[MIC LEC - LE 2] 02 - DNA Viruses (V2).pdf

MICROBIOLOGY | TRANS 2 LE DNA Viruses JANUARIO E. SIA-CUNCO | Lecture Date (09/13/2024) | Versi...

MICROBIOLOGY | TRANS 2 LE DNA Viruses JANUARIO E. SIA-CUNCO | Lecture Date (09/13/2024) | Version # 2 02 OUTLINE → Can be inactivated by formalin, 𝛃-propiolactone, and I. Non-Enveloped DNA Viruses E.Cytomegalovirus/CMV/ oxidizing agents like oxygen, hydrogen peroxide, and A. Parvoviridae HHV5 chlorine → B. Adenoviruses F. Human Herpesvirus Type 6 REPLICATION PROCESS OF PARVOVIRIDAE C. Papovaviridae And 7 II. Enveloped DNA Viruses G. Poxviruses Viral DNA replication occurs in the nucleus A. Herpesviruses H. Hepatitis B Virus Parvoviruses are dependent on host cellular functions B. Herpes Simplex Virus III. Review Questions for replication Types 1 And 2 (HSV-1, IV. References It enter cells through endocytosis then enters the nucleus HSV-2 V. Formative quiz → Inside the nucleus, the genome is encoded C. Varicella Zoster Virus VI. Appendix Parvoviruses lack the ability to induce cells into their DNA (HHV-3) replication stage called the S-phase D. Epstein-Barr → It must wait in the nucleus until the host cell enters Virus/EBV/HHV-4 Must Lecturer Book Previou Youtube ❗️ S-phase on its own. Infected cells that enter S-phase are forced to synthesize viral DNA ❗️ Know 💬 📖 📋 s Trans 🔺 Video Translation of mRNA leads to the accumulation of capsid proteins in the nucleus that assemble into empty capsids Genomes are then encapsidated, when complete virions SUMMARY OF ABBREVIATIONS have been formed cell lysis occurs to release virions DFA Direct Fluorescent Antibody NAAT Nucleic Acid Amplification tests LEARNING OBJECTIVES ✔ Discuss the properties of the individual DNA viruses ✔ Discuss the pathogenesis and pathology of each individual viruses ✔ Describe the different illnesses produced by a particular DNA virus ✔ Correlate the signs and symptoms produced with the particular DNA virus ✔ Identify the methods used to diagnose a particular DNA virus ✔ Discuss treatment and prevention of each DNA Virus I. NON ENVELOPED DNA VIRUSES A. PARVOVIRIDAE Figure 1. Diagram of Virus Families [Lecturer’s PPT] Parvoviruses are the smallest DNA viruses They are non enveloped, icosahedral, with single Figure 2. Parvo virus replication [Lecturer’s PPT] stranded linear DNA Human B19 parvovirus is difficult to culture Parvovirus B19 is a pathogenic virus for humans → Only primary erythroid progenitors are permissive for → It has a tropism for erythroid progenitor cells B19 infection → 20 nm in diameter → The cellular receptor for B19 is blood group P-antigen Virions: or globocide → Resistant to inactivation ▪ P-antigen is expressed on mature erythrocytes, → Stable within a pH of 3-9 erythroid progenitors, megakaryocytes, endothelial → Can withstand heating at 56oC for 60 minutes cells, placenta, and fetal liver and heart → Parvovirus has a propensity to infect rapidly dividing tissues LE 2 TG 14 | K. Supelana, N. Suzara, J. Sy, L. Sy, M. BE | S. Ruiz & P. Roces AVPAA | C. Rival PAGE 1 of 28 TRANS 2 Sy, R. Sy, E. Tabunda, C. Talavera, K. Tan VPAA | D. Patajo & M. Pelayo MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP ❗️ImmaturePATHOGENESIS OF PARVOVIRIDAE Clinical Features: erythroid lineage cells are principal targets for → Prodrome of mild fever Human B19 virus → Malaise before the onset of the rash The major sites of virus replication in patients are in the → Nausea bone marrow, and some blood cells, and the fetal liver → Headache Viral replication causes cell death interrupting red blood → Diarrhea cell production → There would be erythrocyte maturation arrest with ❗️→ Myalgia The illness produces a biphasic rash → An intense erythema occurs over malar areas and this erythroblast intranuclear inclusions In immunocompromised patients, persistent B19 infections is called Slapped cheek syndrome result in chronic anemia → Usually resolves once antibody production has occurred Chronic infections can cause severe infections in the → At this stage, the immunocompetent individual is no fetus, resulting in fetal death The respiratory tract is the usual portal of entry ❗️ longer infectious A widespread fine lacy maculopapular rash at the trunk and limbs occur The virus can be transmitted through: → Blood transfusion → The rash fades in 2-4 days → Infected blood products (e.g. Coagulation Factors) Arthralgia usually occur in adults and is more common in → Vertical transmission (mother to fetus) women → It presents predominantly as a symmetrical small joint arthritis of the hands or fingers → May last several weeks to months Figure 3. Parvovirus pathogenesis [Lecturer’s PPT] EPIDEMIOLOGY OF PARVOVIRIDAE Infections occur throughout the year in all age groups and Figure 4. Lace pattern rash [Lecturer’s PPT] may be commonly seen as outbreaks in schools Parvovirus infection is common in childhood Transfer of virus occurs among siblings and children in schools/daycare centers → The main factor of transmission Source of maternal infection during pregnancy is usually the mother’s older child CLINICAL ILLNESS ERYTHEMA INFECTIOSUM (FIFTH DISEASE) Erythema infectiosum is a common viral disease found in ❗️ children with a peak of 5-18 years of age The most common manifestation of parvovirus B19 It is also called fifth disease as it is one of the six most common viral rash illnesses found in children Figure 5. Erythema Infectiosum [Lecturer’s PPT] Transmission is via respiratory