BMED2404 – Semester 1L2:)Epidemiology)&)Transmission)of)Disease))!...
Transcript of BMED2404 – Semester 1L2:)Epidemiology)&)Transmission)of)Disease))!...
BMED2404!!–!Semester'1"Understand)the)principles)of)the)current)problems)and)emerging)threats)that)are)posed)by)microorganisms.)It)is))not)necessary)to)remember)the)statistics)of)infectious)diseases)that)are)presented,)but)you)should)define)and))understand)the)terms)used)))
Mortality) Cause)of)death"mostly"due"to"infectious"killers"(e.g."pneumonia,"TB,"malaria,"HIV)"
Morbidity) • Impact"of"illness"="condition)of)being)diseased"
• So"sick"→"cannot"contribute"to"the"community"(measured"as"disability"adjusted"life"
years"–"DALYs)"
Virulence) Degree)or)intensity)of)pathogenicity"�"Increased)virulence)=)more)likely)to)harm"
Normal)Human)Microbiota)
• Residents"associated"with"healthy"individuals""
• Aid)resistance)to)infection"by"competing"with"pathogenic"invaders"for"nutrients"and"
attachment"sites"
• Stimulate)immune)response)+)aid)digestion"
• Note:"Some"normal"flora"become"pathogenic"if"they"move"to"a"new"location"(e.g.)Staphylcoccus)aureus)becomes)pathogenic)if)it)invades)deep)skin)tissue)"
Emerging)infections) New,)reDemerging)or)drug)resistant)infections)whose)incidence)in)humans)has)increased))within)the)past)2)decades)or)whose)incidence)threatens)to)increase)in)the)near)future)
Influenced"by:"
• Human"demographics"and"behaviour"""
• Technology"and"industry"""
• Economic"development"and"land"use"""
• International"travel"and"commerce""�"known"infections"spreading"to"new"areas"
• Microbial"adaptation"and"change"�"causing"new"infection"types"
• Old"infections"reemerging"as"a"result"of"antimicrobial"resistance"in"known"agents"
or"breakdowns"in"public"health"measures"""
Methods)of)eradicating)disease:)
• Active)immunization"�"establish"longOlasting"immunity"against"pathogens""
• Sex)education"(prevent"spread"of"STIs)"
• Free)medical)treatments"in"low"socioOeconomic"areas"
• Defending)national)borders"to"protect"against"microbial"invaders"
!
!! )
Be)familiar)with)the)characteristics)of)parasitism)))
Pathogens:"
• Organisms"that"invade)the)body/host"and"thrive"by"causing"tissue"damage"or"infectious)diseases"
• Transmission"via"air,"water"or"contact"etc.""
• Medical)microbiology)is)the)study)of)the)medically)important)microorganisms)that)cause)infection)and)disease)in)humans)))
)
Understand)the)dynamics)of)the)host/parasite)battle)in)which)each)tries)to)get)the)upper)hand)))
)HOST/PARASITE)BATTLE"is"a"CONTINUING)BATTLE"where"the"winner)dominates)the)relationship"
!Understand)what)factors,)both)in)the)host)and)in)the)microbe,)govern)where)a)host/microbe)relationship)will)fit))on)the)symbiosis)spectrum)))
SYMBIOSIS'SPECTRUM'='DYNAMIC'whereby"the"BALANCE)DEPENDS)ON"BOTH"the"microbe"AND"host"
!Both)microbe)
and)host)benefit!One)benefits"while"other"remains"unaffected! Microbe)benefits)
while)host)is)harmed)
!Factors)affecting)symbiosis:)
1. Number)of)organisms) Increased"numbers"" Shifts"to"parasitism"(increased"disease)"
2. Virulence)of)organisms) Increased"virulence"(intensity)" Shifts"to"parasitism"(more"likely"to"harm)"
3. Host’s)defence)or)resistance) Decreased"resistance"" Shifts"to"parasitism"
" Healthy"host" High"resistance"(little"effect)"
*All"about"a"dynamic"relationship"between"the"host"and"microbe"–"winner"dominates"relationship"
"
NOTE:)
• SARS"epidemic"due"to"virus"acquiring"new"virulence"factors"to"produce"atypical)pneumonia"
• Bacteria,"Virus,"Fungi"and"Protists"(e.g."trypanosomes)"can"all"act"as"pathogens"
"
! )
L2:)Epidemiology)&)Transmission)of)Disease))!Koch’s)Postulates:"The"same"pathogen"from"the"pure"culture"must:")
1."present)in)every)case)of"the"disease""
2."be"isolated)from)the)diseased)host)and"grown"in"pure"culture""
3."cause)the)disease)when"inoculated"into"a"healthy,"susceptible"laboratory"animal""
4."again"be"isolated)from)the)inoculated)animal)and"must"be"shown"to"be"the"
original"organism""
*NOTE:"Koch’s"postulates"do"not"consider"viruses,"which"cannot"be"cultured"
!Be)familiar)with)the)terms)used)in)the)science)of)epidemiology)))
!!
