Medical Microbiology Notes (Year 3 course) PDF

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Medical!Microbiology! ~Date&of&exam~& & & & & & & & & & & & & & & & & & & ! ! ! ! !

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Contents! 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) &

Viral!Pathogenesis:&3& Emerging!&!Re-Emerging!Viruses:&9& Virus!Diagnostics:&15& Innate!Immunity:&19& Viral!Immunomodulation:&26& Respiratory!Viruses:&33& Persistent!DNA!Viruses:&39& Influenza!Pandemics:&48& Hepatitis!Viruses:&58& Antiviral!Drugs:&67& Viral!Vaccines:&72& Mycobacterium:&81& Mycobacterium!Treatment:&91& Pathogenic!E.coli:&101& Shigella!Pathogenesis:&117& Pseudomonas&aeruginosa:&126& &

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Lecture!1:!Viral!Pathogenesis!! ! Viral!Classifications!! Order:!-virales! Family:,-viridae!! Subfamily:,-virinae! Genus:,-virus! ! Increasingly!taxonomy!is!sequence!based!using!sophisticated!algorithms!to!produce!molecular! phylogenetic!trees.! !

Recent!Outbreaks! 1) MERS,coronavirus!in!2012.!This!affected!the!UK,,France,,Italy,and,Saudi,Arabia,!along!with! introduced!and!imported!cases!in!Germany!and!Tunisia.!! ! 2) Avian!influenza!viruses!often!cross!from!ducks!to!poultry,!but!come!to!attention!when!they! become!highly!pathogenic!in!chickens!(where!it!becomes!known!as!highly,pathogenic,avian, influenza,,HPAI).!Most!avian!flus!however!remain!apathogenic!for!humans.! ! H7N9, H5N1, China! ! Apathogenic!in!poultry! Pathogenic!in!poultry! Pathogenic!in!humans! Pathogenic!in!humans! Limited!human-human!transmission! Incapable!of!human-human!transmission! !!

Viral!Pathogenesis! Pathogenesis:!A!qualitative!description!of!disease,!or!the!process!by!which!viruses!cause!disease.! ! Viruses!may!be!described!in!terms!of!mortality,!morbidity,!temperature!change,!weight!loss!and! affect!on!tissue!or!biochemical!function.!Only,related,viruses,,such,as,wild-type,and,mutants,! should,be,compared!meaning!that!saying!‘Ebola!is!more!virulent!than!measles’!is!technically! incorrect.!Viral!pathogenesis!is!primarily,about,interactions,of,the,virus,with,the,whole,organism,! but!is!dependent,on,viral,life,cycles!and!evolves,as,a,consequence,of,virus,epidemiology!(the! interaction!of!viruses!with!host!populations).!This!is!all!complicated!by!the!‘virus,quasispecies’! concept.! !

Viral,Life,Cycle,and,its,Influence,on,Viral,Pathogenesis, Like!us,!the!virus!is!measured!not!so!much!by!its!ability,to,sire,offspring,as,by,its,ability,to, produce,‘grandchildren’,!often!described!as!its!fitness.!Routes!of!transmission!therefore!have! major!influence!on!pathogenesis. ! ! ! ! ! !

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! ! Important,steps,in,virus,life,cycle,that,shape,pathogenesis:, • Transmission:!From!primary!to!secondary!case.! • Entry:!Via!various!routes!into!the!body!and!then!into!susceptible!cells.! • Local,replication:!In!susceptible!cells,!possibly!with!spread!to!different!cell!types.!They!must! cope!with!the!host’s!innate!responses!typically!by!avoidance!or!modulation.!!! • Dissemination:!Via!blood!(including!within!cells),!lymphatics!or!nerves.!! • Secondary,replication:!In!susceptible!cells.! • Shedding:!In!fluids,!cells,!aerosols,!skin!or!excrement.! • Transmission:!From!secondary!to!tertiary!case.! !

