Medically Important DNA Viruses 2025 PDF

BIOM 611G, Medical Microbiology PCOM Georgia MEDICALLY IMPORTANT DNA VIRUSES Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Professor of Microbiology and Immunology...

BIOM 611G, Medical Microbiology PCOM Georgia MEDICALLY IMPORTANT DNA VIRUSES Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Professor of Microbiology and Immunology BMS1 & BMS2 Department of Biomedical Sciences January 14, 2025  Reading Murray’s Medical Microbiology, 9th Ed Virus specific chapters (Recommended) Mims’ Medical Microbiology: The Pathogen Parade: viruses LEARNING OBJECTIVES Through the study of this content and recommended reading, the successful student will be able to……. 1. Classify the DNA viruses according to structure & genome (i.e. single-stranded vs double- stranded) 2. Discuss the importance of latency to clinical disease 3. For the following viruses (herpesviruses, adenoviruses, papillomaviruses, polyomavirus, parvoviruses, hepatitis B virus & poxviruses): Describe a. source & transmission b. timeline of infection within the infected host c. disease associations & clinical manifestations d. whether or not it is vaccine-preventable 2 IF I NAME A DNA VIRAL FAMILY, Classify CAN YOU DNA viruses according to DESCRIBE IT’S structure & genome (i.e. single-stranded vs double- GENOME stranded) STRUCTURE? 3 GENERAL NEED TO KNOW ABOUT DNA VIRUSES OF MEDICAL IMPORTANCE (HUMAN) 7 viral families (-viridae)  Genome: # of families  Linear: 4 families  Circular: 3 families  Replication: # of families  Partially circular: 1  Nucleus: 6  Cytoplasm: 1  Partially double-stranded: 1  Encodes viral DNA-dependent DNA polymerase: 6  Double-stranded: 6  Utilizes cellular DNA-dependent DNA polymerase: 1  Single-stranded: 1  mRNA Synthesis: # of families  Utilizes cellular DNA-dependent RNA polymerases: 6  Capsid Symmetry: # of families  Encodes viral DNA-dependent RNA polymerase: 1  Icosahedral: 6  Complex: 1 Be able to answer which families are being described by each bulleted 4 description  DNA VIRUSES AND THEIR CHARACTERISTICS Enveloped, linear Non-enveloped, linear, 5. Herpesviridae (icosahedral, icosahedral dsDNA) Herpes Simplex Virus, HSV1 1. Parvoviridae (ssDNA) HSV2 Parvovirus B19 Varicella Zoster Virus, VZV Epstein Barr Virus, EBV 2. Adenoviridae (dsDNA) Cytomegalovirus, CMV Enveloped, partially circular, Adenovirus Human Herpes Virus 6, HHV6 icosahedral Non-enveloped, circular, HHV7 7. Hepadnaviridae ( pdsDNA) icosahedral HHV8 – Kaposi’s sarcoma Hepatitis B Virus 3. Papillomaviridae (dsDNA) Human Papilloma Virus 6. Poxviridae (complex, dsDNA) (HPV) Molluscum contagiosum Cowpox Virus 3. Polyomaviridae (dsDNA) Variola Virus (smallpox) JC Virus Vaccinia Virus BK Virus Monkeypox Virus  HOW DOES LATENCY BENEFIT THE VIRUS? DOES Discuss IT AFFECT THE importance of latency to clinical disease HOST AT ALL? 6 SEVERAL POSSIBLE OUTCOMES POST-INFECTION WITH DNA VIRUS  Acute  cell death (lytic infection)  clearance/resolution  Chronic  replication without cell death (persistent infection)  +/- resolution  can result in immortalization of the cell  transformation oncogenesis  Latency  presence of virus with no replication  potential for reactivation  no clearance by CD8+ T cells bc don’t recognize cells as being infected  minimal available targets for antivirals during latency -only viral transcripts made to inhibit v. replication (if made) can be potentially targeted  Reactivation of latent infection  productive infection  infection is endogenous & does not require re-exposure to virus  may be frequent in immunocompromised hosts  +/- clinical disease, however, infected individual infectious  recurrent infections less severe, more localized & cleared more quickly: memory 7  Occurs with DNA or retroviruses VIRAL LATENCY  Ability of virus to remain dormant within host cell, sometimes establishing lifelong infection  Immune response does not recognize cell is infected  escape from cell-mediated host response  Generally maintained by no or very few viral genes being expressed  Viral genome remains latent in one of two ways 1. As episome 