Epidemiology! the"study"of"the"distribution"and"determinants"of"healthOrelated"states"or"events"
(including""disease),"and"the"application"of"this"study"to"the"control"of"diseases"and"
other"health"problems!Sporadic)disease! Unpredictable"with"no"pattern"of"occurrence"(random)!Outbreak! sudden,"unexpected"increase"in"incidence;"usually"isolated"to"a"single"part"of"a"society!Endemic)disease! Disease"constantly)present"in"a"population"usu."at"low"frequency"(cyclic"+"no"outbreaks)"
Epidemic)disease) Disease"suddenly"increases)in)population""
Pandemic)disease) Disease"increases)WITHIN)large)widespread)populations"usu."worldwide""
)
! )
Understand)with)how)epidemiologists)recognise)epidemics)))
"!2"types"of"epidemics""
1. Common)source)epidemic) • rapid"increase"and"decrease"in"incidence""
2. Propagated)epidemic) • increases"over"longer"period"of"time;"
• "usually"transmitted"between"people;""
• dependent)on)susceptibility"of"individual"
"
Herd"Immunity"O"Thresholds""
"
Those"who"are"vaccinated"or"survived"the"disease"protect"
those"who"are"susceptible"�"thus"reducing"spread"
"
As"the"number"of"susceptible"people"reduce,"the"
spread"also"decreases"as"less"people"to"infect"
Be)familiar)with)the)properties)of)influenza)virus)and)its)disease)))
!HA)trimer! Allows"virus"to"bind"to"host!NA)tetramer! Allows"virus"to"punch"holes"in"the"cell"wall"so"virus"DNA"
can"get"in!Drift! Small)alteration"to"a"single"protein"�"not"effectively"
recognised"by"the"immune"system!Shift) Major)alteration"�"completely"no"longer"recognised"by"
the"immune"system"
Influenza"pandemics"resulting"from"antigenic"shifts"
H1N1)) different"H"and"N"strains"due"to"mutations"in"HA"and"NA"
! !
Danger?)CoOinfection"with"animal"and"
human"strains"can"produce"different"virus"
strains"due"to"genetic"recombination)Spread?)Easy"transmission"via"aerosolised"
particles)Who)at)risk?"Children,"elderly,"those"who"have"never"been"infected"before"
Understand)the)relationship)between)epidemiology)and)the)infectious)disease)cycle)AND)how"the"links"in"the"infectious"disease"cycle"interrelate))
Infectious)disease)cycle:)
!*Virulence)=)intensity)of)pathogenicity)
!Understand)the)interrelationship)between)virulence)and)transmission)in)the)host)pathogen)interaction.)))TRANSMISSION)METHODS:)
) Method) Disease)example)
AirDborne) aerosols:"coughing,"talking,"sneezing:") ‘flu,"chicken"pox,"mumps,"measles"etc)
) dust:"hospitals"="nosocomial"infection) )
Contact) Direct"usu."skin"to"skin) utensils,"STI’s)
Vehicle) contaminated"food"/"water) cholera,"food"poisoning)
Vectors) Mosquitoes,"rats" malaria,"trypanosomiasis"
"
MAJOR)RELATIONSHIP)between)virulence)and)transmission:)
• Highly"virulent"pathogens"will"cause"host"to"be"bedridden."This"means"there"is"reduced"contact"and"hence,"
less"transmission"of"the"pathogen."Similarly,"pathogens"that"are"dependent"vector"transmission"(e.g."African"
sleeping"sickness)"may"also"experienced"reduce"spread"if"vector"absent"(since"virulence"is"independent"to"
transmission)"
• Conversely,"the"common"cold"is"low"in"virulence"but"can"be"easily"transmissible"as"host"remains"active"and"
can"continue"to"make"contact."