droplets → Vertical transmission (mother to fetus), and transmission IMMUNODEFICIENT PATIENTS, DURING through blood and blood derived products is also PREGNANCY, AND APLASTIC CRISIS possible. Parvovirus B19 may cause persistent infections and may Viral entry is through the upper respiratory tract cause chronic suppression of the bone marrow inducing The incubation period is usually 1-2 weeks A short period of viremia occurs 7-10 days post exposure lasting around 1 week ❗️ chronic anemia in immunocompromised patients The disease is called Pure red cell aplasia The condition is seen in immunodeficiency, malignancies, → During the period of viremia the virus is present in nasal AIDS, and organ transplantation patients washes and gargle specimens identifying the pharynx Patients are dependent on blood transfusion and the upper respiratory tract as the site of viral Patients with chronic parvovirus infection due to B19 shedding infection may remain infectious months or years MICROBIOLOGY - LEC DNA Viruses PAGE 2 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP DURING PREGNANCY → Respiratory droplets Acute infection in pregnancy may cause B19 infection in → Contaminated fomites the fetus, leading to non-immune fetal hydrops or fetal loss due to severe anemia ❗️ ▪ Hand to eye transfer is important for eye infections Replicate well ONLY in cells of epithelial origin Maternal fetal transmission occur most commonly in pregnant women with high plasma viral loads APLASTIC CRISIS Parvovirus may be fatal in individuals with hematological conditions such as: → Sickle cell anemia → Thalassemia Transient but abrupt disruption to erythropoiesis triggers an aplastic crisis DIAGNOSIS OF PARVOVIRIDAE Viral DNA can be detected using Polymerase Chain Reaction or PCR in serum, blood cells, tissue samples, and respiratory secretions Serologic assays can determine both recent and past exposures to Parvovirus B19 Figure 6. Summary of the Replication of → IgM can be positive from 7-10 days of exposure and is Adenoviruses[Lecturer’s PPT] indicative of recent infection → IgG antibodies from 15 days after exposure REPLICATION OF ADENOVIRUSES In immunodeficient patients with chronic B19 EARLY PHASE infections antibody might not be detected The virus attaches to host cells via the fiber and is → Infection is diagnosed by detecting viral DNA internalized into endosomes Uncoating starts in the cytoplasm and is completed in the TREATMENT & PREVENTION OF HUMAN nucleus PARVOVIRUS Host cell is induced to enter the S phase of the cell cycle Severe anemia may require blood transfusion therapy to create conditions that are conducive to viral replication Commercial immunoglobulin preparations contain → Causes expression of viral function that protect the neutralizing antibodies to human parvovirus infected cell from host’s immunological defense → Can be used for persistent B19 infections in mechanisms and causes synthesis of viral gene ❗️ immunocompromised patients There is no vaccine or antiviral drug available against human parvovirus products needed for viral DNA replication Viral DNA Replication takes place in the nucleus Handwashing, use of facemask, and not sharing LATE PHASE drinks from the same glass or straw will help control the Begins with the onset of viral DNA synthesis spread of B19 through respiratory secretions, aerosols, Late genes (L genes) are expressed, responsible for and fomites coding viral structural proteins which are synthesized in the cytoplasm B. ADENOVIRUSES Capsomeres assemble into empty shell capsids in the Non-enveloped, Icosahedral, contains double-stranded nucleus and the naked DNA enters the pre-formed linear DNA. capsid Important structures About 100,000 virus particles are produced per cell → Fiber: Projecting from the twelve vertices (Penton Virions are released through host cell lysis Bases) ▪ Contain type-specific antigen that are useful for ADENOVIRUS EFFECTS serotyping Encode gene products that can counter the host antiviral ▪ Associated with hemagglutinating activities defense mechanisms → Penton Bases: Toxin-like activity that causes erratic Viral associated RNA (vaRNA) cytopathic effects and detachment of cells from the → Non-coding RNA in adenoviruses that protect it from surface on which they are growing. antiviral effects of Interferons ▪ A group reactive antigen is also exhibited by the Adenovirus E3 region protein Pentone Base → Can inhibit cytolysis of infected cells Adenovirus Types: E3 gp19-kDa protein → Respiratory: 1, 2, 3, 5 and 7 → Blocks the movement of the major histocompatibility → Gastroenteritis: 40 and 41 complex class 1 antigens to the host cells surface → Swimming Conjunctivitis: Water-borne and occur ▪ Thereby protecting the infected host cells from during the summer and is caused by type 3 and 7 cytotoxic T-lymphocyte mediated lysis → Types 3, 4, and 7 are common among military recruits and young adults in groups or institutional settings. Adenoviruses are spread by: → Direct contact → Fecal-oral route MICROBIOLOGY - LEC DNA Viruses PAGE 3 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP ADENOVIRUS RESPIRATORY ILLNESSES IN INFANTS Adenoviruses cause about 5% of acute respiratory diseases in young children and occurs year round and most prevalent during winter to summer → May lead to viral pneumonia which has a mortality rate of 10% in infants → Types 3, 7, 21 are responsible to 10-20% pneumonia in childhood ❗️ Incubation period of 3-10 