Virulence! Virulence:!A!quantitative,!but!non-scalar!(relative)!measure!of!the!extent!of!disease!caused!by!the! virus.!This!is!the!capacity!of!a!virus!to!produce!disease!and!is!determined!by!both!host!and!viral! factors.,! !

Host,Factors, • • • •

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Species., Genetic!factors.&For!example!the!Mx!allele!determines!resistance!of!mice!to!influenza.! Age., Immune,status,specific!to!the!pathogen.!This!includes!naïve!(not!immune),!partially!immune! (infected!with!a!similar!virus,!or!infected!a!long!time!ago),!immune!(cannot!be!infected)!and! tolerant!(can!become!infected,!but!are!not!affected,!usually!due!to!exposure!to!the!virus!in!the! womb).! Overall!immuno-competence.!Immunosuppression!by!organ!transplantation,!pregnancy!or!coinfection!(for!example!HIV!and!measles)!can!make!a!host!most!susceptible!to!viral!infection.!

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Virus,Factors, • •

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Strain!and!dose.! Routes!of!shedding,,transmission,and,entry,!including!zoonotic!agents!and! xenotransplantation!(transplantation!between!different!species.!This!is!complicated!by!EVEs! and!ERVs).! Within-host,replication!and!spread.! Tissue!and!cell!tropism.! Cell,injury,and/or,disruption!of!other!aspects!of!host!function.! Virus!‘life-style’,strategy.!An!important!part!of!this!is!persistence:!acute!versus!chronic!and! latent!or!recurrent.!

! All!of!these!are!influenced,by,viral,genetics,!virulence!determinants!and!immuno-modulators.! !

Transmission:!Routes!of!Viral!Spread! Human,to,Human, •

Normal!routes!include:!the!skin!(HSV,!HPV!and!molluscum!contagiosum);!conjunctiva,!the! mucus!membrane!that!covers!the!eye,!and!respiratory,aerosols!(adenovirus,!influenza,! measles,!rhinovirus!and!VZV);!saliva!(EBV!and!CMV);!blood!(HBV);!urine,and,faeces!(norovirus,! enterovirus!and!rotavirus)!and!sexual,contact!(HIV,!HSV,!HPV,!Zika!and!HBV).!

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Artificial,(iatrogenic),routes,!which!are!infections!caused!by!medical!examinations!or! procedures.!Examples!include:!hypodermic,needles!(HIV,!HBV!and!HCV)!and!medical,devices, and,transplants!(including!blood!transfusions!like!CMV).! Mother,to,baby.!This!is!also!known!as!vertical,transmission!and!includes!rubella,!CMV!and! parvovirus!B19.!Intra-partum,(during,labour),and,post-partum,(after,birth)!can!also!transmit! viruses!in!blood,and,milk.!Examples!include!HIV!and!HSV.!

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Other,Vertebrate,to,Human, Other!vertebrates!may!transmit!viruses!by!bites!(saliva;!rabies),!urine!(hanta!virus),!faeces,and, blood,(ebola!virus).!Transmission!by!xenotransplantation!is!also!thought!to!be!possible!with!the! porcine!viruses.! !

Arthropod,Vector,to,Human, Arthropods,!such!as!insects!and!crustaceans,!can!transmit!viruses!by!bites!only!(saliva,!yellow! fever!virus,!dengue!virus,!West!Nile!virus!and!Japanese!encephalitis!virus).! !

Virus,Spread,from,Non-Human,Sources, Zoonotic,virus,infections,spread,from,animals,to,humans,,with,or,without,the,action,of,vectors.!! They!frequently!cause!little,or,no,harm,to,the,normal,host!species,!but!can!have!high,mortality, rate,in,humans.!This!is!thought!to!be!due!to!lack,of,evolutionary,pressure,for,co-adaptation!of! the!human!and!virus.!It!has!implications!for!the!emergence!of!new!pandemic!viruses!and!for!our! understanding!of!virus/host!co-evolution.! !

