M39+HumanHerpesvirusesDentalMicrobiology2023.pdf

Christopher B. [email protected] Dental Microbiology BMDN 516 Microbiology and Immunology April 18, 2023 Human Herpesviruses Disclosure I have no conflicts of interest to disclose for this course. Herpe svirid ae  Large do uble -stran ded DNA viru ses replic ating inthe n ucl eus of...

Christopher B. [email protected] Dental Microbiology BMDN 516 Microbiology and Immunology April 18, 2023 Human Herpesviruses Disclosure I have no conflicts of interest to disclose for this course. Herpe svirid ae  Large do uble -stran ded DNA viru ses replic ating inthe n ucl eus ofthe host ce ll.  Lin ear gen omeco ding for approxi mately 100 ge nes  latent and lytic infections  Alp ha, beta, and ga mma  Gam maherpes viruses establis hlatent infection in lymphocytes. Herpesvir idae Philogen etic Tree European Respiratory Journal 2013 Human Herpesvirus (HHV) classification NameSynonym SubfamilyPrimary Target Cell Pathophysiology Site of Latency Means of Spread HHV -1 Herpes simplex virus - 1 (HSV -1) α ( Alpha) Mucoepithelial Oral and/or genital herpes (predominantly orofacial), as well as other herpes simplex infections NeuronClose contact (oral or sexually transmitted infection) HHV -2 Herpes simplex virus - 2 (HSV -2) α Mucoepithelial Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infections NeuronClose contact (oral or sexually transmitted disease) HHV -3 Varicella zoster virus (VZV) α MucoepithelialChickenpox and shingles NeuronRespiratory and close contact (including sexually transmitted disease) HHV -4 Epstein– Barr virus (EBV) γ ( Gamma) B cells and epithelial cells Infectious mononucleosis, Burkitt's lymphoma, CNS lymphoma in AIDS patients, post -transplant lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV -associated hairy leukoplakia B cell Close contact, transfusions, tissue transplant, and congenital HHV -5 Cytomegalovirus (CMV) β ( Beta) Monocytes, granulocytes, lymphocytes and epithelial cells Infectious mononucleosis -like syndrome, retinitis MonocyteSaliva, urine, blood, breast milk HHV -8 Kaposi's sarcoma- associated herpesvirus (KSHV) γB cells, endothelial cells, macrophages, and epithelial cellsKaposi's sarcoma, primary effusion lymphoma, some types of multicentric Castleman's disease B cell Close contact (sexual), saliva? Herpesvirus Lytic Program (Liesegang et al 1992) HSV Properties  Belong to the alphaherpesvirussubfamily of herpesviruses  Double stranded DNA enveloped virus with a genome of around 150 kb  The genome of HSV -1 and HSV -2 share 50 -70% homology.  They also share several cross -reactive epitopes with each other. There is also antigenic cross -reaction with V Z V.  Man is the only natural host for HSV. HSV and Immune Response  IFN and NK cells limit initial infection.  TH1 and CD8 killer T cells needed to resolve acute infection.  HSV subverts host immune responses  Virus blocks IFN induced inhibition of viral protein synthesis.  Escapes antibody neutralization via cell-to -cell spread and syncytia formation.  Viral glycoproteins function as antibody and complement receptors which reduces humoral immune response HSV Epidemiology  HSVisspread bycontact, asthe virus isshed insaliva, tears, genital andother secretions .  Most common form of infection results from a kiss given to a child or adult from a person shedding the virus.  Incubation period2-12 days (avg4-6 days) .  Primary infection lasts10-21 days.Recurrent 3-7 days .  Primary infection isusually trivialorsubclinical inmost individuals .  Thereare2peaks ofincidence, thefirst at0-5 years andthe second inthe late teens, whensexual activity commences .  About10% ofthe population acquiresHSVinfection throughthe genital routeandtherisk isconcentrated inyoung adulthood. Herpes Simplex Viruses  Herpes simplex virus type 1 (HSV-1) and type 2 (HSV -2) are distinguished by two main criteria  Antigenicity and location of lesions.  