INFECTIOUS DISEASE OF PATHOLOGY

(Part-1)

Dr.Naila Awal

(Postgraduate student)

Categories of infectious agents

• Prion

• Viruses

• Bacteria

• Fungi

• Protozoa

• Helminths

• Ectoparasites

PRION

• DefinitionDefinition- Infectious particle composed of protein (prp)

• Diseases-Diseases- Human 1) kuru 2)Creutzfeldt- Jackob Disease (CJD) 3)Variant CJD Animal- Bovine spongiform encephalopathyTransmission-Transmission-

Iartogenically Organ transplantation Surgery Blood transfusion

PathogenesisPathogenesis-- Prp normally found in neuron. Disease occur when prp conformational change protease resistant prp

INormal Protease I Abnormal Sensitive prp ------ prp ---Neuronal damage

Inactivation-Inactivation- By protein and lipid disrupting agent such as -

Phenol NaOH Ether Hypochlorite

New and Emerging infectious diseases

• Definition-Definition-

Newly identified & previously unknown agent that appeared in human population & causes public health problem is known as emerging infectious disease.

These includes-

1) Disease caused by newly developed strains/ microorganism-

Ex- MDR-TB MRSA XDR-TB Chloroquine resistant malaria

2) Disease caused by pathogens, endemic in otherspecies (birds) that recently entered into human population-Ex-HIV, SARS

3) Disease caused by pathogens that have been present in human population but show recent incidence

Ex-Dengue fever

Factors contributing to emergence—

1)Enviornment–

Climate & changing ecosystem

Urbanization & deforestation

2)International travel

3)Breakdown of public health measures

(war, overcrowding)

Bioterrorism

• Definition- Intentional release of viable bacteria, virus & toxin in order to harm people, animal/plant.

• Category A-->Highest risk

-->Easily disseminated/ transmitted from person to person

-->High mortality

• Anthrax- Bacillus anthracis

• Botulism- Clostridium botulinum

• Plague- Yersinia pestis

• Small pox- Variola major virus

• Viral hemorrhagic fever- Filovirus

• Category BModerately easy to

disseminatedModerate morbidity but low

mortality

• Brucellosis- Brucella• Melioidosis- Burkholderia

pseudomallei• Glanders- Mallei• Staphylococcal

enterotoxin B• Epsilon toxin of Clost.

perfringes• Food safety threatsSalmonella, Shigella, E.coli• Water safety threats- V.cholerae, Cryptosporidium

pavum

• Category C • Emerging pathogens-

Nipah virus

Hanta virus

Transmission & dissemination of microbes

• ROUTE OF ENTRYROUTE OF ENTRY

• SKIN-

Natural barrier-1)Dense keratinized layer of skin

2)Low pH

3)Fatty acid- the growth of micro organism

• Unbroken skin-

• Penetrate through broken skin

• I/V catheter

• Schistosoma larva

Release collagenase, elastase

dissolve ECM penetrate swimmers skin

• Superficial prick-Fungus• Wound-Staph• Burn-Pseudomonas

• Bacteremia

• Needle stick• Insect bite

• Animal bite

• HBV,HCV,HIV• Tick transmit-

Rickettsiae-RMSF

Brucella-Lyme disease• Flea--Y.pestis- plague• Mosquito-Malaria, Filaria• Sand fly- L.donavani-

leishmaniasis• Dog-Rabies

• GIT

• Natural defense-1)Mucosal covering of intestinal epithelium

2) Mucosal antimicrobial agent-defensin

3)Lytic pancreatic enzyme & bile detergent

4)Normal flora

5)Secretory IgA

1)Enteropathogenic bacteria-1)Enteropathogenic bacteria-

1)Staphgrow in contaminated food release enterotoxin food poisoning without multiplication in the gut.

2)V. cholerae, ETEC multiply inside the mucus layer covering gut epithelium exotoxin release watery diarrhea.

3)Salmoella,Shigella,Champylobacterinvade & damage intestinal mucosa & lamina propria ulceration, inflammation & hemorrhage dysentery.

4)S.typhisystemic infection.

• Fungus-Fungus-

Candidal infection- mainly in immunocompromised person.

• Intestinal protozoa-Intestinal protozoa-Giardia lamblia

Entamoeba histolytica

Cryptosporidia

• Intestinal helminths-Intestinal helminths-Ascaris lumbricoides gut obstruction/invade &

damage the bile duct

Hookworm IDA

Diphyllobothrium latum vit B12 depletion-

megaloblastic anemia

T.Solium larva- encyst in muscle

E. Granulosus larva-encyst in lung, liver

• Respiratory tract-

• Natural defense-1)Mucocilliary apparatus large particles are trapped.