days Acute Febrile Pharyngitis → Most common manifestations in infants and children → Characterized by cough, sore throat, nasal congestion and fever → May be indistinguishable from other common respiratory viral infections → Usually involves group C viruses (1, 2 and 5) IN ADOLESCENTS AND ADULTS [Lecturer’s PPT] Infections associated with Adenovirus serotypes 3, 4 and Figure 7. Adenovirus Effects PATHOGENESIS OF ADENOVIRUSES ❗️7 are usually seen in adolescents and adults Acute respiratory diseases → Occur primarily in epidemics among new military Transmitted through small droplets and aerosols Infect and replicate in epithelial cells of the respiratory recruits tract, eyes, gastrointestinal tract and urinary tract but will → Due to lowered resistance brought about by being not spread beyond regional lymph nodes exposed to new strains, fatigue and crowded living Approximately 1/3 of the known virus serotypes are conditions, promoting spread of infection commonly associated with human illnesses → This disease is caused by types 4, 7 and occasionally → Adenoviruses 1-7: Most common serotypes worldwide by type 3 and account for most cases of adenovirus associated → Vaccination for military recruits have been used to ❗ illness prevent large scale epidemics in military training camps TAKE NOTE: A single serotype may cause different Culture and Nucleic Acid Amplification testing clinical diseases and conversely, more than one type may depending on laboratory capabilities cause the same clinical illness CLINICAL ILLNESSES OF ADENOVIRUSES ❗️→Pharyngoconjunctival ADENOVIRUS EYE INFECTIONS fever Prevalent on school age children and occurs more sporadically and in outbreaks → Mild ocular involvement, part of the respiratory pharyngeal syndromes → AKA Swimming pool conjunctivitis, it often occurs in family groups or groups using the same swimming facilities → Associated with types 3 and 7 → Duration of conjunctivitis lasts 1-2 weeks and leaves no ❗️ lasting sequelae Epidemic Keratoconjunctivitis → More serious eye infection → Caused by types 8, 19, 37 → Occurs mainly in adults and is highly contagious → Transmission: ▪ Remains viable for several weeks in sinks, towels and handkerchiefs ▪ Can also be through ophthalmic solutions, person-to-person contact and improperly sterilized ophthalmologic instruments → Disease is characterized by acute conjunctivitis and other manifestations such as: Figure 8 : Clinical Illnesses Caused by Adenovirus [Lecturer’s PPT] ▪ Conjunctival injections (redness of the eye) ▪ Teariness (excessive tearing) ▪ Foreign body sensation (feeling that there is something in your eye) Space intentionally left blank ▪ Keratitis (corneal inflammation) − May be resolved in 2 weeks but may leave subepithelial opacities in the cornea for up to 2 years MICROBIOLOGY - LEC DNA Viruses PAGE 4 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP GASTROINTESTINAL & OTHER INFECTIONS TREATMENT & PREVENTION OF ADENOVIRUSES Serotypes 40 and 41 No specific treatment → Etiologically associated with infantile gastroenteritis Handwashing is the simplest way to prevent infection and may account for 5-15% of viral gastroenteritis in Surfaces may be disinfected by Sodium hypochlorite young children. (Zonrox) → Found abundantly in diarrheal stools Single use paper towels are advisable because repeated Serotypes 1-7 use of towels may be a source of infection in outbreaks → Cause respiratory diseases in transplant patients Water-borne outbreaks can be minimized by chlorination that may progress to severe pneumonia or of swimming pools disseminated infection and may be fatal → Pediatric liver transplants may develop Adenovirus C. PAPOVAVIRIDAE Hepatitis in the allogram A. SUBFAMILY → Pediatric heart transplant patients may develop PAPILLOMAVIRINAE/PAPILLOMAVIRIDAE Myocardial Adenovirus infections and are at an increased risk of graft lost → Pediatric hematopoietic stem cell transplant patients may develop infections with a wide variety of Adenovirus types AIDS patients may develop GIT infections Other Adenovirus serotypes are known to cause acute self-limited hemorrhagic cystitis which occurs primarily in males → Characterized by Hematuria and can be recovered in the urine RESISTANCE TO CLINICAL DISEASE Directly related to the presence of circulating, neutralizing antibodies which may persist for life The type-specific neutralizing antibodies against Adenovirus may protect against the occurrence of disease symptoms but it may not always prevent reinfections Adenovirus infections frequently occur without the production of overt illness Maternal antibodies can usually protect infants against severe Adenovirus Respiratory infections. DIAGNOSIS OF ADENOVIRUSES Virus may be found in respiratory samples, conjunctiva, throat, blood, stool or urine Samples must be collected early for optimal virus detection Can be identified via immunofluorescence test by using an anti hexon antibody on the infected cells Figure 9. Double Stranded DNA viruses [Lecturer’s PPT] → Hexon protein is the largest and most abundant protein in the capsid of Adenovirus Naked virus, icosahedral nucleocapsid, that contain Hemagglutination inhibition and neutralization test supercoiled double stranded circular DNA → Measure type-specific antigens and can be used to Currently divided into 16 genera identify specific serotypes Transmission: Basal epithelial cells of the patient may be stained → Requires direct contact with infected