Important,Zoonotic,Virus,Infections, A!dead-end,infection,is,an,infected,host,that,does,not,typically,allow,for,spread,to,another,host.! Severe!zoonotic!infections!often!kill!the!host!via!an!uncontrolled!immune!response!(a!cytokine! storm)!because!the!immunomodulators,of,the,virus,no,longer,work.!! ! Dead-end!infections!include!rabies!(which!infects!many!mammals),!Herpesvirus,B!(which!infect! primates)!and!cowpox (which!infect!rodents,!often!via!cats).! ! Viruses!with!potential,to,spread,within,human,populations!include!influenza,A!(found!in!ducks,! chickens!and!pigs),!monkeypox!(found!in!African!squirrels!via!primates),!Arenaviruses!(found'in' rodents),!Filoviruses!(probably)found)in)bats)and)spread)to)humans)via)primates,)but)this)is) debated),(Nipah/Hendra,viruses!(found!in!fruit!bats),!SARS,and,MERs,coronavirus!(found'in'bats! via!civet!cats,!and!camels)!and!Arboviruses!(spread(via!arthropod!vectors.!Yellow!fever!and! Dengue!are!included!in!this!grouping).! !

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Within-Host!Factors!Affecting!Pathogenesis! Localised,vs.,Systemic,Replication, Localised,infections,are,restricted,to,site,of,entry,such!as!skin!(papillomaviruses!and!molluscum! contagiosum!poxvirus),!respiratory!mucosa!(parainfluenzavirus,!rhinovirus!and!coronavirus),! gastrointestinal!mucosa!(rotavirus),!genital!mucosa!(papillomaviruses).! ! Systemic,infections,require,dissemination,via,blood!and!include!measles,!varicella!zoster!virus! (VZV,!chicken!pox/shingles),!rubella!(German!measles),!yellow!fever,!variola!virus!(smallpox),! poliovirus,!human!cytomegalovirus,!Epstein-Barr!virus!and!HIV.! ! ! !

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Systematic!infections!can!also!be!spread!via,the,nervous,system,,but,this,is,rare!and!has! pathological!consequences.!Examples!of!this!include!the!Zika,!rabies!virus,!herpes!simplex!virus!1! (HSV-1),!VZV,!poliovirus!and!the!measles!virus., !

Molecular!Basis!of!Tropism! Virus!tropism!refers!to!a!virus’s!preferential!replication!in!particular!cell!types.!The!destruction!or! alteration!of!particular!cell!populations!is!a!major!determinant,of,virus,pathogenesis.!Tropism!is! often!governed!by!the!use!of!particular!cell!surface!receptors!(different!receptors!are!often!used! for!processes!of!attachment!and!membrane,fusion!or!penetration)!and!by!the!distribution!of! those!receptors!between!different!cell!types.!However,!there!is!more!to!virulence!than!receptor! recognition.!For!example,!another!coronavirus!also!recognises!the!ACE2!receptor,!but!is!no!where! near!a!virulent!as!SARS.! ! ! ! ! ! ! ! ! ! ! However,!factors!other!than!receptor!usage!may!influence!a!virus’s!tropism.!This!can!be!achieved! by!tissue,or,cell,type-specific,transcription,factors.!For!example,!the!JC,papovavirus,enhancer!is! active,only,in,glial,cells,!retroviral!promoters!can!also!have!strong!cell!type!specificity!and!the! HCMV,major,IE,gene,enhancer,is,differentiation,dependent,in,myeloid,cells.!Tropism!is!also! achieved!by!tissue,or,cell,type-specific,translation,factors.!For!example,!Poliovirus!translation!in! motor!neurons!is!dependent!on!host!factors.! ! Some!viruses!also!have!the!ability!to,control,host,interferon,response.!Many!viruses!are!now! known!to!regulate!type!I!interferon!induction,!signalling!and!effectors,!as!well!as!other!restriction! mechanisms!(HIV!vif!modulates!APOBEC3G)!some!of!which,may,be,tissue/cell,specific.! !