"
Know)how)these)links)can)be)broken)in)order)to)control)epidemics))
Source)of)pathogen)) Transmission)–)most)effective) Host)susceptibility))
• Eliminate"contaminated"food"or"
water""
• Quarantine"carriers"and"diseased"
individuals""(e.g."smallpox)"
• Destroy"animal"carriers"""
• Identify"reservoir"(e.g."bats"in"
SARS"outbreak)"
• Change"behaviour""�"sex"ed"""
• Destroy"insect"vectors"–"mosquitos"
and"malaria"
• Control"animal"vectors"–"cattle,"TB"
• Improve"nutrition"
• "Vaccinate"""
• Problem"with"lack"of"
immunoincompetence"
" )
L3:)Pathogenicity and virulence factors )Know)the)microbial)strategies)and/or)products)that)allow)microbes)to)accomplish)each)of)the)following)steps:)colonisation,"invasion,"evasion,"and"damage"their"host))Virulence)factors)function)to:)
1. Aid"colonisation""
2. Invasion"="Allow"penetration"of"host"tissue"
3. Evade"immune"host"response""
4. Cause"direct"damage"(e.g."toxicity)"
5. "
Virulence"Factor" Explanation"
Colonisation" Specific"Attachment""
• Afrimbrial)Adhesins/Ligands) bind"to"receptors"on"the"cell"
• Adhesive)Pili)and)Fimbriae) short"stumpy"brush"border"used"for"adhesion"+"very"
tight"bonding"
• Viral)protein)spikes) binds"to"receptors"on"the"cell""(e.g."influenza)"
"
NonO"Specific"Attachment""
• Glycocalyx"–"sugar"contributes"to"stickiness"that"assist"in"adhesion""
"
Invasion"
(Host)Cell)Penetration)&)Growth))
)
Uptake"of"bacteria"via:"
• Invasins) some"bacteria"produce"surface"proteins"that"promote"its"
ingestion"by"cells"undergoing"mitosis"
• Endocytosis) non"phagocytic"cells"(e.g."influenza"virus)"
"
"
"
"
• Exocytosis) actin"tail"propulsion"
• Phagocytosis) microorganism"engulfed"
• Membrane)fusion) membranes"fuses"(e.g."measles"virus)"
"
"
"
""
Enzymes"
)(survival,)penetration,)damage)to)host))
Enzymes"crucial"for"microbial"survival"and"dissemination:"
• Coagulase) Coagulates"blood"
• Kinases) Digests"fibrin"clots"
• Hyaluronidase) Hydrolyses"hyaluronic"acid"
• Collagenase) Hydrolyzes"collagen"
• IgA"proteases) Destroys"IgA"antibodies"="survival"
• " ""
Evasion"of"
immune"
response"
)
1. Alter)surface)proteins"(antigenic"change"or"mimicry)"to"evade"immune"response"""
2. Large)thick)slime/glycocalyx)capsules"hide"antigenic"sites"and"create"protective"barrier"to"evade"detection"
3. Produce"antibody)proteases:"destroy"immunoglobulins""
4. Intracellular)survival"within"phagocyte"
5. Either:"
o destroy"phagocyte"or""
o inhibit"phagocytosis"by"resisting:"
- "lysosomal"enzymes"
- chemotaxis"and""
- phagosome/lysosome"fusion"
Damaging"the"
host"
• Microbial)toxins)–)endotoxins)and)exotoxins)))
• Pathogenicity)islands)� )contribute)to)pathogenicity)