individuals via directly to detect viral antigens sexual contact or with contaminated surfaces or fomites Polymerase chain reaction (PCR) assays → Diagnosis of Adenovirus infections in respiratory ❗️ (e.g. communal bathroom floors) All papillomavirus induce hyperplastic epithelial lesions in the host species samples, blood, tissues and body fluids Direct examination of fecal extracts by electron Human papillomavirus (HPV) exhibit great tissue and cell microscopy, by enzyme-linked immunosorbent assay or by specificity latex agglutination test → It infects only surface epithelia of the skin and mucous → Can identify enteropathogenic Adenovirus membranes Complement fixation test HPVs within this tissue specific groups have varying → Can identify any member of the adenovirus group potential for causing malignancies: → Four-fold or greater rise in complement fixing antibody → Type 16 and 18 produce lesions which can progress to titer the acute phase and convalescent phase may malignancy like cervical carcinoma indicate recent infection ▪ HPV 16 and 18 are responsible for more than 70% of all cervical cancers with type 16 being the most common one → Others produce mucosal lesions that can progress to malignancy like tongue cancer MICROBIOLOGY - LEC DNA Viruses PAGE 5 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP → Others produce lesions with lower frequency PATHOGENESIS OF PAPILLOMAVIRINAE ▪ Anogenital warts AKA condyloma acuminata which is a sexually transmitted disease − 90% of anogenital warts are caused by HPV types 6 and 11 ▪ Laryngeal papillomas, the most common benign epithelial tumors of the larynx − In children they are called recurrent respiratory papillomatosis are caused by HPV 6 and 11 o Acquired during passage along the birth canal of a mother with genital warts → Other virus types are associated only with benign ❗️ lesions like the common flat and plantar warts HPV genital infections are the most common viral infections of the reproductive tract → HPVs are accepted as the cause of anogenital cancers; more than 99% of cervical cancers and more than 80% of anal cancers are linked to genital infections with HPVs Immunocompromised patients and men who have sex with men are high risk for HPV infection and development of anal cancer Oropharyngeal cancers are also linked to HPV infections especially by type 16 25% of mouth and 35% of throat cancers are associated with HPV All HPV associated cancers occur more frequently in persons with HIV/AIDS Figure 11. Papillomavirus Pathogenesis [Lecturer’s PPT] REPLICATION OF PAPILLOMAVIRINAE Papillomaviruses cause infections at cutaneous and mucosal sites → Can lead to development of different kinds of warts including: ▪ Skin warts ▪ Plantar warts ▪ Flat warts ▪ Anogenital warts ▪ Laryngeal papillomas → Several cancers including those of the cervix, vulva, penis and anus, and a subset of head and neck cancers Transmission of viral infections occurs by close contact HPV genital infections are sexually transmitted Malignant progression: Figure 10. Papillomavirus Replication [Lecturer’s PPT] → Occurs primarily in warts located on mucosal surfaces Papillomaviruses are highly tropic for epithelial cells of like those of the genital tract the skin, and mucous membranes → Binding affinity between virus early proteins and cellular → Viral nucleic acid can be found in basal stem cells anti-oncoproteins p53 and pRb which inactivate the The virus replication cycle proceeds in parallel with the cellular regulatory proteins correlates with high risk for steps of keratinocyte differentiation malignant progression → End with the terminally differentiated cornified layer of Cervical cancer develops slowly usually taking years to the growing wart decades to develop Replication cycle: Expression of viral early genes → → Multiple factors are involved in progression to multiplication of viral genome → assembly of progeny virus malignancy; Persistent infection with a high-risk HPV in the most superficial layers of the wart is a necessary component to the process. The early genes E6 and E7 from high-risk types of papillomavirus are the primary oncoproteins → They manipulate cell cycle regulators, induce ❗️ chromosomal abnormalities, and block apoptosis The infection is non-lytic and restricted to the epithelium, HPV is protected from the host’s immune Space intentionally left blank response MICROBIOLOGY - LEC DNA Viruses PAGE 6 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP CUTANEOUS WARTS HPV type 6 and 11 can also be spread to the oral mucosa via oral sexual contact → HPV infections caused by these types produce anogenital warts or condyloma acuminata which are large but usually benign and will regress spontaneously HPV type 16 and 18 are associated with a large percentage of all cervical cancers → The high risk HPV types are linked to the development of anal, penile, vaginal, vulvar, and oropharyngeal cancers DIAGNOSIS OF PAPILLOMAVIRINAE Figure 12. Cutaneous Warts [Lecturer’s PPT] Cutaneous warts are primarily caused by types 1-4 These warts may be classified as common and seen in fingers and hands, on plantar areas, or it may be flat warts of the arms, face, and knee Epidermodysplasia verruciformis → Another category of cutaneous lesions occur in patients with possible inherited predisposition for multiple warts that do not regress but instead spread to many body sites → These lesions frequently give rise to squamous cell carcinomas