بسم الله الرحمن الرحيمبسم الله الرحمن الرحيم

Islamic university of GazaIslamic university of GazaFaculty Of MedicineFaculty Of Medicine

Medical MicrobiologyMedical MicrobiologyPathogenesisPathogenesis

Prepeared by / Prepeared by / Fadi Al- AidiFadi Al- Aidi

NO. / 120061550NO. / 120061550

PathogenesisPathogenesis

The ability of viruses to cause disease can The ability of viruses to cause disease can be viewed onbe viewed on two distinct levelstwo distinct levels : :

((11 ) )the changes that occur withinthe changes that occur within individual individual cellscells..

((22 ) )the process that takes place inthe process that takes place in the the infected patientinfected patient . .

THE INFECTED CELLTHE INFECTED CELL There are There are fourfour main effects of virus infection on the cell main effects of virus infection on the cell: :

((II ) )deathdeath..((22 ) )fusion of cells to form multinucleated cellsfusion of cells to form multinucleated cells..

((33 ) )malignant transformationmalignant transformation..

((44 ) )no apparent morphologic or functional changeno apparent morphologic or functional change . .

A- Death of the cell is probably due to inhibition of macromolecular synthesis. A- Death of the cell is probably due to inhibition of macromolecular synthesis. Inhibition of host cell protein synthesisInhibition of host cell protein synthesis frequently occurs first and is probably frequently occurs first and is probably the most important effect. Inhibition of DNA and RNA synthesis may be a the most important effect. Inhibition of DNA and RNA synthesis may be a secondary effectsecondary effect. It is important to note that. It is important to note that synthesis of cellular proteins is synthesis of cellular proteins is inhibited but inhibited but viral protein synthesis still occursviral protein synthesis still occurs..For example, poliovirus inactivatesFor example, poliovirus inactivates an an initiation factor )IF(initiation factor )IF( required for cellular required for cellular

mRNA to be translated into cellular proteins, but poliovirus mRNA has a special mRNA to be translated into cellular proteins, but poliovirus mRNA has a special ribosome-initiating site that allows it toribosome-initiating site that allows it to pass the IF so that viral proteins can pass the IF so that viral proteins can

be synthesizedbe synthesized. . ..

- -Infected cells frequently contain Infected cells frequently contain inclusion bodiesinclusion bodies , ,which are discrete areas containing which are discrete areas containing viral proteins or viralviral proteins or viral particlesparticles. They have a characteristic . They have a characteristic intranuclear intranuclear or or intracytoplasmic intracytoplasmic location and appearance dependinglocation and appearance depending on the viruson the virus..

- -One of the best examples of inclusion bodies that can One of the best examples of inclusion bodies that can assist in clinical diagnosis is that of assist in clinical diagnosis is that of NegriNegri bodiesbodies, which , which are eosinophilic are eosinophilic cytoplasmiccytoplasmic inclusions found in inclusions found in rabies rabies virus-infected brain neuronsvirus-infected brain neurons..

- -An other important example is the An other important example is the owl's eye inclusionowl's eye inclusion seenseen in the in the nucleus of cytomegalovirus-infected cellsnucleus of cytomegalovirus-infected cells..

B- Fusion of virus-infected cells produces B- Fusion of virus-infected cells produces multinucleatedmultinucleated giant cellsgiant cells, which characteristically form after, which characteristically form after

infection withinfection with herpesviruses herpesviruses and and paramyxovirusesparamyxoviruses . .

Micrograph with numerous rabies virions (small dark grey rod-like particles) and Negri bodies, larger pathogenomic cellular inclusions of rabies infection.

--The clinical diagnosis of The clinical diagnosis of herpesvirus skin infectionsherpesvirus skin infections is is aidedaided

by the finding of by the finding of multinucleatedmultinucleated giant cellsgiant cells with eosinophilic with eosinophilic intranuclear inclusionsintranuclear inclusions in skin scrapings in skin scrapings . .

--A hallmark of viral infection of the cell is the A hallmark of viral infection of the cell is the cytopathiccytopathic effect )CPE(.effect )CPE(. This change in the appearance of the This change in the appearance of the infected cell usually culminates in either infected cell usually culminates in either lysis lysis or or giant cell giant cell

formationformation . .