2)Alveolar macrophage & neutrophil particle<5micro meter alveoli phagocytosed by alveolar macrophage & neutrophil.

Mechanism-

1)Micro organism attached to lower respiratory tract & laryngeal epithelium

Example-

Influenza virus-has 2 cell surface proteins-

– Hemagglutinin (function at the beginning of the infection)

-Neuraminidase-(function at the end of the infection. They degrade the protective layer of mucus in respiratory tract)

Influenza virus

Hemagglutinin Neuraminidase

Bind with epithelial surface receptor 1)Cleave the sialic acid allow the virus to release from host cell

Host cell engulf the virus 2) the viscosity of mucus facilitate viral transit within respiratory tractReplicate within the cell

2) Impaired ciliary activity-Example-

• H. Influenzae & B. pertussis- release toxin ciliary paralysis.

• Mycoplasma pneumoniae- produce ciliostatic substances

• Smoker/people with cystic fibrosis-chronic damage to mucociliary apparatus

3)Some respiratory pathogen avoid phagocytosis/destruction after phagocytosis

Example-• M tuberculosis- escape killing within phagolysosome

of macrophage

4)Opportunistic fungus- infect when CMI /when leukocyte are in number.

Example- Pneumocystis jirovechi in AIDS Aspergillus followed by chemotherapy.

• Urinary tract

• Natural defenseRegular flushing of urinary tract by urine

Spread & dissemination of microbes

Some micro-organism proliferate locally at the site of infection & others spread to distant site via-lymphatic's, blood & nerve.

• Local-

a) Confined to lumen of hollow viscera- V. cholerae.

b) Adhere /proliferate in/on epithelial cell-

HPV/dermatophytes.

Invasive-

• Lymphatics-Ex- Staphylococcus-localized abscess/furuncle through

lymphatic drain into regional lymph node sometimes bacteremia & colonize to distant organ.

• Blood-Most of bacteria & fungus, Virus- HBV, Polio

Protozoa- African trypanosoma

All helminths. WBC- MTB,LD, Toxoplasma, HIV, Herpes

RBC- Plasmodium, Babesia

• Nerve- Polio virus

Placental-fetal route-

• Bacteria- Mycoplasma placentitis premature delivery/still birth.T.Pallidum2nd trimester osteochondritis, periostitis

leads to multiple bony lesion.• Virus-Rubella1st trimester-Congenital heart disease, Cataract, Deafness. 3rd trimester-Little damage

• Infection during passage of birth canal-

Rickettsia/Chlamydia-Conjuctivitis

• Milk-- CMV,HBV,HTLV-1

Release of microbes from the body

It depends on the location of infection.

Transmission from person-person-• Respiratory route- Virus & bacteria.

• Saliva- EBV, CMV, Mumps

• Feco-oral route- HAV, HEV , Rota virus,

Hookworm, Schistosomes

• Blood & blood product- HBV, HCV,HIV

• Sexual transmission

• Transmission from animal-human-

1) Direct contact / Consumption of animal fat

Ex- Bacillus anthracis.

2) Indirectly via invertebrate host.Ex- Malaria – by mosquito.

Sexually Transmitted Infection

• Definition- Infection that are transmitted through sexual route.

• High risk group-1)Adolescent

2)Homosexual men

3)Illegal drug abuser

• Site- Initial site-Vagina Urethra

Rectum Oropharynx

General features-

Infection with 1 STI associate organism the risk for additional STI

Ex-

N. Gonorrhea/ Chlamydia trachomatis epithelial injury local tissue damage chance of co-infection with the other & also the risk of HIV infection. .

STI can spread by vertical transmission & causes severe damage to fetus/ child

Ex- Chlamydia trachomatis Conjunctivitis

Syphilis Miscarriage

Examples of STI

• Bacteria• Neisseria gonorrhoeae• Treponema pallidum• Haemophilus ducreyi• Klebsiella granulomatis• Chlamydia trachomatis

• Ureaplasma urealyticum

• Gonorrhea• Syphilis• Chancroid• Granuloma inguinale• Lymphogranuloma

venereum• Urethritis

• Virus• HSV• HBV • HPV• HIV• Protozoa• Trichomonas vaginalis

• Herpes• Hepatitis• Condyloma acuminatum• AIDS

• Urethritis• Vaginitis

Nosocomial Infection

• DefinitionThese are hospital acquired infection which

develops 48hrs after hospitalization /within 48 hrs after release from hospital.