several years after the initial appearance of the original warts especially in areas of skin exposed to sunlight ORAL INFECTIONS Figure 15. Paps Smear Collection [Lecturer’s PPT] Diagnosis of cutaneous warts generally involves no more than the visual inspection Biopsy may be done if the diagnosis is uncertain, in immunocompromised patients, or for pigmented and ulcerated lesions The lack of any tissue culture system for recovery of the virus, typing is done by quantitative DNA amplification techniques or PCR For HPV associated cancers and pre-cancerous lesions cervical screening using Pap smear can be done. Figure 13. Oral Infections [Lecturer’s PPT] → Perform Pap screening regardless of vaccination status Oral infections are caused by types 13 and 32 TREATMENT, CONTROL & PREVENTION OF Oral and nasopharyngeal mucosal surfaces can be PAPILLOMAVIRINAE infected by some HPV types Most of these infections resolve in benign papillomas GENITAL TRACT INFECTIONS Figure 14. Genital Tract Infections (Genital Warts) [Lecturer’s PPT] Around 30 different types of HPV can infect the genital tract → Type 6 and 11 cause 90% of genital papillomas All of the genital tract HPV infections are sexually transmitted Figure 16. Treatment Options for Papillomavirus [Lecturer’s PPT] MICROBIOLOGY - LEC DNA Viruses PAGE 7 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP Treatment of warts generally involves surgical removal, There are 3 human polyomaviruses cauterization or destruction of the wart tissue with → BKV liquid nitrogen, laser vaporization, or cytotoxic → JCV chemicals such as podophyllin or trichloroacetic acid → Although such treatment remove the warts, HPV often remains present in cells of the surrounding tissue and ❗️ → MCV JCV has been associated with Progressive Multifocal Leukoencephalopathy (PML) which is a rare fatal recurrence occurs demyelinating disease that occurs only in patients with Patient applied anogenital wart removal consists of: → Imiquimod ❗️ impaired immune function like AIDS patients BKV can cause hemorrhagic cystitis in the same → Podofilox → Sinecatechins 15% ointment Provider administered wart removal: ❗️ population MCV DNA can be detected in the majority of cases of Merkel cell carcinoma which is a rare and aggressive → Cryotherapy form of skin cancer → Surgical removal The human polyomavirus BKV and JCV are transmitted → Use of trichloroacetic acid or bichloroacetic acid from droplets of the upper respiratory tract of infected Interferon given orally has been shown to cause persons and possible through contact with their urine regression of laryngeal papillomas Infection with these viruses usually occurs in childhood Transmission of the infection is by direct inoculation, avoiding contact with wart tissue is the primary means CLINICAL MANIFESTATIONS OF POLYOMAVIRINAE of prevention PROGRESSIVE MULTIFOCAL In genital tract warts all of the procedures for prevention of LEUKOENCEPHALOPATHY sexually transmitted disease are appropriate Vaccine against the foremost common HPV types are available as GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) → It contains viral capsids from HPV type 6, 11, 16, and 18 ▪ Types 6 and 11 cause most genital warts ▪ Types 16 and 18 cause the majority of cervical cancers → Originally recommended for young females as a protection against cervical cancer; however, the vaccine is now recommended for young males as well B. SUBFAMILY POLYOMAVIRINAE/POLYOMAVIRIDAE Figure 18. MRI of Progressive Multifocal Leukoencephalopathy [Lecturer’s PPT] The immunocompromised can be associated with the development of progressive multifocal leukoencephalopathy → Named because the lesions are restricted to white matter PML is thought to be caused by reactivated JC virus that has entered the CNS via the blood, it occurs as complication of a number of diseases that affect immune competence JC virus carries out cytocidal infection of the brain → Specifically of oligodendrocytes leading to demyelination Early development of impaired speech and mental capacity is rapidly followed by paralysis and sensory abnormalities with death commonly occurring within 3-6 months of onset of the initial symptoms. Space intentionally left blank Figure 17. Polyomavirus Infection [Lecturer’s PPT] MICROBIOLOGY - LEC DNA Viruses PAGE 8 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP HEMORRHAGIC CYSTITIS Figure 21. The Enveloped DNA Viruses: Herpesviruses[Lecturer’s PPT] Herpesvirus variance consists of an icosahedral capsid enclosed in an envelope derived from the host nuclear Figure 19. Clinical Manifestations of BK Virus membrane and contains viral glycoprotein spikes. The BK virus (Human Polyomavirus 1) is also found in Tegumen is an amorphous proteinaceous material that lies the urine but rarely has pathologic consequences except between the envelope and the capsid in immunocompromised patients who may develop → Contains virus-encoded enzymes and transcription hemorrhagic cystitis factors essential for the initiation of the infectious cycle The genome is a single molecule of linear MERKEL CELL CARCINOMA Merkel cell carcinomas are relatively rare but are ❗️ double-stranded DNA A prominent property of Herpes viruses is their ability to establish lifelong persistent infections in their host, and aggressive and develop more frequently in older individuals. it can undergo periodic reactivation Develop more often in persons who are → Reactivation may be frequent in the