o MECHANISM"OF"Pathogenicity"islands"include:"
o Large"segments"of"DNA"that"contain"insertionOlike"sequences"="mobile,"encode"major"
virulence""factors"and"associated"with"tRNA"encoding"genes"""
o Pathogens"may"have">1"Pathogenicity"Islands"""
o Maybe"plasmids"""
o CellOcell"acquired"by"horizontal"gene"transfer"""
• EXAMPLES:"
o "alter"actin"microfilaments"to"mediate"adherence""
o modulate"host"activities"
"
! )
Compare)and)contrast)the)actions)and)effects)of)exoD)vs)endotoxins)produced)by)bacteria)on)the)human)body)
) Exotoxins) Endotoxins!Source) Gram"+ve" Gram"–ve"
Metabolic)Product) By"products"of"growing"cell"" Present"in"LPS"of"outer"membrane"
Chemistry) Protein) Lipid)
Fever) No" Yes)
Neutralised)by)antitoxin) Yes) No"(as"lipid"based)"
)
" "
"
Know)and)understand)how)some)of)these)toxins)exert)their)effects)on)host)cells))
Bacterial"Exotoxins"(their"target"and"effect)"
Membrane)disrupting)exotoxins)
(Clostridium)perfringens)aOtoxin"�"causes"gas"
gangrene)"
"
"
"
• Channel/pore"forming"toxin"causes"
change"osmolarity"�"cell"lysis"
• Phospholipase"chops"off"phosphate"
heads""
• Destroys"the"integrity"of"the"
membrane"
ADB)exotoxins)))
(e.g.)cholera'exotoxin)produced)by)vibrio)cholera)�)causes)massive)fluid)efflux)=)diarrhea))
)
)
)
)
)
)
'
• A)=)active"protein"""
• B)=)binding"protein"""
Mechanism"of"action)
• B"binds"and"releases)A)into)the)cell"or)
• A"and"B"ingested"via"endocytosis)
• A"binds"to"regulator"protein"and"
changes"response")
)
Superantigens) • able"to"create)massive)immune)response"""
• Class"of"antigens"which"cause"nonO
specific"activation"of"TOcells"resulting"
in:"
"polyclonal"T"cell"activation"and"
"massive"cytokine"release"""
"
Rare)strains)of)Staphylococcus)aureus)produce)TSSFtoxin)(toxic)shock)syndrome)))
"
Bacterial"Endotoxins"(their"target"and"effect)"
"
" "
Key"feature"of"GramDpositive)bacteria:"• Thick)peptidoglycan"layer,"LTA,)TA)� )less"
endotoxic"than"LPS"
Key"feature"of"GramDnegative)bacteria:"• LPS)layer)� )lipid"based"toxin"that"causes"fever,"septic"shock"
+"greater"inflammatory"response"
)Inflammatory"Action"of"Endotoxins""
!! )
Be#able#to#describe#examples#of#infection#caused#by:## Staphylococcus#aureus#(pyogenic*skin*infection)# Chlamydia#trachomatis#(intracellular*dependent)# Mycobacterium#tuberculosis#(chronic*inflammatory*respiratory*infection)#
Characteristics# • Gram#+ve#• Clustered*Cocci**
• <0.45μm!
• Small*genome*(has*RNA*+*DNA)*BUT#has*prokaryotic*ribosomes!
• Gram#–ve!
• Obligate*intracellular*parasite*(needs*host)!
• Cell*wall*=*No*peptidoglycan*and*muramic*acid!
• Aerobe!
• Fastidious!
• Slow*growing!