Viruses!and!Disease! Viruses!cause!disease!by!several!mechanisms.!Firstly,!the!virus,itself,may,cause,damage!by! destruction!of!host!cells,!interference!with!the!differentiated!functions!of!host!cells!or!virusinduced!transformation!of!host!cells.!Viruses!may!also!cause!damage,by,activation,of,the,host, immune,system,,which,is,known,as,immuno-pathological,damage.!The!mechanism!behind!this!is! that!the!immune!system!can!mediate!destruction!of!host!cells,!which!is!mediated!by!directly! antiviral!immune!response!against!virus-infected!cells!or!uninfected!bystanders.!This!can! sometimes!invoke!a!cytokine,storm,!causing!severe!inflammation.!! !!

Tissue,Destruction,, • •

Necrosis:!Resulting!from!virus!replication!or!attack!by!immune!cells!! Apoptosis:!Induced!by!the!virus!or!the!host!(by!signalling!within!the!infected!cell!or!by!immune! cells,!for!example!via!Fas!ligand),!but!only!where!the!virus!fails!to!inhibit!its!induction.!Many! viruses!encode!proteins!that!inhibit!apoptosis,!especially!viruses!causing!persistent!or!latent! infections,!such!as!HSV-1!(ICP34.5),!EBV!LMP!(induces!bcl-2!expression),!adenovirus!(E1B!19kD!

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protein).!However!viruses!causing!acute!infection,!such!as!poxviruses!(vaccinia!crmA),!can!also! inhibit!apoptosis.!! Cell-cell,fusion:!Some!viruses!induce!formation!of!multinucleate!syncitia!by!the!action!of!virus! envelope!fusion!proteins.!This!is!often!seen!with!enveloped!protein!that!can!fuse!with!host! cells!via!glycoproteins!on!their!surface.!When!these!are!expressed!on!the!host!cell!before!viral! budding!it!can!cause!host!cells!to!fuse!together!and!form!syncita.!

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Loss,or,Alteration,of,Function! • • •

Cell,cycle,dysfunction,!such!as!rubella!virus!that!causes!congenital!defects.! Metabolic,dysfunction,!such!as!viral!hepatitis.! Immune,dysfunction.!Many!viruses,!including!measles!and!large!DNA!viruses!(poxviruses!and! herpesviruses),!may!cause!infection!of!immune!cells!or!by!release!of!soluble! immunomodulators.! Oncogenesis,!such!as!human!papillomavirus,!Epstein-Barr!virus!and!HTLV-1.! Undefined,dystunction,,such!as!Zika!

• • ! Immunopathological!damage!can!be!mediated!by!the!host!antiviral!immune!response.!For! example!in!innate,immunity,,IL-1,can,cause,a,fever,and,IFNs,can,cause,flu,like,symptoms.! Alteration!of!antibodies,can,cause,immune,complex,disease!and!alteration!of!T-cells,can,cause, lymphocytic,choriomeningitis,,influenza,pneumonia,and,the,measles,rash.! ,

Viral!Lifecycle!Stratergies! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

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Viral,Persistence, Viral!persistence!has!advantages!for!the!virus,!such!as!buying,time,to,find,a,new,(näive),host.! However,!there!are!also!consequences,for,the,host,!such!as!causing!long-term!tissue! damage/chronic,disease!(HBV,!HCV,!Measles!(which!can!hide!in!neural!tissues!and!reactivate!later! in!life!and!cause!SSPE)),!recurrent!disease!(HSV,!VZV)!or!cause!disease!upon!immunosuppression! (HCMV!and!other!herpesviruses).!HIV-1!also!causes!immunodeficiency!and!other!viruses!(HPV,! HBV,!HCV,!EBV,!HTLV-1)!can!cause!cellular!transformation,and,oncogenesis.!! ! ! ! 7 !

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Virus-Induced,Transformation,of,Host,Cells, • • • • • • !