Source1)Hands of health worker 4)Blood transfusion

2)Contaminated surface 5)Organ transplantation

3)Used equipment & instrument

Organism causing Nosocomial Infection

• Bacteria-• Gram positive

• Gram negative

• Staph aureus• MRSA,VRSA• Staph epidermidis• Strep pneumoniae• Clostridium tetani

• Pseudomonas• Proteus• E coli

• Virus

• Fungi

• Parasite

• HBV,HCV,HDV• HIV, HSV,CMV

• Candida

• Pneumocystis jiroveci• Toxoplasma

Risk factor-• Long time hospital stay• Mechanical ventilation• I/V catheter• Use of indwelling catheter• Overdose of antibiotic• Failure of health care worker to wash hand.

• Prevention1) Frequent hand washing can transmission of MRSA &

VRE.

2) Proper sterilization & disinfection of inanimate object of the hospital.

3) Proper disposal of hospital waste.

4) Rational use of antibiotics.

5)Personal hygiene of patient, attendants, doctor & medical stuff.

6) Detection of proper carrier & proper diagnosis.

Host defense against infection

• 1) Innate immunity-a) Intact skin-Intact skin- Sebaceous gland--> contain fatty acid antibacterial

& antifungal

Low pH- antimicrobial.b) Mucous membrane-Mucous membrane- Mucociliary apparatus- prevent the entry of microbes

through URT

Lysozyme in tear & mucus- degrade peptidoglycan layer of bacterial cell wall protect from infection.

c) Cellular component-Cellular component- Macrophage, neutrophil phagocytose the microbes.

N-K cellproduce toxic substances perforin destroy microbes.

d) d) Soluble component-Soluble component- Complement activation-->formation of MAC

destroy cellular Ag.

IFN, IFN –released by virus infected cell this IFN replication of viruses. (that’s why viral infection are self limiting)

• 2) Acquired immunity- develops after exposure to microbes.

They are B & T lymphocyte.

Ex- Measles virus enters into the body

Ab production

Ab binds with measles virus Provides specific immunity

Virus eliminated

How micro-organism causes diseaes

• By 3 mechanisms-1)They can directly enter into host cell causes cell

death.

2)They may-release toxins kill the cell

3)They may-release enzymes degrade tissue components/damage blood vessel ischemic necrosis.

4)They induce host cell responses causes additional damage.

Mechanism of viral injury

Virus can directly damage the host cell by entering & replicating within it.

• Virus has a affinity for specific body tissue which is determined by –

1)Presence of receptor on host cell-1)Presence of receptor on host cell-Ex- gp120 of HIV binds with CD4 on Tcell CXC R4(T cell) CCR5(macrophage)gp350 of EBV binds with CR2/CD21 on B cell

2) Cellular transcription factor that recognize Cellular transcription factor that recognize viral enhancer & promoter sequenceviral enhancer & promoter sequence

Ex- JC virus causes leuko encephalopathy, replicate specially in oligodendroglia in CNS. (B/c enhancer & promoter sequence regulating viral genes are active in

glial cell).3) Physical barrier-Physical barrier-Ex- Entero virus replicate in intestine b/c they can resist

inactivation by acid, bile & digestive enzyme.

4)Temparature-)Temparature-Ex- Rhinovirus infect only within URT b/c they replicate at

lower temperature of URT.

Virus can damage the host cell by a number of mechanism-

• 1) Direct cytopathic effect-Direct cytopathic effect- Virus can kill the cell directly by-

a) Prevent the synthesis of host macromolecules (DNA,RNA/protein)

Ex-Polio virus- inactivate cap binding protein which is essential for translation of host cell mRNA.

b) Producing degradative enzyme & toxic proteins

Ex- HSV-Produce protein that synthesis of cellular DNA & mRNA & other proteins that degrade host DNA.

c) Inducing apoptosis by producing pro-apoptic proteinEx- HIV vrp protein.

2)Anti viral immune response-

• Viral protein on the surface of host cell may be recognized by immune system & lymphocyte may attack the virus infected cell.

Ex- In HBV infection, acute liver failure is caused by cytotoxic T cell mediated destruction of infected hepatocytes.

3)Transformation of infected cells--> benign/ malignant neoplasm

• Oncogenic virus stimulate cell growth & survival by following M/A-

Expression of virus encoded oncogeneAnti-apoptic strategiesInsertional mutagenesis

Mechanism of bacterial injury

• 1) Adherence to the host cell surface- a) Adhesin - is present in bacterial cell surface. Through

this they bind to host cell/ECM.Ex- Strep. pyogens adhere to host tissue by protein F &

teichoic acid. b) Pili - Ex- E.Coli through P pili bind with gal-gal moiety of

uroepithelium.c) Glycocalyx -Ex-Stap. epidermidis/ Strep. viridians bind with heart

valve.

