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