elderly and immunocompromised immunosuppressed patients The herpes viruses that commonly infect humans are II. ENVELOPED DNA VIRUSES → Herpes simplex virus types 1 and 2 (HSV-1 and A. HERPESVIRUSES HSV-2), → Varicella-zoster virus (VZV) → Epstein-Barr virus (EBV → Cytomegalovirus (CMV) → Herpesvirus 6 (HHV-6) → Herpesvirus 7 (HHV-7) → Herpesvirus 8 (HHV-8) also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV) CLASSIFICATION OF HERPESVIRUSES Herpesviridae have been divided into 3 sub-families based primarily on biologic characteristics Alphaherpesvirinae or the Herpes simplex virus group → They have rapid cytocidal or lytic growth cycles and establish dormant or latent infections in nerve ganglia. → Examples: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and Varicella-zoster virus (VZV) Betaherpesvirinae or Cytomegalovirus group → These viruses have a relatively slow replication cycle that results in the formation of characteristic multinucleated giant host cells → Latency is established in non-neural tissues, primarily lymphoreticular cells and glandular tissues → Examples: Human cytomegalovirus (HCMD) and Human herpesvirus 6 (HHV-6) and 7 (HHV-7) Gammaherpesvirinae or Lymphoproliferative group → The viruses replicate in mucosal epithelium and establish latent infections, primarily in B cells → They induce cell proliferation and immortalize lymphoblastoid cells → A virus recovered from cells of Kaposi’s Sarcoma is a human member of the gammaherpesvirinae ▪ It has been designated as human herpesvirus 8 Figure 20. The Enveloped DNA Viruses [Lecturer’s PPT] (HHV-8), and can establish latency and immortalize endothelial cells (eg. Epstein-Barr virus (EBV)) MICROBIOLOGY - LEC DNA Viruses PAGE 9 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP Table 1. Classification of Herpesviridae Adsorption: The herpesvirus enters the host cell by Subfamily Scientific name Common name Acronym fusion with the cell membrane after binding to specific Human Herpes simplex HSV-1 cellular receptors via envelope glycoproteins herpesvirus 1 virus type 1 The capsid is then transported through the cytoplasm to a Alpha- Human Herpes simplex nuclear pore, uncoating occurs, and the DNA becomes HSV-2 herpesvirinae herpesvirus 2 virus type 2 associated with the nucleus Human Varicella-zoster The viral DNA forms a circle immediately upon release VZV herpesvirus 3 virus from the capsid Human herpesvirus 5 Cytomegalovirus HCMV Newly synthesized viral DNA is packaged into pre-formed Beta- Human empty nucleocapsids in the cell nucleus. HHV-6 The virus acquires an envelope by budding through the herpesvirinae herpesvirus 6 Human nuclear membrane HHV-7 The completed virus is transported by a vacuole to the herpesvirus 7 Human surface of the cell Epstein-Barr virus EBV Gamma- herpesvirus 4 The end result of this productive lytic cycle is cellular herpesvirinae Human Kaposi’s Sarcoma death because most cellular synthetic pathways are HHV-8 herpesvirus 8 associated virus turned off during viral replication REPLICATION OF HERPESVIRUSES B. HERPES SIMPLEX VIRUS TYPES 1 AND 2 (HSV-1, HSV-2) There are two distinct HSV: Herpes simplex virus 1 and Herpes simplex virus 2 Transmission of both HSV types: → Direct contact with virus-containing secretions with lesions on mucosal or cutaneous surfaces Primary or recurrent infections in the oropharyngeal region → Caused primarily by HSV-1, accompanied by virus release into saliva (i.e. kissing and saliva-contaminated fingers) Genital tract infections → Caused primarily by HSV-2, present in genital tract secretions → Major modes of transmission: ▪ Sexual intercourse and passage of newborns through the birth canal of infected mothers Both HSV-1 and HSV-2 multiply in epithelial cells of the mucosal surface onto which they have been inoculated, → Results in production of vesicles or shallow ulcers ❗️ containing infectious virus A lifelong latent infection established in the regional ganglia → Due to the entry of infectious variants into sensory neurons that terminate at the site of infection → Oropharyngeal HSV infections result in latent infections in the trigeminal ganglia → Genital HSV infection leads to latently infected sacral ganglia → Provocative stimuli like axonal injury, fever, physical or emotional stress, and exposure to ultraviolet light can reactivate the virus from the latent state The virus transits via axons back to the peripheral site and replication proceeds of the skin or the mucous membranes Immunocompromised patients are at increased risk of developing severe HSV infections Figure 23. Replication of Herpesviruses: Absorption → Entry → Individuals with malnutrition and renal, cardiac and bone → Capsid transport to the nucleus → Transcription → marrow transplant recipients Translocation → Replication → Capsid assembly → → Patients with hematologic malignancies and patients Glycosylation → Glycoprotein export to the cell surface → with AIDS. Endocytosis of glycoprotein-containing plasma membrane → Envelopment → Virus release [Lecturer’s PPT] Space intentionally left blank MICROBIOLOGY - LEC DNA Viruses PAGE 10 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP Primary infections in adults commonly cause pharyngitis and tonsillitis → Fever sores a cluster of vesicles most commonly localized at the border of the lip is produced by the current disease. → This initially causes intense pain, but spans over 4 to 5 days → Lesions progress through the