• 2)Virulence of intracellular bacteria-• Facultative intracellular bacteria infect-->Epithelial cell (Shigella, ETEC)

-->Macrophage (MTB,ML)

-->Both (S. typhi)

• Growth of bacteria in cell may allow the bacteria to escape the immune system /facilitate the spread.

Ex- MTB macrophage lung to other site.

Bacteria have a number of mechanism to enter into the cell-

a) Bacteria is coated with Ab/ complement phagocytosed by macrophage.

• Ex-MTB activate alternative pathway of complement opsonization with C3b C3b coated MTB bind with CR3 on macrophage endocytosis into macrophage.

b) Gm- bacteria use complex secretion system to enter into epithelial cell.

• This system consists of needle like structure form pore inside host cell membrane inject protein rearrangement of cell cytoskeleton bacteria entry.

• Ex- L. monocytogenes.

c) Effect of bacteria inside the host cell-c) Effect of bacteria inside the host cell-

a) Shigella, E. coli- host protein synthesis within 6 hours host cell lysis.

b) Within macrophage most bacteria killed when phagosome fuse with lysosome & form phagolysosome. But certain bacteria evade this defense.

Ex- MTBMTB- block the fusion of phagosome with lysosome unchecked proliferation within macrophage.

L. Monocytogenes-L. Monocytogenes- produce pore forming protein-listeriolysin O & 2 phospholipase degrade phagosome membrane bacteria escape into cytoplasm.

3) Toxin production-

• A) Endotoxin- is a LPS, component of Gm- bacterial cell wall.

It is both beneficial & harmful.

Beneficial-Activate protective immunity. Induction of cytokine & chemokineexpression of co-stimulatory molecules enhance T cell

activation.Harmful-

High level of LPS induction of excessive level of cytokines TNF, IL-1,IL-12Septic shock, DIC, ARDS.

• B) Exotoxin- secreted from bacteria & causes celluar injury.

1)Enzymes- bacteria secret protease, coagulase, hyaluronidase, fibrinolysin

Ex-• Stap. aureus produce protease degrade protein that

hold keratin together detachment of epidermis from deeper skin.

2)Toxin that alter intercellular signaling & regulating pathway—

• Most of the toxins have

A sub unit- enzymatic activity

B sub unit- binds with the receptor on cell surface & delivers the A subunit into cell cytoplasm.

Ex- Bacillus anthracis, V. cholerae.

3) Neurotoxin-• Clostridium botulinum, Clostridium tetani• release of neurotransmitters paralysis respiratory

failure death.

• 4) Super Ag-• Stimulate T lymphocyte massive Tcell proliferation &

release of cytokines high level of cytokines Capillary leakage & shock.

Injurious effects of host immunity

1) Immune response to microbes sometimes causes tissue injury.

• a) MTB- causes granulomatous inflammation--delayed hypersensitivity prevents the spread of bacilli but also

causes tissue damage & fibrosis.

• b) HBV,HCV- causes liver damage due to immune

response to infected hepatocyte, not to cytopathic effect.

.

2)Humoral immune response to microbes has also pathological consequence

• S. pyogenes- Ab produce against streptococcal M protein cross react with cardiac protein damage heart valve RHD.

• S. pyogenes- anti streptococcal Ab cross react with glomerular basement membrane form Ag-Ab complexes deposit in renal glomeruli Post streptococcal GN.

• 3)Infection may be associated with chronic inflammatory disorder as well as cancer.Ex-

• HBV/HCV Hepatitis HCC• H.Pylori Gastritis gastric adenocarcinoma• Schistosomia Chronic cystitis bladder carcinoma.

Immune evasion by microbes

Micro organism develops many M/A to evade host immune system.

1) Growth in niches that are inaccessible to host immune response

a) Microbes are multiply in the lumen of the intestine (C. difficili) / gall bladder (S. typhi)

b) Some organism are rapidly invade host cell before humoral immune response become effective.

Ex- • Malarial parasite--sporozoite enters into hepatocyte.• Trichinella/T. cruzei-enters into skeletal/cardiac muscle.

c) Some Parasite form cyst in host cell.

Ex- Tapeworm

d) During viral latency, viral genes are not expressed.

Ex- Herpes virus

2)Antigenic variation- Virus can escape immune attack by changing their Ag.