• Gram#+ve#
• HIGH#INCIDENCE#(1/3#infected#worldwide)#due*to:*o HIV*epidemic**(AIDS*infection*with*atypical*strains)*o Antibiotic*resistance#*
Transmission# Direct*contact*or*inoculation* Intimate*direct*contact*+*STI* Aerosol*
Symptoms# • Red*pimply,**• Pus*and*red*boils*
• Scalded*skin*
*
MALES# FEMALES#
• Pain*urinating*
• Inflammation**
• Discharge***
• Slight*discharge*–*80%*asymptomatic***
• Inflammation*of*cervix***
• Burning*urinating****
• Bad*chronic*cough**�*Coughing*up*blood/sputum*
• Chest*pain***
• No*appetite*�*massive*weight*loss***
• Chills**• Fever*
Pathogenesis# *
Cell#wall#component# Effect#
Capsule# Provides*adhesion*and*hides*antigenic*sites*
Protein#A# AntiPphagocytic*(stop*ingestion*by*macrophage)*
Peptidoglycan# AntiPphagocytic*+*stimulates*endotoxic*shock*
Technoic#acid# Allows*invasion*and*mucosal*attachment*
*
**
• Unique#metabolism*–*synthesise*own*proteins,*nucleic*acids*and*lipids*BUT#needs#host#to#obtain#ATP*
• BINDS#TO#MUCOSA#→#Causes*scarring*that*blocks*fallopian#tubes,*urethra#or#vas#deferens**
• Can*reach*ovary*
*• Infection*spreads*W*salpingitis*PID*
• RESULT:*→*infertility**
• Waxy#(mycolic!acid)#lipids#→#resistant#to#disinfectants*(acid*fast*stain)*
• NO#TOXIN#PRODUCED#1. Enters*URT*in*small*aerosol*droplets**
2. Bypasses*ciliated*mucosa**3. Ingested*by*macrophages**and*replicates*intracellularly*4. Kills*phagocytes*to*stimulate*the*immune*response*to*recruit*more*
phagocytes*and*immune*cells*=*TUBERCLE#FORMATION*(casseous*necrosis*traps*TB*by*surrounding*it*with*macrophages*and*T*cells*to*seal*offWcalcify)*→*possible*dissemination**
• Preferential*uptake*by*complement*and*mannose*receptor*–*inhibits*uptake*by*Fc*receptor***
• Inhibits*phagosome/lysosome*fusion*****
• Th1*cells*secrete*IFNW γ*+***Macrophage*secrete*TNF*[OPTIMUM#activation#OF#MACROPHAGES#→#release#ROS,#enzymes#to#kill]**
o Consistent*activation*leads*to*granuloma***
Enzymes:!# *
βPlactamase## inactivates*Penicillin*
Catalase## Breaks*down*reactive*oxidative*species*(H2O2)*in*phagocytosis**
Coagulase##Host*fibrinogen*→*fibrin*→*coating*on*Staph.*→*cells*clumping*(antiWphagocytic)*
*
Toxin# *
Enterotoxins## GIT,*cause*food*poisoning**
Cytotoxic#haemolysins##
• α:!erythrocytes,!skin!!
• β:!erythrocytes,!sphingomyelin!!
• δ!&!γ:!erythrocytes**
Leukocidins##
• Kill*PMNs*• Inhibit*phagocytosis*by*
granulocytes*→*cell*death*and*pus*formation*(necrotic*PMNs)*
• Release*of*granule*contents*from*lysed*PMNs*�*tissue*necrosis*and*inflammation*
Exfoliative#toxins#A#&#B## Surface*layers*of*skin;*shedding**
Toxic#shock#syndrome## Systemic*effects*→*fever*+*shock**
*
*
!Infective!elementary!bodies!(black!full!arrows)!and!large!reproducing!reticulate!bodies!(white!arrows)!