HSV -1: above the waist (~ 65% of worlds population infected with HSV - 1)  Acute gingivostomatitis ,  a contagious mouth infection - painful sores, blisters, and swelling. It usually spreads through the saliva of an infected individual or by direct contact with a lesion or sore. Common in young children, usually under 6 years.  Recurrent herpes labialis(cold sores),  Keratoconjunctivitis (keratitis) (inflammation of the cornea)  Encephalitis (inflammation of the brain)  HSV-2: below the waist (~12% of worlds population infected with HSV - 2)  herpes genitalis (genital herpes),  Neonatal encephalitis and other forms of neonatal herpes  meningitis Transmission  HSV 1: transmitted primarily in saliva.  HSV 2: transmitted by sexual contact  Oral–genital sexual activity: HSV-1 infections of the genitals and HSV -2 lesions in the oral cavity.  – 10– 20% of cases HSV Pathogenesis  Duringtheprimary infection, HSV spreads locallyandashort -lived viremia occurs, whereby thevirus isdisseminated in the body .Spread tothe craniospinal ganglia occurs.  Thevirus thenestablishes latencyinthe trigeminal (HSV1) or sacral (HSV2) ganglia.  Reactivation -It is well known thatmany triggers canprovoke arecurrence .These include physical orpsychological stress, infection; especially pneumococcal and meningococcal, fever,irradiation (including sunlight),andmenstruation. Clinical Manifestations HSVisinvolved inavariety ofclinical manifestations which includes : 1. Acute gingivostomatitis 2. Herpes Labialis (cold sore) 3. Ocular Herpes 4. Herpes Genitalis 5. Other forms of cutaneous herpes 7. Meningitis 8. Encephalitis 9. Neonatal herpes Clinical Findings: HSV-1  causes several forms of primary and recurrent disease.  Gingivostomatitis  Occurs primarily in children and is characterized by fever, irritability, and vesicular lesions in the mouth.  The primary disease is more severe and lasts longer than recurrences.  The lesions heal spontaneously in 2 to 3 weeks.  Many children have asymptomatic primary infections  Herpes labialis  fever blisters or cold sores  characterized by crops of vesicles, usually at the mucocutaneous junction of the lips or nose  Recurrences frequently reappear at the same site. Gingivostomatitis Clinical Findings: HSV-1  Keratoconjunctivitis  characterized bycorneal ulcers andlesions ofthe conjunctival epithelium.  Recurrences can lead to scarring and blindness  Encephalitis  necrotic lesion in one temporal lobe.  Fever, headache, vomiting, seizures, and altered mental status HSV-2  Genital Herpes Neonatal Herpes Infection  Infection occurs during passage through birth canal via mother shedding HSV-2  Progression to CNS results in death, intellectual disability even with treatment  Cell- mediated immune response is not yet developed in neonate  Transmission can be prevented by Caesarean section Diagnosis  Culture -CPE in 24 h.  Detection of antigen by immunofluorescence.  Detection of viral DNA by in situ hybridization or PCR  Cytology -Tzanck smear –giant multinucleated cells HSV Management Antiviralchemotherapy issuggested wheretheprimary infection is especially severe,wherethereisdissemination, wheresightisthreatened, and herpes simplex encephalitis . Acyclovir –this the drug of choice for most situations at present -  I.V. (HSV infection in normal and immunocompromised patients)  Oral (treatment and long term suppression of mucocutaneousherpes and prophylaxis of HSV in immunocompromised patients)  Cream (HSV infection of the skin and mucous membranes)  Ophthalmic ointment Famciclovir and valacyclovir –oral only, more expensive than acyclovir. Other older agents – e.g. idoxuridine, trifluorothymidine, Vidarabine(ara- A).  These agents are highly toxic and is suitable for topical use for opthalmic infection only ACV Mechanism Varicella -Zoster Virus Properties  Belong tothe alphaherpesvirus subfamilyofherpesviruses  Double stranded DNAenveloped virus  Genomesize125kbp,long andshort fragments withatotal of 2 isomeric forms. Varicella-Zoster Virus Epidemiology  Primary varicella isan endemic disease.Varicella isone of the classic diseases ofchildhood, withthehighest prevalence occurringinthe 4-10 years oldage group.  