Mechanism• High mutation rate

• Genetic ressortment

• Genetic rearrangement

• HIV • Influenza virus• Influenza virus• Rota virus• N. gonorrhoeae• Borrelia• Trypanosoma• Plasmodium

3) Resistance to innate immune response

• Resistance to antimicrobial peptide (defensin, cathelicidins& thrombocidin)- prevents killing of microbes by neutrophil & macrophage.

• Carbohydrate capsule -present on the surface of the micro organism prevent phagocytosis by neutrophil.

• Ex- Pneumococci, meningococci, H.influenza

• Bacteria by covering with host protein -evade immune defense.

Ex- Staphylococcus aureus covered by protein A that bind with Fc portion of Ab phagocytosis.

• Some bacteria secret protease degrade Ab.

Ex- Niesseria, Haemophilus, Streptococcus

• Some organisms replicate within phagocytic cell.Ex- MTB, Liesteria, Leishmania, Trypanosoma,

Toxoplasma, Cryptococcus neoformans.

• Virus can produce molecules that innate immunity.

Ex- Herpes virus, Pox virus produce protein block complement activation.

• Some virus produce homologous of IFNFIFN R which the action of IFN.

4) Recognition of infected cell by CD4 TH cell/ CD8 cytotoxic T cell.

Ex- HSV,CMV,EBV bind/ alter the localization of MHC-1 impair the peptide presentation to CD8 T cell.

Infection in immunosuppressed hosts

• Inherited-Inherited-• 1)Patient with Ab deficiency-

Ex- X-linked aglobulinaemia-• Severe bacterial infection- • Strep . pneumoniae• Haemophilus influenzae• Stap. Aureus

• 2)T cell defect- susceptible to infection with intracellular pathogens, virus, some parasite.

• 3) Complement deficiency-• Strep . pneumoniae• Haemophilus influenzae• Neisseria menigitidis

• 4) Defect in neutrophilic function-• Stap. Aureus• Gm- bacteria• Fungi

Acquired-

• 1) AIDS • 2) Impaired production of leukocyte leukemia fills the bone

marrow with cancerous cell & vulnerable to infection.

• 3)Iartogenic cause of immunosuppression-• Ex-Immunosuppressive drug.

• Disease of organ systems other than immune system-

• Cystic fibrosis---- RTI with P. aeruginosa• S. aureus

• Sickle cell disease----Strep. pneumoniae

• Burn---- P. aeruginosa.

Spectum of inflammatory responses to infection

• 5 major histological patterns of tissue reaction in infections are-

1) Suppurative inflammation-

2)Mononuclear & granulomatous inflammation

3)Cytopathic- cytoproliferative reaction-

4)Tissue necrosis-

5) Chronic inflammation & scarring-

1) Suppurative inflammation-

Characterized by production of large amount pus/purulent exudates consisting of neutrophil, liquefactive necrosis & edema fluid.

• Sometimes the lesion are destructive.

Ex- Pneumococci spare alveolar wall lobar pneumonia.

Staphylococci & Klebsiella destroy alveolar wall form abscess fibrosis.

Suppurative inflammation

2)Mononuclear & granulomatous inflammation

Granulomatous inflammation- is a distinctive pattern of chronic inflammation characterized by accumulation of activated macrophages- epithelioid cells which may fuse to form giant cells. In some cases there is a central area of caseous necrosis.

• Ex- TB

Mononuclear cell predominate-Mononuclear cell predominate-• Plasma cell abundant Primary & secondary

syphilis.

• Lymphocyte predominate HBV infection/viral infection of brain.

3) Cytopathic- cytoproliferative reaction-

It is characterized by cell necrosis/cellular proliferation, usually with scattered inflammatory cell.

a) Some virus replicate within cytoplasm/nucleus & visible as inclusion body.

• Ex-Herpes virus, Adeno virus.

b) Some virus induce cell to fuse & form multinucleated giant cell.

• Ex- Warthin- Finkeldy cells in measles. Herpes virus.c) Some virus causes epithelial cell to detach &

form blister• Ex- Herpes virus.d) Some virus causes epithelial cell to proliferate &

form wart.• Ex- HPV, Pox virus.e) Finally they contribute to develop malignant

neoplasm.

4)Tissue necrosis-

Ex-• Clostridium perfringes- secret toxin gangrenous

necrosis.• E. histolytica- liquefactive necrosis.• Herpes virus (brain)/ HBV (Temporal lobe)-severe

necrosis.• 5) Chronic inflammation & scarring-Ex-• Chronic HBV cirrhosis• Schistosoma egg Pipe-stem fibrosis of liver• TB Constrictive fibrous pericarditis.