--Detection of virus in a clinical specimen frequently is Detection of virus in a clinical specimen frequently is based on the appearance of CPE in cell culturebased on the appearance of CPE in cell culture . .

C -Infection with certain viruses causes C -Infection with certain viruses causes malignantmalignant transformation,transformation, which is characterized by unrestrained which is characterized by unrestrained growth, prolonged survival, and morphologic changesgrowth, prolonged survival, and morphologic changes . .

D - Infection of the cell accompanied by virus productionD - Infection of the cell accompanied by virus productioncan occur can occur withoutwithout morphologic or gross functional changes morphologic or gross functional changes . .

--This observation highlights the This observation highlights the wide wide variations in the variations in the nature of the interaction between the virus and the cell, nature of the interaction between the virus and the cell, ranging fromranging from rapid destruction of the cell to a symbiotic rapid destruction of the cell to a symbiotic relationship in which the cell survivesand multiplies relationship in which the cell survivesand multiplies despite the replication of the virusdespite the replication of the virus..

THE INFECTED PATIENTTHE INFECTED PATIENT

Pathogenesis in the infected patient involvesPathogenesis in the infected patient involves ((II ) )transmissiontransmission of the virus and its entry into the host of the virus and its entry into the host

((22 ) )replication replication of the virus and damage to cellsof the virus and damage to cells..

( ( 33 ) )spreadspread of the virus to other cells and organs of the virus to other cells and organs . .

((44 ) )the the immuneimmune response response..

((55 ) )persistencepersistence of the virus in of the virus in some some instancesinstances . .

--The The stagesstages of a typical viral infection are of a typical viral infection are-: -:

an an incubation periodincubation period during which the patient during which the patient

is asymptomatic, a is asymptomatic, a prodromal periodprodromal period during which during which

nonspecific symptoms occur, a nonspecific symptoms occur, a specific-illness specific-illness periodperiod during which the characteristic symptoms during which the characteristic symptoms and signs occure and a and signs occure and a recovery periodrecovery period during during which the illness wanes and the patient regains which the illness wanes and the patient regains good healthgood health..

In some patients, the In some patients, the infection persistsinfection persists and a and a chronic carrier state or a latent infection occurschronic carrier state or a latent infection occurs..

Transmission & Portal of EntryTransmission & Portal of Entry - -person-to-person spread occurs by transfer of person-to-person spread occurs by transfer of

respiratory secretions, saliva, blood, or semen respiratory secretions, saliva, blood, or semen and by fecal contamination of water or foodand by fecal contamination of water or food . .

--The transfer of The transfer of bloodblood, either by , either by transfusion transfusion or by or by sharing sharing needlesneedles during intravenous drug use, during intravenous drug use,

can transmit various viruses )and bacteria(can transmit various viruses )and bacteria( . .

--Transmission can occur also between mother and offspring in Transmission can occur also between mother and offspring in uteroutero across the placentaacross the placenta, at , at the time of deliverythe time of delivery, or , or during breast feedingduring breast feeding..

--Transmission between mother and offspring is called Transmission between mother and offspring is called verticalvertical transmissiontransmission..

--Person-to-person transmission is called Person-to-person transmission is called horizontal transmissionhorizontal transmission..

- -Animal-to-human transmission can take place eitherAnimal-to-human transmission can take place either directlydirectly from the bite of a reservoir host as in rabies or from the bite of a reservoir host as in rabies or indirectlyindirectly through the bite of an through the bite of an insect vectorinsect vector, such as a, such as a mosquito, which transfers the virus from an animalmosquito, which transfers the virus from an animal reservoir to the personreservoir to the person . .

--In addition, In addition, activation of a latentactivation of a latent, , nonreplicating virusnonreplicating virus to form an active to form an active , ,replicating virus can occur within the individual, withreplicating virus can occur within the individual, with no transmission from an external sourceno transmission from an external source..

Localized or Disseminated Localized or Disseminated InfectionsInfections

--Viral infections are either Viral infections are either localized localized to the portal of entry or spread to the portal of entry or spread systemically systemically through the bodythrough the body . .

--The best example of the localized infection is the The best example of the localized infection is the common coldcommon cold , ,which involves which involves only the upper respiratory tractonly the upper respiratory tract . .

