a 2nd Adhesin OPA
proteins
Neisseria - Evasion of immune response
Use antigenic variation of OPA proteins to escape immune response A single clone of bacteria several multiple antigenic types
Pili Protein are altered by genetic recombination
Whooping cough
Gram (-) coccobacilli Acute highly communicable Paroxysm of violent cough followed by loud
inspiratory whoop Colonizes the brush border of bronchial
epithelium Laryngotracheobronchitis Virulence is regulated by BVG locus
Virulence factor :Regulated by Bordetella virulence gene locus (bvg)
BVGS – senses signals that
induce expression of Virulence factor
Transcription of mRNA for ADHESINS
TOXINS
Adhesins – binds resp.
epithelial cells
Pertusis Exotoxins
paralyze cilia
Pseudomonas Infection
Opportunistic gram-negative bacterium Frequent, deadly pathogen of patients
with cystic fibrosis, severe burns, or neutropenia.
Coregulated pili Adherence proteins that mediate
adherence to epithelial cells and lung mucin
Endotoxin that causes the symptoms and signs of gram-negative sepsis.
Distinctive Virulence Factor
•a mucoid Biofilm•covers the bacteria•Resistant to antibacterial antibodies, complement, and phagocytes.
Alginate
•Inhibits protein synthesis
Exotoxi
n A-
Distinctive Virulence Factor
Phospholipase C
• Lyses red blood cells • Degrades pulmonary
surfactant ,
Elastase
• Degrades extracellular matrix proteins
• Important in tissue invasion and destruction of the cornea in keratitis.
Distinctive Virulence Factor
•Extremely toxic to endothelial cells •Cause the vascular lesions characteristic of this infxn
Iron-containing
compounds
Syphilis- Treponema pallidum Sexual intercourse is the usual mode of
transmission Transplacental transmission of T.
pallidum occurs readily, & active disease during pregnancy results in congenital syphilis.
Pathology - syphilis
Chancre
Sensored A single firm, nontender, raised, red lesion3
weeks after contact
Heals in a few weeks with or without therapy
• 2 to 10 weeks after the primary chancre
• Diffuse mucocutaneous rash• oral cavity, palms and soles• Codyloma latum
• Broad based elevated whitish plagues
• Fever, LNpathy, Headache, and Arthritis.
• These lesion resolve spontaneously.
The secondary stage of syphilis
The tertiary stage of SyphilisOccurs >5years after the primary lesion
Cardiovascular Syphilis : Active inflammatory lesions :• aorta, heart and
central nervous system
NeuroSyphilis• 1/3 asymptomatic• Symptomatic
• Tabes dorsales • General paresis• Chronic
meningovascular dse
Benign Tertiary Syphilis• Quiescent lesions
Gummas :• involving the liver,
bones, and skin.
Immune response to Syphlis
Host humoral and
cellular immune
responses
• may prevent the formation of a chancre on subsequent infections with T. pallidum
Immune evasion
• Outer membrane contains 100-fold less proteins than usual gram-negative bacteria lacking antigens.
• Down-regulation of helper T cells of the TH 1 class.
Pathogenesis of Syphilis
Obliterative endarteritis
ANAEROBIC BACTERIA
Clostridia Infection
Clostridial Infections
Clostridium species are gram-positive bacilli
There are four types of Clostridium that cause human disease:
1.Clostridium perfringens (welchii), septicum
2.Clostridium tetani 3.Clostridium botulinum 4.Costridium difficile
Clostridium perfringens (welchii)
Anaerobic cellulitis – foul , thin discolored exudate, quick tissue destruction ( versus pyogenic )
Myonecrosis (gas gangrene)- 1to 3 days after infection
Invade traumatic and surgical wounds Contaminate illegal abortions Cause uterine myonecrosis, Cause mild food poisoning, Infect the small bowel of ischemic or
neutropenic patients to produce severe sepsis.
Clostridium tetani
Proliferates in: puncture wounds umbilical stump of newborn infants
Releases a potent neurotoxin, called tetanospasmin causes convulsive contractions of
skeletal muscles (lockjaw).
Clostridium botulinum
Grows in inadequately sterilized canned foods
Releases a potent neurotoxin that blocks synaptic release of acetylcholine
Causes a severe paralysis of respiratory and skeletal muscles (botulism).
Clostridium difficile
Overgrows other intestinal flora in antibiotic-treated patients
Releases multiple toxin Causes pseudomembranous colitis
Pathogenesis- Clostridium Perfringens
• Degrade extracellular matrix proteins
• Contribute to bacterial invasiveness,
Colagenase and
hyaluronidase
• Contributes to nerve sheath damage.
Sphingomyelinase activity
•Alpha toxin•O toxin•Beta toxin
14 Toxins
Alpha Toxin- Properties
Phospholipase C
•Degrades lecithin•a major component of cell membranes,•Destroys red blood cells, platelets, and muscle cells, causing myonecrosis.
Beta toxin
Enterotoxin
Enteritis
Food poisoning in malnourished
persons who eat the meat of infected
animals.
Form pores in the target epithelial cell
membranes
O Toxins
Clostridium tetani
Neurotoxin - Protease
• Toxin is bound by gangliosides on peripheral nerves• Cleaves Synaptobrevin
• Mediates fusion of neurotransmitter- containing vesicle with neuron membrane
Block vesicle fusion
• Prevents release of - Aminobutyric acid ( inhibits motor nueron Leading to the tetanal contractions.