Varicella ishighly communicable, withanattack rateof 90% inclose contacts .  Mostpeople become infectedbeforeadulthood but10% of young adultsremain susceptible. Varicella-Zoster Virus Pathogenesis  The virus gains entryviathe respiratory tractandspreads shortly after tothe lymphoid system.  Afteranincubation periodof14 days, thevirus arrives atits main target organ, theskin .  First appears asred bumps, formsvesicles, pustules, thencrust overto from scabs whichfalloffabout 5 days later.  Following theprimary infection, thevirus remains latentinthe cerebral orposterior rootganglia.  The virus reactivates inthe ganglion andtracks downthe sensory nervetothe area ofthe skin producing avaricella form rash. Varicella  Primaryinfection resultsinvaricella (chickenpox)  Presents fever,headache, weaknessandawidespread vesicularrash.  Thefeatures aresocharacteristic thatadiagnosis canusually bemade on clinical grounds alone.  Complications arerare butoccurs morefrequently andwith greater severity inadults andimmunocompromised patients.  Mostcommon complication issecondary bacterialinfectionofthe vesicles .  Severe complications whichmaybelife threatening includeviral pneumonia, encephalititis ,and haemorrhagic chickenpox. Herpes Zoster (Shingles)  Shingles: reactivation of varicella-zoster  Occurrence increases with age (10- 20% of infected population)  Immunosuppressed patients especially susceptible  Thelatent virusreactivates inasensory ganglion  Thereisacharacteristic eruptionofvesicles inthe dermatome which isoften accompanied byintensive painwhich maylastfor months Shingles Varicella-Zoster Virus  Diagnosis -clinical appearance, PCR, ELISA  Treatment  No treatment usually needed for children but acyclovir, famciclovir, and valacyclovir are approved.  VZIg can prevent viremic spread  Varivax vaccine for 1 year olds. Zostavax for adults over 60. Cytomegalovirus Properties  Belong to the betaherpesvirus subfamily of herpesviruses  double stranded DNA enveloped virus  Most infections are asymptomatic, but it is the most common viral cause of congenital defects  Slow replication rate (5 days in culture)  Incubation period 30-60 days Cytomegalovirus Clinical Features  Transmission: close contact, sexually transmitted, virus can be recovered from all body fluids such as saliva, urine, semen, & cervical secretions  Clinical features  high infection rates in early childhood and early adulthood  usually asymptomatic  Systemic CMV infection; pneumonia and hepatitis in immunosuppressed patients (transplant patients)  In AIDS patient; opportunistic infection resulting in retinitis, colitis, esophagitis, pneumonitis and neurological disorders Epidemiology  CMVcanbetransmitted verticallyorhorizontally usuallywithlittle effect onthe host .  Transmission mayoccur inutero, perinatally orpostnatally .Once infected, theperson carriesthevirus forlife which maybeactivated from timetotime, during whichinfectious virionsappear inthe urine and thesaliva .  Reactivation canalso lead tovertical transmission .It is also possible forpeople whohave experienced primaryinfection tobe reinfected withanother orthe same strainofC M V, thisreinfection does notdiffer clinically fromreactivation.  Indeveloped countrieswithahigh standard ofhygiene, 40%of adolescents areinfected andultimately 70%ofthe population is infected .In developing countries,over90% ofpeople areultimately infected. Pathogenesis  Perinatalinfectionisacquired mainlythrough infected genital secretions, orbreast milk.Overall, 2-10 % ofinfants areinfected by the age of6months worldwide.  Postnatal infectionmainlyoccurs through saliva.  