2. Integrated into host chromosome  Allows replication of the viral genome during host cell division  Trigger  latency highly variable  Depends on virus  Host cell context (replication phase, growth, nutrients, etc) is always determining  Latency usually stops upon viral genome reactivation, often promoted by cellular stress signals  Benefit to viruses is ability for widespread dissemination into host population  Example: ~ 90% of human population infected with varicella-zoster virus 8 http://viralzone.expasy.org/all_by_species/ WHO, WHAT, For the following viruses (herpesviruses, adenoviruses, WHEN AND papillomaviruses, polyomavirus, parvoviruses, hepatitis B virus & poxviruses): HOW OF DNA Describe VIRAL a) b) source & transmission timeline of infection within the INFECTIONS c) infected host disease associations & clinical manifestations d) whether or not it is vaccine- preventable 9 NONENVELOPE Parvoviridae D/ NAKED DNA Adenoviridae VIRUSES Papillomaviridae Polyomaviridae 10  1. PARVOVIRUS B19 Nu DNA virus clei c ss linear aci d Icosahedral  Parvo: from Latin, “small” Str uct Non-enveloped ure  Source & Transmission: respiratory, direct contact with Fa Parvoviridae oral secretions mil y/ Human Parvovirus B19 Vir  Tropism: erythroblasts (mitotically active erythroid us precursor cells in bone marrow)  Receptor: erythrocyte P antigen  Outcome: cell lysis  drop in mature RBCs  anemia  Geography: worldwide, more common in late winter/spring 11  B19 PATHOGENESIS  Phase 1 (lytic):  Initial infection at site of entry  Inoculates nasal cavity (URT)  6-day incubation  viremia and fever  Virus infects and lyses erythroid precursor cells in bone marrow  mildly reduced reticulocytes, lymphocytes, neutrophils, platelets  Phase 2 (immune complexes):  Viremia resolves, IgG  erythema infectiosum: rash with “slapped cheek” appearance, arthralgias for several days (rare)  Contagious until rash appears 12 B19 CLINICAL PRESENTATION  Children (4 -15yo)  Erythema infectiosum (fifth disease)  High fever during viremia followed by rash  Adults: flu-like illness, arthralgia and arthritis (with or without rash)  Erythematous, sharply demarcated raised rash on face  Lacy reticular maculopapular rash (trunk, extremities) several days later  Complications Due to Patient Status  Pregnancy: may lead to severe anemia and hydrops fetalis  fetal death  Chronic anemia (sickle cell, thalassemias)  transient aplastic crisis  severe reticulocytopenia, normal myeloid lineage  Immunosuppressed : persistent, anemia VisualDx →Erythema infectiosum (in search bar) 13 https://www.visualdx.com/visualdx/diagnosis/erythema+infectiosum?diagnosisId=51574&moduleId B19 DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL Diagnosis  Clinical appearance (rash)  Confirmation by PCR to detect viral DNA (blood)  Serology: IgM and IgG Treatment  Supportive (children)  RBC transfusion in severe cases  Immunodeficient patient: passive transfer of Ig Prevention and Control  None 14 2. ADENOVIRUSES Nu DNA virus cle ic ds linear  Upper respiratory and GI diseases aci d Icosahedral  100+ serotypes Str uct Non-enveloped ure  Source & Transmission: aerosols, fecal-oral, Fa mil Adenoviridae close contact, auto inoculation  eye y/ Adenovirus Vir  Tropism: mucosal epithelium of upper us respiratory and GI tracts  Receptor: CAR (coxsackievirus and adenovirus receptor)  Outcome: lytic, persistent, and latent infections  Geography/ Season: worldwide, no seasonal incidence 15  ADENOVIRUS PATHOGENESIS  Infect mucoepithelium in tissues at portal of entry: respiratory tract, gastrointestinal tract, and conjunctiva/ cornea  Initial infection (respiratory) pharynx, conjunctiva, or upper respiratory tract for most types then spreads to lymph nodes and possibly LRT  Transmitted by inhalation of respiratory droplets; across eye by direct contact via contaminated hands, towels or eye drops, inadequately chlorinated swimming pools/ponds  GI serotypes transmitted via fecal- oral route 16  ADENOVIRUS PATHOGENESIS, CON’T  Lytic infection but often becomes latent and persists in lymphoid tissue (e.g., tonsils, adenoids, Peyer