Clostridium Botulinum- Neurotoxin
Are released when the organisms die and autolyse
Act at the peripheral nerve endings, Cleaving either synaptobrevin (as
described for tetanus toxin) or synapse-associated proteins, called SNAP-25 and syntaxin.
Unable to release acetylcholine at the neuromuscular junction and at the synaptic ganglia and parasympathetic motor end-plates of the autonomic nervous system Descending paralysis from the
cranial nerves down to the extremities.
Clostridium difficile
Produces toxin A Which is an enterotoxin a potent chemoattractant for granulocytes
toxin B a cytotoxin, which causes distinctive cytopathic effects
in cultured cells and is used in the diagnosis of C. difficile infections
Obligate Intracellular Bacteria
Chlamydia trachomatis is an obligate intracellular pathogen
Venereal urethritis, lymphogranuloma venereum, and trachoma
Lymphogranuloma venereum results in granulomatous inflammation of the
inguinal and rectal lymph nodes. Trachoma or chronic keratoconjunctivitis, a
leading global cause of blindness, is a disease of poverty and overcrowding, transmitted from eye to eye by aerosols or by hand contact.
Malaria
Intracellular protozoan parasite Plasmodium falciparum is a worldwide
infection that affects 100 million and kills 1 to 1.5 million persons per year and so is the major parasitic cause of death.
Other types (P. vivax, P. ovale, P. malariae) Transmitted by more than a dozen species
of Anopheles mosquitoes widely distributed throughout Africa, Asia, and Latin America.
Malaria P. vivax and P. malariae
mild anemia in rare instances, splenic rupture and
nephrotic syndrome. Acute P. falciparum infections
produce high parasitemias, severe anemia, cerebral symptoms, renal failure, pulmonary edema, and death.
Features of P. falciparum
Infect rbc of all ages Versus young rbc for other species High parasite burden Profound Anemia
Infected rbc clump together Stick to Endothelial lining of small blood vessels
( Sequestration ) Block blood flow Form KNOBs on rbc surface (PfEMP 1)
Plasmodium falc. Eryhtrocyte memb protein Bind Ligands on blood vessel wall Cause poor perfusion to the brain ( Cerebral malaria )
Life cycle of P. falciparum
Features of P. falciparum
Stimulates production of HIGH levels of Cytokines Induce fever Suppress rbc production NO prodn Tissue damage Induce expression of endothelial
receptors for PfEMP 1 Increasing sequestration
Morphology
P. falciparum initially Splenic congestion and enlargement of the spleen Infected rbc taken by reticuloendothelial cells.
The liver becomes progressively enlarged and pigmented with progression of malaria.
Kidneys often enlarged and congested pigment in the glomeruli and hemoglobin casts in the tubules.
Addendum
Sporozoites – Infectious stage During feeding Sporozoites Released in blood w/in
minutes Bind to and invade liver cells by binding to the hepatocyte receptor for the serum
proteins thrombospondin and properdin, located on the basolateral surface of hepatocytes
The binding is accomplished because of the presence of sporozoite surface proteins that contain a domain homologous to the binding domain of thrombospondin.
Within liver cells, malaria parasites multiply rapidly, so as many as 30,000 merozoites (asexual, haploid blood forms)
Merozoites released when the hepatocyte ruptures
Addendum
Merozoites bind by a parasite lectin-like molecule to sialic residues on glycophorin molecules on the surface of red blood cells.
Merozoitesrelease multiple proteases from a special organelle called the rhoptry.
Within the red blood cells, the parasites multiply in a membrane-bound digestive vacuole, Hydrolyzing hemoglobin through secreted enzymes that
include an aspartate protease Most malaria parasites rupture the cell infect new
red blood cells Some parasites sexual forms called gametocytes
infect the mosquito when it takes its blood meal.
Addendum
Maturation change morphologic from ring to schizont form secrete proteins that form 100-nm bumps on the red blood cell surface, called knobs called sequestrins
Sequestrins bind to endothelial cells by ICAM-1, the thrombospondin receptor, and the glycophorin CD46 cause malaria-infected red blood cells to be removed from
circulation Red blood cells containing immature ring forms of the
parasite flexible pass through the spleen, circulate in the blood
Red blood cells containing mature schizonts, rigid sequestration in the spleen.
Schistosoma
Schistosoma
S. mansoni / japonicum eggs liver disease. 1. Substances released from schistosome eggs
Are directly hepatotoxic, 2. Carbohydrate antigens from eggs induce
Granuloma formation mediated by TNF and TH 1 and TH 2 helper cells. TH 2 helper T cells secrete IL-4 Induce IgE synthesis
eosinophilia, mastocytosis, and high levels of serum IgE in human schistosomiasis
Resistance to reinfection by schistosomes after treatment correlates with IgE levels
Whereas eosinophil major basic protein may destroy larval schistosomula
3. Eggs release factors that stimulate lymphocytes secrete a fibrogenic lymphokine Stimulates fibroblast proliferation and portal
fibrosis. This exuberant periportal fibrosis, which
is out of proportion to the injury caused by the eggs and granulomas, Pipestem Fibrosis Occurs in 5% - 10% of persons heavuly infected
with schistosomes Hallmarks of severe schistosomiasis :
Portal hypertension Esophageal varices, Ascites
Pipestem Fibrosis - Liver
S. haematobium infection,
Bladder inflammatory patches due to massive egg deposition and granulomas cause hematuria
The most frequent complication is inflammation and fibrosis of the ureteral walls leading to obstruction, hydronephrosis, and
chronic pyelonephritis.
Schisoma eggs