Sexual transmission mayoccur aswell .Also blood, blood products andtransplanted organ. Congenital Infection  Defined as the isolation of CMV from the saliva or urine within 3 weeks of birth.  Most common congenital viral infection, affects 0.3 -1% of all live births. The second most common cause of mental handicap after Down's syndrome.  Transmission to the fetusmay occur following primary or recurrent CMV infection. 40% chance of transmission to the fetus following a primary infection.  May be transmitted to the fetusduring all stages of pregnancy. Clinical Infectious Diseases, 2017 CMV -Diagnosis and Treatment  Diagnosis  isolation of virus, electron microscopy, serology,  DNA amplification by PCR  Treatment  hyperimmune globulin, ganciclovir Human Herpesvirus 6  Discovered in 1986. 2 closely related subtypes HHV-6 A and HHV -6B. 90% of population infected with HHV6.  HHV-6A more closely associated with MS  HHV-6B primarily causes roseola infantum(fever followed by rash).  Highly communicable. Spread by close personal contact or respiratory route.  Most children infected by age 5.  Replicates in lymphoid tissue (primarily T lymphocytes)  HHV6 can transactivate EBV  Treatment. Acyclovir Human Herpesvirus 7  Discovered in 1990.  Isolated from CD4+ T lymphocytes  97% of adults are seropositive  Also causes roseola but not as frequently as HHV-6B.  HHV -7 also associated with acute febrile respiratory disease, fever, rash, vomiting, diarrhea, low lymphocyte counts, though most often no symptoms present. Epstein -Bar rVirus  Approximat ely95% ofthe world’s population is infected with EB V.  EBV wasnamed after Mich ael Epstein andYvonne Barrwhotogether with Bert Achong discovered thevirus in cultured lymphoblasts fromBurkitt’s L y m phoma in 1964.  EBVestablished asthe etiological agentofinfectious mononucleos isin 1968.  Causes lethal immunoblastic lymphomas in immunocompromised individuals (post-transplant and HIV -associated lymphoproliferative disorders)  Burkitt Lymphoma, Hodgk inLymphoma, Nasophar yngeal Carcinoma, Gastric C arcinoma Epstein -Bar rVirus  E BV persists as eithe ra lytic or latent i nfecti on.  Lytic Cycle  L y tic replic ation primarily occu rs in epi thelial cells  Full co mplement ofover 90gene sexpres se d including g ene senc oding for itsown replic ation.  Primary infe ctio n is usu ally a sym ptom atic but most n ota bly c a use s infe ctio us mo nonucle osis.  L atent Cycl e  Primarily in Bcells butca n be reac tivate dto expres sly tic genes  3 types oflatency ch arac ter iz e d by su bset of gene sexpres se d Raab -T ra ub,Sem Cance rB iol. 12, 2002 B-L ymphocyt es Pr olife rate Oral Muco sa Lymphoid Tissue P eripheral Circulation Res tin g memo ry B -cel ls Cyto ly tic T -cell res ponse EBV Saliv a P ath ogen esis of E BV In fect ion EBV Infection PTLD Hodgkin Lymphoma Burkitt Lymphoma NPC Healthy Individual EBV Latency Types Infectious Mononuclosis  Primary EBV infection is usually subclinical in childhood. However in adolescents and adults, there is a 50% chance that the syndrome of infectious mononucleosis (IM) will develop.  IM is usually a self -limited disease which consists of fever, lymphadenopathy and splenomegaly. In some patients jaundice may be seen which is due to hepatitis.  Complications occur rarely but may be serious e.g. splenic rupture, meningoencephalitis, and pharyngeal obstruction.  In some patients, chronic IM may occur where eventually the patient dies of lymphoproliferative disease or lymphoma. Burkitt’sLymphoma  Burkitt's lymphoma (BL)occurs endemically inparts ofAfrica (where itis the commonest childhoodtumor)andPapua New Guinea. Itusually occursinchildren aged3-14 years .It responds favorablytochemotherapy .  Itis restricted toareas withholoendemic malaria.Therefore it appears thatmalaria infection isacofactor .  Multiple copiesofEBV genome andsome EBVantigens can be found inBL cells andpatients withBLhave hightiters of antibodies againstvarious EBVantigens . Burkitt’sLymphoma  BLcells show areciprocal translocation betweenthelong arm of chromosome 8and chromosomes 14,2or 22.  