patches)  Disease from reactivated virus occurs in immunocompromised children and adults with viremia  Histology: dense, central intranuclear inclusion bodies containing DNA, proteins, and capsids due to inefficient assembly of virions  dark basophilic staining  Resolution dependent on IgG  Viral proteins interfere with immune defenses by blocking IFN and T cells 17  ADENOVIRUS CLINICAL SYNDROMES Disease Patient Population Respiratory Illnesses Acute febrile pharyngitis Young children (8 yo 4. POLYOMAVIRUS Nu DNA virus clei ds circular  c aci Source and Transmission: inhalation or fecal/oral d Icosahedral (contact with contaminated water, stool, urine, or Str uct Non-enveloped saliva) ure Polyomaviridae  Tropism: infection of tonsils and lymphocytes; Fa mil JC Virus latency in kidneys (BK) or kidneys, B cells, y/ BK Virus monocyte-lineage cells (JC) Vir us  Outcome: persistent and latent infection in organs such as kidneys and lungs. Reactivation of productive infection if individual becomes immunosuppressed  Infections are asymptomatic: ubiquitous  Geography/ Season: worldwide, no seasonal incidence 26 POLYOMAVIRUS PATHOGENESIS  Primary Infection  Generally asymptomatic infxn of kidney  latent  Reactivation  In severely immunocompromised individuals and pregnancy  CNS and/or urinary tract replication 27 POLYOMAVIRUS CLINICAL SYNDROMES, DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL Clinical Syndromes  Asymptomatic (immunocompetent)  Hemorrhagic cystitis (BKV)  Progressive Multifocal Leukoencephalopathy (PML)  Subacute demyelinating disease  ~10% of people with AIDS develop PML  >90% fatality rate; often within 2-4 months Diagnosis  Urine cytologic tests  enlarged cells with dense basophilic intranuclear inclusions consistent with JCV or BKV  MRI or CT evidence of lesions  Confirmed by presence of PCR-amplified viral DNA in CSF, urine, or biopsy material  PML diagnosis: Histologic examination of brain tissue (biopsy or autopsy samples) reveal areas of demyelination surrounded by oligodendrocytes with inclusions Treatment, Prevention and Control  Decreasing immunosuppression 28 CLINICAL SCENARIO Progressive Multifocal Leukoencephalopathy (PML)  A 42-year-old AIDS patient has become forgetful and has difficulty speaking, seeing, and keeping his balance, which is suggestive of lesions in many sites in the brain. The condition progresses to paralysis and death.  Autopsy shows foci of demyelination, with oligodendrocytes containing inclusion bodies only in the white matter. 29 ENVELOPED Herpesviridae DNA VIRUSES Poxviridae Hepadnaviridae 30 5. HUMAN HERPESVIRUSES (HHV) Nu cle DNA virus Tegument = space between ic ds linear envelope & capsid aci d Icosahedral Str uct Enveloped ure  Outcome: Lytic, latent, recurrent infections; EBV  Herpesviridae Fa mil Human Herpes Viruses immortalizing; EBV and HHV8/KSHV  oncogenic y/ Vir (HHV)  Causes: cold sores, genital herpes, chicken pox, us shingles, mononucleosis, roseola, others  Source and Transmission: direct contact, bodily fluids; VZV transmitted by aerosol and direct contact  Tropism: varies  Ubiquitous  Geography/ Season: worldwide, no seasonal incidence 31  ALPHA HERPESVIRUSE S Virus Primary target cell Site of Latency Alpha Herpesviruses: rapid cytolytic growth HSV-1 Mucoepithelial cells; fibroblasts Neurons HSV-2 Mucoepithelial cells; fibroblasts Neurons VZV Mucoepithelial cells, T cells Neurons 32  HSV AND VZV PATHOGENESIS Expression of LATs mRNA only prevent transcription of IE genes Recurrences suppressed by: strong cellular immune response (high antibody titer does not 33 prevent)  HERPES SIMPLEX VIRUS: INITIAL INFECTION  Virus replicates to high levels at site of infection  Infection resolves, virus is cleared-- usually within two weeks  Virus travels up axon to sensory nerve ganglion  There is a period of acute infection in the ganglion  HSV-1 – trigeminal ganglion  HSV-2 – sacral dorsal root sensory ganglion  Fraction of neurons left with viral DNA present in episomal form with no productive replication latency 34  HHV PRIMARY TRANSMISSION AND PRIMARY CLINICAL PRESENTATION: HSV 1 &2 Reddened, vesicular lesions and shallow ulcers accompanied by fever, myalgia and malaise can spread without visible lesions HSV-1 Transmission: contact with fluid from vesicles; saliva Primary Manifestations  Children: manifests as gingivostomatitis (herpes labialis). Fever, malaise, lesions last 3 weeks  Adults: pharyngitis or tonsillitis. ~ 1-week duration (rare bc typically acquired in childhood) HSV-2 Transmission: contact with fluid from vesicles; sexual  Lesions on genitalia  2/3 of acquisitions of genital herpes come from clinically asymptomatic partners 35 HHV SECONDARY/ RECURRENT CLINICAL PRESENTATION: HSV 1 & 2 Secondary Manifestations  Lesions on oropharynx, cold sores  Keratoconjunctivitis (HSV-1 infection of eye)  2nd m/c cause of corneal blindness (after trauma), corneal scarring  Herpetic Gladiatorium  Herpes infection of body; (wrestlers) skin abrasions and burn victims  Herpetic Whitlow  Herpes infection of fingers +/- hands  Healthcare workers – esp. working w/ pts  Genital Herpes  Remains localized 36  HHV PRIMARY CLINICAL PRESENTATION: VARICELLA ZOSTER VIRUS (VZV)  Transmission: respiratory droplet inhalation or direct contact  Highly contagious, 90% of cases < 9 years old  97% adults seropositive  More severe, if primary infection occurs in adults  Lifelong immunity, but reactivation  Shingles/Zoster  Trigger: increased age and/or decreased immunity  Additional Complications:  Superimposed bacterial infections  Pneumonia 37  Varicella/ Zoster/ Shingles: VZV SECONDARY CLINICAL Chickenpox: Primary infection reactivation infection PRESENTATION Fever, irritability, Reactivation of latent virus vesicles Dermatome: area of skin where sensory Lymphadenopath Early symptoms: acute pain and y redness of dermatome followed nerves derive from single spinal nerve root by rash Derived from cells of somite  Reddened, Uninfected others  Chicken pox (1)myotome, which forms some of skeletal muscle vesicular (2)dermatome, which forms connective tissues, disseminated including dermis rash (3)sclerotome, which gives rise to vertebrae Virus goes latent Post-herpetic neuralgia (PHN) can be prolonged (weeks-months or more) and very severe 38  HSV 1 AND 2 DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL  Diagnosis  Direct microscopic examination of cells from base of lesion (Tzanck smear)  Multinucleated giant cells and Cowdry type A inclusion bodies in cells Tzanck smear showing  Assay of tissue biopsy, smear, CSF, or vesicular fluid for HSV antigen or genome Multi Nucleated Giant  ELISA, immunofluorescent stain, in situ DNA probe analysis, or PCR cells (MNGs) (pink arrow)  Tissue-specific antibody and PCR for typing (HSV-1 vs -2) and Tzanck cells (red arrow) in herpetic  Treatment infections  Acyclovir + derivatives  Prevention & Control  Antiviral drugs available  No vaccine  Health care workers wear gloves  People with active genital lesions should refrain from intercourse until lesions completely reepithelialized  C-section in infected mothers (genital herpes) 39 https://www.ncbi.nlm.nih.gov/pmc/articles/ VZV DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL  Diagnosis  Clinically visualize  3 stages of lesions present (Varicella)  red bumps, blisters, and scabs  Lesions along single dermatome (Zoster)  Direct microscopic examination of cells from base of lesion (Tzanck smear)  Multinucleated giant cells and Cowdry type A inclusion bodies in cells  Detection of virus via PCR  Treatment  children, no treatment  adults: Acyclovir and derivatives  immunocompromised: Anti-VZV Ig  Prevention & Control  Attenuated VZV live vaccine 40 https://www.ncbi.nlm.nih.gov/pmc/articles/  BETA HERPESVIRUSE S Virus Primary target cell Site of Latency Beta Herpesviruses: slow replication (restricted growth) CMV Leukocytes, epithelial cells, Monocytes, myeloid fibroblasts & others stem cells & others HHV-6 Lymphocytes & ? T cells & ? HHV-7 Lymphocytes & ? T cells & ? 