*
*2*types*of*TB*infections***
Latent*(Controlled)*
• Activated*macrophages*kill*TB***
• Tubercles*calcify*=*granuloma*→Bacteria*survive*inside*walled*off*lesions*in*lungs*and*other*sites*
• No*symptoms*and*not*contagious***
• Can*be*reactivated*though**(≈*20*years*later)*
Diseased/Active#(Uncontrolled)*
• Insufficient#immune#response###
• Centre*of*tubercles*liquefy##*
• Bacteria*coughed*up*in*sputum**
• Dissemination*to*organs*via*blood**
• 50%*mortality*rate***
• Identify#in#sputum#sample**o Stain:*Acid*fast*rod*in*smear**
o Culture*in*Lowenstein*Jensen*medium*[SLOW]*�*dry*waxy*appearance*to*confirm*
o Molecular*techniques*=*PCR*(QUICK)**
• Chest#xPray**(Faster)*
• Tuberculin#(Mantoux)#test#
o Inoculate*tuberculoW*protein*PPD*into*intradermal*skin*�*stimulate*cellWmediated*hypersensitivity*
o Detects*latent/active*TB*or*successful*BCG*vaccination*
o –ve!result!=!no!skin!reaction!post!2!days!�!i.e.!never!infected!(false!+ve!with!TB!meningitis)!
Control# • Personal*hygiene*• Prevent*direct*contact*with*infected*
• Abstinence***• Wearing*protection***
• Communication***
• Limit*transmission*(i.e.*prevent*close#contact)*• Improve*living*conditions***
• BCG#(Bacille#CalmettePGuérin)#vaccines*–*initiates*cell*mediated*response*to*induce*memory*T*cell*protection*
Treatment# Antibiotics*(not*resistance)* Susceptible*to*many*Antibiotics* • >2*drugs*given*together*to*minimize*antibiotic*resistance*–*Isoniazid,!rifampicin,!pyrazinamide!ethambutol*BUT#poor#compliance#by#users*
Describe%the%type%of%vaccines%currently%in%use%%%!
Vaccine%Type% Killed%Inactivated%Vaccines& Live%Attenuated%Vaccines&
Method%of%action& • Micro-organisms&killed&by&physical&or&chemical&inactivation&(formaldehyde)&
• Eliminate&infectivity&without&affecting&antigenicity&
• Micro-organisms&lose&pathogenicity&BUT&still&capable&of&transient&growth&in&host&
• Extensive&culture&in&“abnormal”&media&�&causes&random&or&specific&mutations&to&accumulate&
Example% Salk%Polio%vaccine%(Inactivated&poliomyelitis(IPV))&�&poliovirus&type&1,&type&2&and&type&3;&monkey&kidney&cells&
Obtained&via&inactivation&with&formaldehyde&
Sabin%polio%vaccine:&passage&of&virus&through&monkey&kidney&cells&(e.g.&57&independent&mutations&in&Sabin&1&strain)&&
Disease%treated% Cholera,&HepA. Measles,&mumps,&rubella,&BCG.
Advantages& • Safe%from%reversion&to&virulence&
• Acceptable&for&immuno-compromised&individuals&&
• Stable&for&transport&and&storage&
• Authentic%immune%response%elicited%
• Long-term&protective&immunity&(replicate)&• ONLY&single-dose&(no&adjuvants)&
• Transfer&non-immune&contacts&&
Disadvantages& • Less%effective%than%live%vaccines&(which&provide&cell-mediated&I.R)&
• Multiple%doses&required&&
• Needs&adjuvants&to&enhance&responses&
• Possible%reversion&back&into&virulent&form&(e.g.&1&in&4&mill&for&Sabin)&
• Complications&similar&to&natural&disease&&
• Growth&media/culture&cells&produce&adverse&reactions&
• Limited&shelf&life;&refrigeration&in&tropics&
%
&&
!CASE&STUDY:&Attenuated%vs%Inactivated%vaccines:&Polio:&major&killer&in&1950s&
1954% Salk%vaccine&(inactivated&poliovirus)&
Injected&(SAFE)& • High&levels&circulating&IgG,&little&mucosal&immunity&
• BUT:&did¬&stop&virus&spread&in&GI&
1961% Sabin&vaccine&(attenuated&poliovirus)&
Oral& • Stimulates&high&level&IgA&
• Control&virus&GI&by&limiting&spread&
! !