--Influenza is localized primarily to the Influenza is localized primarily to the upper and lowerupper and lower respiratory tractsrespiratory tracts . .

- -One of the best-understood systemic viral infections is One of the best-understood systemic viral infections is paralytic paralytic poliomyelitis.poliomyelitis.After poliovirus is After poliovirus is ingested,ingested, it infects and multiplies it infects and multiplies within the within the cells of the small intestinecells of the small intestine and then spreads and then spreads to the to the mesenteric lymph nodesmesenteric lymph nodes, where it multiplies, where it multiplies again. It then enters the bloodstream and is transmittedagain. It then enters the bloodstream and is transmitted to to certain internal organscertain internal organs, where it multiplies again, where it multiplies again . .

--The virus The virus reenters the bloodstreamreenters the bloodstream and is transmitted and is transmitted to the to the central nervous system,central nervous system, where damage to the where damage to theanterior horn cellsanterior horn cells occurs, resulting in the characteristic occurs, resulting in the characteristic muscle paralysismuscle paralysis . .

--Viral replication in the gastrointestinalViral replication in the gastrointestinal tract results in the tract results in the presence of poliovirus in the fecespresence of poliovirus in the feces , ,thus perpetuating its transmission to othersthus perpetuating its transmission to others . .

- -reovirus hasreovirus has three three different outer capsid proteins. One ofdifferent outer capsid proteins. One of the proteins the proteins binds to specific receptorsbinds to specific receptors on the cell surface on the cell surface

and thereby determines and thereby determines tissue tropismtissue tropism . .

- -A second protein conveys A second protein conveys resistance to proteolytic resistance to proteolytic enzymes in the gastrointestinal tractenzymes in the gastrointestinal tract and acts as the and acts as the

antigen thatantigen that stimulates the cellular immune response stimulates the cellular immune response . .

--The third protein inhibits The third protein inhibits cellular RNA and protein cellular RNA and protein synthesissynthesis, leading to death of the cell, leading to death of the cell . .

This third protein can play a role in the initiation of This third protein can play a role in the initiation of persistent viral infectionpersistent viral infection . .

Pathogenesis & ImmunopathogenesisPathogenesis & Immunopathogenesis

--The signs and symptoms of most viral diseases are the result of The signs and symptoms of most viral diseases are the result of cell cell killingkilling by by virus-induced inhibitionvirus-induced inhibition of macromolecular synthesis of macromolecular synthesis . .

--Death of the virus-infected cells results in a Death of the virus-infected cells results in a loss of functionloss of function and in the and in the symptoms of diseasesymptoms of disease . .

--For example, when For example, when poliovirus kills motor neuronspoliovirus kills motor neurons, , paralysisparalysis of the of the muscles innervated by those neurons resultsmuscles innervated by those neurons results . .

- -Also, the Also, the hemorrhages caused by Ebola virushemorrhages caused by Ebola virus are due to the are due to the damage to the vascular endothelialdamage to the vascular endothelial cells caused by the envelope cells caused by the envelope glycoprotein of the virusglycoprotein of the virus..

--However, there are some diseases that However, there are some diseases that are not caused by the virus are not caused by the virus damaging or killing the infected celldamaging or killing the infected cell.. For example, For example, rotavirus-induced diarrhearotavirus-induced diarrhea is caused primarily is caused primarily by stimulation of the enteric nervous system, resulting in excess fluid by stimulation of the enteric nervous system, resulting in excess fluid and electrolyte secretion into the bowel lumenand electrolyte secretion into the bowel lumen . .

--There are other diseases in which cell There are other diseases in which cell killing bykilling by immunologic attackimmunologic attack plays an important role in plays an important role in pathogenesis. Both pathogenesis. Both cytotoxic T cellscytotoxic T cells and and antibodiesantibodies play play

a role in immunopathogenesisa role in immunopathogenesis . .