Retroviruses:!Murine!leukemia!viruses!and!human!T!lymphotropic!virus!(HTLV-1)!are!both! associated!with!adult!T!cell!leukemia! Adenoviruses:!Many!types,!associated!with!various!solid!tumors! Papillomaviruses:!HPV!16!and!18!associated!with!human!cervical!carcinoma,!while!others! cause!warts! Polyomaviruses:!SV40,!JC!virus! Hepadnaviruses:!HBV!persistence!is!associated!with!hepatocellular!carcinoma! Herpesviruses:!EBV!is!associated!with!Burkitt’s!lymphoma!and!nasopharyngeal!carcinoma!

Poxviruses! A!‘virulent’,poxvirus,example,is,Smallpox.!The!last!natural!case!was!reported!in!Somalia!in! October!1977,!although!people!have!died!since!then!due!to!lab!accidents.! An!‘attenuated’,poxvirus,example,is,Vaccinia.!Vaccinia!is!still!infectious!but!shows!reduced! virulence,!typically!showing!symptoms!no!more!severe!than!a!fever!and!rash.!It!can!protect!against! smallpox!infection!and!so!can!be!used!as!a!vaccine.!An!‘avirulent’,poxvirus,example,is,Molluscum, contagiosum,!which!produces!self-healing!wart!like!lumps!on!the!body!and!are!otherwise! asymptomatic.!! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

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Lecture!2:!Emerging!&!Re-Emerging!Viruses! ! New!Viral!Infections! New!viral!infections!often!come!from!the!discovery!of!pre-circulating,viruses,and,rapid,,extensive, virus,‘evolution’,along,with,a,species,jump.!Many!so!called!‘emerging!viruses’!are!somewhat!misnamed!because!they!are!already!circulating!in!the!target!species!as!endemic!or!epidemic! infections,!but!are!undetected!because!they!leave!no!distinct!epidemiological!clues!as!to!their! presence!or!cannot!be!propagated!or!isolated!(SARS).!They!would!be!better,classified,as,‘newlydetected’,viruses!and!so!detection!of!such!viruses!is!often!technology!driven!(Hepatitis!C!virus,! Coronavirus!NL-64,!Bocavirus,!Human!metapneumovirus,!Wu!polyomavirus!were!all!detected!by! genetic!sequencing).!Their!number,will,increase,with,wider,use,of,array,technologies,and,‘deep’, sequencing,of,samples!(novel!clade!(X)!of!Human!Rhinovirus.!This!virus!was!always!present!but!it! wasn’t!able!to!be!propagated!in!HaLa!Ohio!cell!cultures,!which!allow!growth!at!colder! temperatures,!unlike!other!Rhinoviruses.!This!meant!for!a!long!time!it!couldn’t!be!detected).! !

Newly,Evolved,Emerging,Viruses, These!are!new,viruses,that,have,recently,emerged,by, mutation!(seasonal!influenza)!or!recombination!(inter-typic! or!non-comparable!influenza;!H5N1,!H1N1,!H7N9).!H7N9,is,a, novel,virus,created,by,the,reassortment,of,avian,H7N?,, H?N9,and,H9N2,leading!to!H7N9!containing!envelope! proteins!from!H7N?!and!H?N9!and!the!genome!of!H9N2! (besides!the!NA!and!HA!genes).!They!can!even!emerge,by, recombination,with,ERVs,and,EVEs,in,the,host,genome.! Some!veterinary!examples!include!feline!leukaemia!virus!B! and!avian!leukosis!virus-J,!both!of!which!contain!a!virus-host! endogenous!provirus.! !