This translocation resultinthe c-myc oncogene beingtransferred to the immunoglobulin generegions .This results inthe deregulation ofthe c-myc gene .Itis thought thatthistranslocation is probably alreadypresent bythe time ofEBV infection andisnot caused byEBV .  Sporadic cases of BL occur, especially in AIDS patients which may or may not be associated with EBV.  In theory BL can be controlled by the eradication of malaria (as has happened in Papua New Guinea). Hodgkin’s Lymphoma  Symptomsincludefever,nightsweats, weightloss,itchyandtired.  About halfofcases ofHodgkin's lymphoma aredue toEBV  People whohave hadillnesses causedbythe Epstein-Barr virus, such asinfectious mononucleosis, aremore likelytodevelop Hodgkin's lymphoma thanarepeople whohaven't hadEpstein-Barr infections .  Havingablood relative withHodgkin's lymphoma ornon-Hodgkin's lymphoma increasesyourriskofdeveloping Hodgkin'slymphoma  Hodgkin's lymphoma ismost often diagnosed inpeople between 15 and 30years oldand those over55  Hodgkin lymphoma maybetreated withchemotherapy, radiation therapy, andstem celltransplant  Cure possible inearly disease Nasopharyngeal Carcinoma  Nasopharyngealcarcinoma(NPC)isamalignant tumorofthe squamous epitheliumofthe nasopharynx .It is very prevalent in S . China, whereitis the most common tumorinmen andthe second mostcommon inwomen.  The tumor israre inmost parts ofthe world, though pockets occur inN.and C.Africa, Malaysia, Alaska,andIceland.  Multiple copiesofEBV genome andEBV EBNA- 1antigen can be found inNPC .Patients withNPC have hightiters of antibodies againstvariousEBVantigens .  Besides EBVthere appears tobe anumber ofenvironmental and genetic cofactors inNPC .  NPC usually presents lateand thus theprognosis ispoor . Immunocompromised Patients  After primary infection, EBV maintains a steady low grade latent infection in the body. Should the person become immunocompromised, the virus may reactivate and lymphoproliferative lesions and lymphoma may develop. These lesions tend to be extranodaland in unusual sites such as the GI tract or the CNS.  Transplant recipients e.g. renal (kidney) -EBV is associated with the development of lymphoproliferative disease and lymphoma.  AIDS patients -EBV is associated with oral leukoplakia and with various Non- Hodgkin’s lymphoma.  X-linked lymphoproliferative syndrome -this condition occurs exclusively in males who had inherited a defective gene in the X - chromosome. This condition accounts for half of the fatal cases of IM. Oral Hairy Leukoplakia  Triggered by EBV  Results in white patches or lesions on the tongue. Not removed with toothbrushing.  Occurs in patients with weak or compromised immune systems (HIV)  Treatment is aimed at treating underlying condition (HIV).  May not need treatment but antivirals are an option. Diagnosis and Treatment  Diagnosis  Detection of atypical lymphocytes  During acute EBV, the number of lymphocytes increases to 50–60% of total leukocytes in the peripheral blood of which 10% are atypical lymphocytes  Serology  Heterophile antibody –nonspecific activation of B cells by EBV produces antibody against Paul -Bunnel antigen on sheep erythrocytes.  Antibodies toward viral antigens o IgM to VCA or EA o IgG to EBNA  No effective treatment or vaccine. Human Herpes Virus 8 –Kaposi’s Sarcoma  Belong tothe gammaherpesviruses subfamilyofherpesviruses  Originally isolatedfromcellsofKaposi’s sarcoma (KS)  Nowappears tobe firmly associated withKaposi’s sarcoma aswell assome lesser known malignancies suchasCastleman’s diseaseandprimary effusion lymphomas  HHV-8 DNA isfound inalmost 100%ofcases ofKaposi’s sarcoma  Mostpatients withKShave antibodies againstHHV-8  Unlike otherherpesviruses, HHV-8does nothave aubiquitous distribution. The seroprevalence ofHHV -8islow among thegeneral population (1-5 % in US) Questions?  [email protected]