((11)) The best-studied system is The best-studied system is lymphocyticlymphocytic choriomeningitis choriomeningitis )LCM( in mice)LCM( in mice; LCM occurs in humans also but is quite ; LCM occurs in humans also but is quite rarerare. When LCM virus is inoculated into the brain of an . When LCM virus is inoculated into the brain of an adult mouseadult mouse, virus replication occurs and , virus replication occurs and deathdeath follows. follows. However, when LCM virus is inoculated into the brain of However, when LCM virus is inoculated into the brain of an an immunosuppressed adult mouse or a newborn immunosuppressed adult mouse or a newborn mouse, the animal remains wellmouse, the animal remains well despite extensive virus despite extensive virus replication. When replication. When immune lymphocytesimmune lymphocytes are inoculated are inoculated into these infected, healthy mice, into these infected, healthy mice, deathdeath ensuesensues . .

--It appears It appears that death of the cells is caused by immune that death of the cells is caused by immune attack by cytotoxic T cellsattack by cytotoxic T cells on the new viral antigens in on the new viral antigens in the cell membrane the cell membrane rather than by virusrather than by virus induced inhibition induced inhibition of cell functionsof cell functions..

((22)) Cytotoxic T cells are involved in the pathogenesisCytotoxic T cells are involved in the pathogenesis of hepatitis caused by hepatitis A, B, and C virusesof hepatitis caused by hepatitis A, B, and C viruses . .

These These viruses do not cause a cytopathic effectviruses do not cause a cytopathic effect, and the, and the damage to the hepatocytes is the result of the recognition of damage to the hepatocytes is the result of the recognition of viral antigens on the hepatocyte surface by viral antigens on the hepatocyte surface by cytotoxic T cytotoxic T cellscells. The . The rash of measlesrash of measles is similarly caused by these cells is similarly caused by these cells

attacking the infected attacking the infected vascular endothelium in the skinvascular endothelium in the skin . .((33)) Immune-mediated pathogenesis also occursImmune-mediated pathogenesis also occurs

when when virus-antibody-complement complexes form andvirus-antibody-complement complexes form and are deposited in various tissuesare deposited in various tissues. This occurs in . This occurs in hepatitishepatitis B virusB virus infection, in which immune complexes play a infection, in which immune complexes play a role in producing the role in producing the arthritis arthritis characteristic of the earlycharacteristic of the early stage of hepatitis B. Immune complexes also cause thestage of hepatitis B. Immune complexes also cause the arthritis seen in arthritis seen in parvovirus B19 and rubella virusparvovirus B19 and rubella virus infections infections . .

- -The pathogenesis of The pathogenesis of pneumoniapneumonia caused by respiratory caused by respiratory syncytial virus in syncytial virus in infants infants is attributed to immuneis attributed to immune complexes formed by complexes formed by maternal IgG and viral antigensmaternal IgG and viral antigens..

VirulenceVirulence --Strains of viruses Strains of viruses differ greatly in their ability differ greatly in their ability

to cause diseaseto cause disease . .

--For example, there are For example, there are strains of poliovirusstrains of poliovirus that have that have mutated mutated sufficiently such that they sufficiently such that they have have lost the ability to cause poliolost the ability to cause polio in in immunocompetent individuals;ie, they are immunocompetent individuals;ie, they are attenuatedattenuated..

- - These strains are These strains are used in vaccinesused in vaccines . .

Evasion of Host DefensesEvasion of Host Defenses Viruses have several ways by which they evade our host Viruses have several ways by which they evade our host defenses. These processes are often called defenses. These processes are often called immune immune evasionevasion. . FirstFirst ,some viruses ,some viruses encode proteinsencode proteins for various for various mediators of immunity such as mediators of immunity such as interleukin-I )IL-1( and interleukin-I )IL-1( and tumor necrosis factor )TNF(.tumor necrosis factor )TNF(. For example, For example, vacciniavacciniavirus encodes a protein that binds to IL-1 and fibromavirus encodes a protein that binds to IL-1 and fibroma

virus encodes a protein that binds to TNF.virus encodes a protein that binds to TNF. When released When released from virus-infected cells, these proteins bind tofrom virus-infected cells, these proteins bind to

the immune mediators and block their ability to interact with the immune mediators and block their ability to interact with receptors on their intended targets, our immune cells receptors on their intended targets, our immune cells

that mediate host defenses against the viral infectionthat mediate host defenses against the viral infection . .By reducing our host defenses, the virulence of the virus is By reducing our host defenses, the virulence of the virus is enhanced.enhanced. These virus-encoded proteins that block host These virus-encoded proteins that block host

immune mediators are often called immune mediators are often called cytokinecytokine decoysdecoys..