Newly,Emerging,Zoonitic,Viruses, Viruses!can!also!begin!to!infect!humans!when!they! become,transmissible,from,an,animal,reservoir!infecting! humans.!This!is!rare,!but!has!been!seen!with!H1N1!and! West!Nile.!This!type!of!jump!frequently,involves, mutations,to,overcome,‘host-range,restrictions’!and!is! often!a!prerequisite,for,sustained,human-human, transmission.!H5N1,,MERS-CoV,and,H7N9,are,a,few, examples,of,viruses,that,could,cause,a,pandemic,if!these! restrictions!can!be!overcome.!There!are!five!stages!of! zoonotic!viral!infections!from!the!virus,only,being,present, in,the,animal,reservoir!(1,!rabies),!to!spreading,to, humans!(2-4),!until!the!virus,evolves,to,become,a,human,specific!virus!(5,!HIV).!Ebola!is!now! capable!of!human-to-human!transmission!and!has!progressed!to!Stage!4!after!the!2014!outbreak.! ! Zoonotic,infections,make,up,around,58%,of,human,pathogens!(viruses!15%)!and!73%,of, emerging,pathogens!(viruses!43%).!Important!examples!of!zoonotic!viruses!include!Ebola,! Marburg,!Coronaviruses!(SARS),!Influenza!and!retroviruses.! ! !

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Multiple,Emergent,Events, Simian,immunodeficiency,virus,from,chimpanzees!(SIVcpz)! emerged!at!least!three,times,to,produce,HIV,(groups,M,,N,and,O)! in!humans.!The!multiple!emergence!of!HIV!from!SIVcpz,!which! required!overcoming!host!restriction!factors,!was!probably!due!to! hunting,and,bushmeat-trade.!The!source!species!is!suspected!to! be!Pan$troglodytes$troglodytes&and!not&Pan&troglodytes& schweinfurthii.&All!clades!of!HIV1!evolved!at!similar!times,!perhaps! due!to!an!increased!demand!for!bush!meat!pushing!hunters!further! ! in!the!jungle.! ! Several!factors!were!involved!in!the!emergence!of!HIV!such!as! changes,in,human,demographics,!for!example!an!increased!market! for!bush!meat!and!increased!human!migration.!There!is!also!a! range!of!pathotypes!(disease!causing!variants)!meaning!that!there!is!variability,in,the,ability,to, adapt,to,humans.!HIV!also!has!a!persistent,phenotype!and!this!long!latency!increases! transmission!and!permits!high!mortality.!HIV!is!predicted!to!be!a!100-year!epidemic!due!to!the! human!rate!of!reproduction.!! !

Why!do!Viruses!Re-Emerge?! There!are!several!conditions!for!that!need!to!be!met!from!emerging!viruses.!Firstly!there!must!be! environmental,changes,!such!as!climate!change!affecting!vector!distribution!or!usage,!altered! farming!practise!or!ecological!changes,!such!as!species!introductions!or!predator!loss.!There!must! also!be!a!larger,susceptible,population.!This!can!be!achieved!by!loss!of!cross-protective!immunity! (loss!of!wild!virus!or!cessation!of!vaccination)!or!population!growth!by!influx!of!new!and!naive! population,!birth!of!naïve!population!or!predator!loss.! , 1) Changes!in!land,use,or,agricultural!practices! 2) Changes!in!human,demographics!and!society! ! 3) Poor!population,health!(HIV,!malnutrition)! 4) Hospitals,and!medical!procedures! 5) Pathogenic,evolution!(resistance!to!host!immunity!or!vaccine!immunity,!altered!host!and! vector!range!or!tropism).! 6) Contamination!of!food!or!water!supplies! 7) International!travel! 8) Failure,of,public,health!programs! 9) International!trade! 10) Climate,change, !

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Limits!to!Emerging!Viruses! Receptor,specificity,,innate,immunity,,natural,antibodies,and,cross,protection!from!other!viral! infection!can!all!act,to,limit,the,spread,of,an,emerging,virus.!Some!examples!of!cross!protection! include!smallpox/vaccinia!protecting!from!monkeypox,!measles!infection/vaccine!protecting!from! canine!distemper!virus!and!poliovirus!infection/vaccine!may!protect!against!other!enteroviruses.! ! ! This!cross!protection!is!important!because!if,!for!example,!the!measles,vaccination,were,stopped, after,eradication,it,might,mean,that,canine,distemper,virus,would,evolve,into,a,human, pathogen?! !

Emerging!Viruses!and!Virulence! Emerging!viruses!are!frequently,highly,virulent.!This!is!due!to!the!lack!of!adapt...