pustular and encrusted stages, and healing follows without scarring → Lesions may recur repeatedly at various intervals. HSV infections may be a cause of severe keratoconjunctivitis The current lesions of the eye are commonly encountered and appear as dendritic keratitis, corneal ulcers, or vesicles on the eyelids The corneal stroma becomes classified with recurrent keratitis and can lead to blindness GENITAL HERPES Figure 24. A. Establishment of latent infection, B. Reactivation of latent virus[Lecturer’s PPT] CLINICAL MANIFESTATIONS OF HERPES SIMPLEX VIRUS TYPES 1 AND 2 (HSV-1, HSV-2) HSV-1 and HSV-2 may cause clinical infections that may be primary or recurrent. → Primary infections occur in persons without antibodies and may be subclinical ▪ But will result in antibody production and establishment of latent infections in sensory ganglia → Recurrent lesions are common Primary infections of HSV-1 are oropharyngeal disease, gingivostomatitis, or fever sores. HSV-2 typically presents as herpes genitalis, which is Figure 25. Genital Herpes[Lecturer’s PPT] sexually transmitted, Genital herpes is more often caused by HSV-2. There is an increase in the frequency of occurrence of → Although HSV-1 can also cause clinical episodes of sexually transmitted HSV-1 and HSV-2 oral infections genital herpes making them indistinguishable without laboratory testing. There are painful vesico-ulcerative lesions of the penis Primary HSV-1 infections are usually asymptomatic in male or of the cervix, vulva, vagina, and perineum in Symptomatic diseases or gingivostomatitis females. → Occurs most frequently in small children of about 1 to 5 → The condition may be associated with fever, malaise, years of age, and involves the buccal and gingival dysuria, and inguinal lymphadenopathy mucosa of the mouth → Complications include: extragenital lesions and → Incubation period: about 3 to 5 days aseptic meningitis → Clinical illness: around 2 to 3 weeks → Viral secretion persists for about 3 weeks → Symptoms include fever, sore throat, vesicular and There is an antigenic cross reactivity between HSV-1 and ulcerative lesions, gingivostomatitis, and malaise HSV-2 → Gingivitis or swollen and tender gums is the most → An initial HSV-2 infection in a person already immune to striking and common lesion HSV-1 tends to be less severe → Recurrence of genital herpetic infections are common, but are usually milder A person shedding the virus is infectious and can transmit it to sexual partners Genital HSV infections increase the acquisition of human immunodeficiency virus infections due to the ulcerative lesions in the mucosal surface HERPETIC SKIN INFECTIONS HSV infections of the skin are uncommon in healthy persons. Localized lesions caused by HSV-1 or HSV-2 may occur in abrasions that become contaminated with the virus like in traumatic herpes Figure 24. Gingivostomatitis[Lecturer’s PPT] Herpetic skin infections are often severe and life threatening in individuals with disorders of the skin (i.e. eczema or burns) because this allows extensive local viral replication and spread. MICROBIOLOGY - LEC DNA Viruses PAGE 11 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP → Eczema herpeticum is a primary infection usually with → Sources of infection include family members and HSV-1 in a person with chronic eczema hospital personnel who are shedding the virus → This condition can become fatal Majority of neonatal herpes infections are caused by → Severe meningitis or encephalitis may be produced HSV-2 by herpes virus There is no difference between the nature and severity of Herpetic whitlow are lesion seen on the fingers of neonatal herpes in premature or full term infants in dentists and hospital personnel infections caused by either HSV 1 or 2 It exhibits 3 categories of disease: → Lesions localized to the skin, eye, and mouth → Encephalitis with or without skin involvement → Disseminated disease involving multiple organs, including the Central Nervous System ▪ The worst prognosis is in infants with disseminated infection, with a mortality of 80% Primary infection before 20 weeks of gestation is associated with spontaneous abortion DIAGNOSIS OF HERPES SIMPLEX VIRUS TYPES 1 AND 2 (HSV-1, HSV-2) Polymerase chain reactions (PCR) or Nucleic Acid Amplification tests → Detect viruses in vesicle swamps, blood, and CSF → Sensitive and specific Figure 26. Herpetic Whitlow[Lecturer’s PPT] → PCR examination of CSF is sensitive in the diagnosis of Herpes gladiatorum are lesion seen on the bodies of Herpes Meningitis and Encephalitis wrestlers → Test of choice for CSF and the gold standard due to its HSV-1 infections are considered the most common cause sensitivity and rapid turnaround time of sporadic fetal encephalitis in the U.S. Virus culture is used most commonly in diagnosing → This disease has a high mortality rate, and those who mucocutaneous disease survive often have residual neurologic deficits → Virus may be isolated from herpetic lesions, respiratory NEONATAL HERPES samples, tissues, and body fluids both during the primary infection and asymptomatic periods Staining scrapings from the base of a vesicle with giemsa stain is a rapid cytologic method that can reveal the presence of multinucleated giant cells → Indicates the presence of either Herpes virus 1, 2 or Varicella zoster Serologic methods available include neutralization, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) TREATMENT & PREVENTION OF