--SeconedSeconed, some viruses )eg, HIV, cytomegalo- , some viruses )eg, HIV, cytomegalo- virus( virus( can reduce the expression of class I MHCcan reduce the expression of class I MHC proteins, proteins, thereby reducing the ability of cytotoxic T thereby reducing the ability of cytotoxic T cells to kill the virus-infected cells,cells to kill the virus-infected cells, and others )eg, and others )eg,

herpes sim- plex virus( herpes sim- plex virus( inhibit complementinhibit complement . .

- -MeaslesMeasles virus blocks synthesis of virus blocks synthesis of IL-12IL-12. . - -ThirdThird ,several viruses )HIV, Epstein-Barr virus, ,several viruses )HIV, Epstein-Barr virus,

and adenovirus( and adenovirus( synthesize RNAs that block the synthesize RNAs that block the phosphorylation of an initiation factorphosphorylation of an initiation factor )elF-2(, )elF-2(, which reduces the ability of interferon to block which reduces the ability of interferon to block

viral replicationviral replication. .

--Collectively, these viral virulence factors are called Collectively, these viral virulence factors are called virokinesvirokines..

--FourthFourth, important way by which viruses evade our host , important way by which viruses evade our host defenses is by having defenses is by having multiple antigenic typesmultiple antigenic types )also )also known as known as multiple serotypesmultiple serotypes(. The clinical importance of (. The clinical importance of a virus having multiple serotypes is that a patient can be a virus having multiple serotypes is that a patient can be infected with one serotype, recover, and have antibodies infected with one serotype, recover, and have antibodies that protect from infection by that serotype in the future; that protect from infection by that serotype in the future; however, that person can be infected by another however, that person can be infected by another serotype of that virus. The classic example of a virus with serotype of that virus. The classic example of a virus with multiple serotypes is multiple serotypes is rhinovirusrhinovirus, which has more than , which has more than 100 serotypes100 serotypes. This is the reason why the ". This is the reason why the "common common cold" caused by rhinoviruses is so commoncold" caused by rhinoviruses is so common. . Influenza Influenza virus also has multiple serotypesvirus also has multiple serotypes..

--HIV and hepatitis C virus have multiple serotypesHIV and hepatitis C virus have multiple serotypes, which , which contributes to the difficulty in obtaining a vaccine against contributes to the difficulty in obtaining a vaccine against these virusesthese viruses. Note that only some viruses have multiple . Note that only some viruses have multiple serotypes. Many important human pathogens )such as serotypes. Many important human pathogens )such as measles virus, rubella virus, varicella-zoster virus, and measles virus, rubella virus, varicella-zoster virus, and rabies virus( rabies virus( have only one serotypehave only one serotype, and some have , and some have only a only a few serotypesfew serotypes )eg, poliovirus has three )eg, poliovirus has three serotypes(serotypes(..

Persistent Viral InfectionsPersistent Viral Infections In most viral infections, the virus In most viral infections, the virus does not remain in the bodydoes not remain in the body for a for a significant period after clinical recover However, in certain instances, significant period after clinical recover However, in certain instances, the virus the virus persists for long periodspersists for long periods either intact or in the form of a either intact or in the form of a subviral component, eg, the genome. The mechanisms that maysubviral component, eg, the genome. The mechanisms that may play a role in the persistence of viruses includeplay a role in the persistence of viruses include

((11 ) )integration of a DNA provirus into host cell DNAintegration of a DNA provirus into host cell DNA, as occurs with , as occurs with retrovirusesretroviruses..

((22 ) )immune tolerance, because neutralizing immune tolerance, because neutralizing antibodies are not formedantibodies are not formed..((33 ) )formation of virus-antibody complexesformation of virus-antibody complexes, which remain infectious, which remain infectious..

((44 ) )location within an location within an immunologically shelteredimmunologically sheltered eg, the brain eg, the brain..((55 ) )rapid antigenic variationrapid antigenic variation..

((66 ) )spread from cell to cell spread from cell to cell without an extracellular phasewithout an extracellular phase, so that virus , so that virus is not exposed to antibodyis not exposed to antibody..