41  BETA HERPESVIRUS TRANSMISSION & PRIMARY INFECTION Cytomegalovirus  Virus present in blood, organs & secretions  Saliva; blood transfusions; sexually transmitted; organ transplants; in utero; breast feeding  Productive & latent infections in various cell types  Monocytes/macrophages, lymphocytes, epithelial cells, fibroblasts  Primary infection often asymptomatic  Congenital disease 42  CMV SECONDARY CLINICAL PRESENTATIONS  Mononucleosis-like syndrome  Heterophile antibody negative mononucleosis  Responsible for 5-10% of cases of infectious mononucleosis  Less severe than EBV mononucleosis but similar symptoms  Fever, fatigue, lymphadenopathy, malaise, myalgias, headache, splenomegaly  Exudative pharyngitis is rare (unlike EBV mononucleosis)  Immunocompromised individuals – at risk for disseminated disease  Pneumonia & encephalitis  Retinitis & colitis or esophagitis are common manifestations in AIDS patients  Responsible for failure of many kidney transplants  Can complicate heart, lung, liver & bone marrow transplants 43  HHV-6 & HHV-7 TRANSMISSION, PATHOGENESIS & PRIMARY INFECTION  Transmitted in saliva  Ubiquitous, primary infection occurs early in childhood  Productive & latent infection in CD4 T cells  Primary infection often asymptomatic  Exanthem subitum (roseola, sixth disease) in infants  HHV-6 more frequently than HHV-7 44  GAMMA HERPESVIRUSE S Virus Primary target cell Site of Latency Gamma Herpesviruses: lymphoproliferative EBV B cells & epithelial cells B cells KSHV/ B cells, some endothelial cells, B cells HHV-8 epithelial cells, monocytes 45 GAMMA HERPESVIRUSES – EPSTEIN- BARR VIRUS (EBV)  Transmission – sexual; possibly saliva, organ transplants, iv drug use  Primary infection  Immunocompetent – usually asymptomatic  Immunocompromised – fever, splenomegaly, lymphoid hyperplasia  EBV receptor  CR2 / CD21 (receptor for C3d component of complement)  Expressed on B cells & epithelial cells of oropharynx & nasopharynx  B cells – productive, immortalizing or latent infection; transformation  Epithelial cells – productive infection; transformation  Co-receptor  MHC class II  Non-productive infection of B cells  Latency, immortalization or transformation 46 OUTCOMES OF INFECTION WITH EBV 47 CLINICAL COURSE OF INFECTIOUS MONONUCLEOSIS  T cell response to EBV-immortalized B cells  B cells stimulated to divide & secrete antibody (polyclonal activation)  Heterophile antibodies  IgM recognizes Paul-Bunnell antigen on sheep, horse & bovine erythrocytes  EBV-activated B cells eliminated by T cells  Activation & proliferation of T cells  Large, atypical T cells (Downey cells)  Reactivation common in tonsils & oropharynx  Asymptomatic, but virus shed in saliva 48  HHV-8 CLINICAL PRESENTATIONS  Kaposi sarcoma  cancer of the lymphatic endothelial lining  bluish-red cutaneous nodules  Primary effusion lymphoma  Also called body cavity-based lymphomas  Often co-infected with EBV  Multicentric Castleman’s disease  Lymphoproliferative disease  Fever, splenomegaly, hepatomegaly, generalized lymphadenopathy 49  Most common primary infection Reactivation of productive infection Mild infectious mononucleosis * * 50 * not a productive infection; consequence of transformation 6. POXVIRIDAE  Replication in cytoplasm  Source and Transmission: direct contact, respiratory Nu DNA virus cle ic ds linear  Tropism: varies aci d Complex Str  Outcome: Lytic uct Enveloped ure Fa  Causes: smallpox, vaccinia, cowpox, mil y/ Poxviridae monkeypox, molluscum contagiosum Vir us 51 MOLLUSCO M CONTAGIOS UM  Transmission  Skin-skin contact or exposure to contaminated  Clinical disease fomites  White, pink or flesh colored dome-shaped  Usually in children AST  HBV immunoglobulin (HBIG) – post aspartate aminotransferase, exposure alanine aminotransferase  Infants born to infected mothers Clinical signs  Spouses of infected patients Jaundice (30%)  HCW following needle stick injury RUQ discomfort  Antivirals Serology & antigen detection HBsAg vs anti-HBs  IFNα, Lamivudine Anti-HBc IgM vs anti-HBc  Liver transplant IgG  Lifestyle mod-no alcohol HBeAg vs anti-HBe  indicates infectivity  Prevention and Control PCR  Recombinant vaccine Detects viral DNA Quantifies viral load in 59  Consists of HBsAg administered at: 0, 1, 6 months serum