((77 ) )immunosuppression, as immunosuppression, as in AIDSin AIDS..

There are There are three typesthree types of persistent viral infections of clinical of persistent viral infections of clinical importance. They are distinguished primarily by whether virus is importance. They are distinguished primarily by whether virus is usually produced by the infected cells and by the timing of the usually produced by the infected cells and by the timing of the appearance both of the virus and of the symptoms of diseaseappearance both of the virus and of the symptoms of disease . .

A. CHRONIC-CARRIER INFECTIONSA. CHRONIC-CARRIER INFECTIONS

Some patients who have been infected with certainSome patients who have been infected with certain viruses continue to viruses continue to produce significant amounts of theproduce significant amounts of the virus for long periodsvirus for long periods. This carrier state can follow an. This carrier state can follow an asymptomatic infection as well as the actual disease andasymptomatic infection as well as the actual disease and can itself either be acan itself either be asymptomatic symptomatic or result in or result in chronicchronic illnessillness . .

Important clinical examples are Important clinical examples are chronic hepatitischronic hepatitis, which , which occurs in hepatitis B and hepatitis C virus carriers, and occurs in hepatitis B and hepatitis C virus carriers, and neonatal rubella virus and cytomegalovirus infectionsneonatal rubella virus and cytomegalovirus infections, ,

in which carriers can produce virus for in which carriers can produce virus for yearsyears . .

B. LATENT INFECTIONSB. LATENT INFECTIONS

In these infections, best illustrated by the In these infections, best illustrated by the herpesvirus herpesvirus groupgroup, the patient recovers from the , the patient recovers from the initial infectioninitial infection and and virus production stopsvirus production stops. Subsequently, the symptoms may . Subsequently, the symptoms may recurrecur, accompanied by the , accompanied by the production of virusproduction of virus. In herpes . In herpes simplex virus infections, the virus enters the latent state simplex virus infections, the virus enters the latent state in the in the cells of the sensory gangliacells of the sensory ganglia. . HerpesHerpes simplex virus simplex virus type 1type 1, which causes infections primarily of the eyes and , which causes infections primarily of the eyes and face, is latent in the face, is latent in the trigeminal gangliontrigeminal ganglion. whereas . whereas herpes herpes simplex virus type 2simplex virus type 2, which causes infections primarily of , which causes infections primarily of

the genitals, is latent in the the genitals, is latent in the lumbar and sacral ganglialumbar and sacral ganglia . .--Varicella-zoster virusVaricella-zoster virus, another member of the herpesvirus , another member of the herpesvirus

family, causes family, causes varicellavaricella )chickenpox( as its )chickenpox( as its initialinitial manifestation manifestation and then remains latent, primarily in the and then remains latent, primarily in the trigeminal or thoracic ganglion cellstrigeminal or thoracic ganglion cells. It can recur in the . It can recur in the form of the form of the painful vesicles of zosterpainful vesicles of zoster )shingles(, usually )shingles(, usually

on the on the face or trunkface or trunk . .

C. SLOW VIRUS INFECTIONSC. SLOW VIRUS INFECTIONS

--The term "slow" refers to the The term "slow" refers to the prolonged periodprolonged period between the between the initial infection and the onset of diseaseinitial infection and the onset of disease, which is usually , which is usually measured in measured in yearsyears. It is . It is not,not, that virus that virus growth is slowgrowth is slow; ; rather, the rather, the incubation periodincubation period and the progression of the and the progression of the

disease are disease are prolongedprolonged . .

--Two of these diseases are caused by conventional viruses, Two of these diseases are caused by conventional viruses, namely, namely, subacute sclerosing panencephalitis, which subacute sclerosing panencephalitis, which follows several follows several yearsyears after measles virus infections, and after measles virus infections, and progressive multifocal leukoencephalopathy )PML(, which progressive multifocal leukoencephalopathy )PML(, which

is caused by JC virusis caused by JC virus..

--Other slow infections in humans, eg, Other slow infections in humans, eg, Creutzfeldt-JakobCreutzfeldt-Jakob disease and disease and kurukuru, may be caused by unconventional , may be caused by unconventional agents called agents called prionsprions..