HERPES SIMPLEX VIRUS TYPES 1 AND 2 (HSV-1, HSV-2) Figure 27. Neonatal Herpes[Lecturer’s PPT] HSV infections of the newborn may be acquired in utero during the birth process or after birth → The mother is the most common source of infection in all cases Figure 28. Acyclovir Tablets [Lecturer’s PPT] The newborn infant is unable to limit the replication and Newborns acquire passively transferred maternal spread of HSV, and it has a propensity to develop severe antibodies though they are lost during the first 6 disease months of life. → The most common route of infection of HSV for a → Greatest susceptibility to primary herpes infection newborn is during birth by contact with herpetic occurs between ages 6 months to 2 years lesions during the passage in the birth canal After a primary infection, the virus is carried in a latent To circumvent this problem, delivery by cesarean section state in the presence of antibodies. has been used in pregnant women with genital herpes → These antibodies will not prevent the infection or lesions reactivation of latent virus but may modify subsequent It is postnatally acquired through exposure to either HSV-1 disease or HSV-2 MICROBIOLOGY - LEC DNA Viruses PAGE 12 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP Antiviral drugs like Acyclovir, Valacyclovir, and CLINICAL MANIFESTATIONS OF VARICELLA ZOSTER Vidarabine have been proven effective against Herpes VIRUS (HHV-3) Simplex Virus infections VARICELLA (CHICKENPOX) → MOA: viral DNA synthesis inhibitors → Use of these drugs suppress clinical manifestations, shorten healing time, and reduce recurrences of genital herpes Patients with genital herpes should be counseled that asymptomatic shedding occurs and the risk of transmission can be reduced by antiviral therapy and condom usage C. VARICELLA ZOSTER VIRUS (HHV-3) Figure 30. Chickenpox appearance [Lecturer’s PPT] Transmission is through the Mucosa of the Upper Respiratory Tract (URT) or Conjunctiva Infectious from short-living appearance of rash to the first few days of rash Primary Viremia → The virus infects nearby lymph nodes, replicates, and enters the bloodstream Secondary Viremia → Results from the replication in liver and spleen Infected mononuclear cells transport the virus to the skin Figure 29. Varicella Zoster Virus virion structure [Lecturer’s PPT] ❗️HHV-3 causes chickenpox, a mild highly contagious disease occurring mostly in children where a typical rash develops The Varicella Virus Encoded Protein ORF 61 antagonizes the beta interferon pathway → It is highly communicable and is a common epidemic → Contributes to the pathogenesis of viral infection disease of childhood → Incubation period: 10-21 days → Spread via airborne droplets and direct contact Malaise and fever are the initial symptoms followed by → A varicella patient is infectious from shortly before the rashes developing first on the trunk, then the face, limbs, appearance of rash to the first few days of rash. and the buccal and pharyngeal mucosa in the mouth in a ▪ They can be the source of varicella in susceptible centrifugal pattern children → Successive fresh vesicles appear in crops so that you → Major clinical characteristic can see all stages of macules, papules, vesicles, and ▪ Generalized vesicular eruption of the skin and crusts at one time mucous membranes Complications are rare in normal children and mortality − Severe in adults and immunocompromised rate is very low individuals → Life threatening encephalitis may occur in rare cases In comparison to Herpes Zoster (Shingles) ▪ Survivors may be left with permanent sequelae → Sporadic disease in the elderly and → Varicella pneumonia is rare in healthy children but is immunocompromised the most common complication in neonates, adults, → Characterized by a painful vesicular rash limited in and immunocompromised patients, potentially distribution to the skin, innervated by a single sensory causing death ganglion and at times dermatomal The virus is widely disseminated and may prove fatal → Lesions are similar to Varicella since both diseases Neonatal varicella is contracted from the mother just are caused by the same virus but varicella is the acute before or after birth. disease that follows primary contact with the virus while Pediatric leukemia patients are prone to developing zoster is the response of the partially immune host to severe disseminated VCV diseases reactivation of latent varicella virus present in Previous infection with varicella is believed to confer neurons in sensory ganglia lifelong immunity to varicella Both varicella and herpes zoster occur worldwide MICROBIOLOGY - LEC DNA Viruses PAGE 13 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP HERPES ZOSTER Varicella has been found in many specimens like tissue, blood, CSF, and body fluids. In Tzanck smear, cellular materials from the base of a vesicle are examined for the presence of multinucleated giant cells. DFA is used directly to detect viral proteins from clinical materials using antibodies to VCV NAATs → Most sensitive method in detecting VCV from clinical material → Gold standard diagnostic assay → Recommended in detecting VCV in CSF and from different sources Virus is detectable in crusting lesions when a vesicle is Figure 31. Herpes Zoster [Lecturer’s PPT] not present HZ patients can be the source of Varicella in susceptible Blood may be used for immunocompromised patients children. suspected of disseminated zoster who do not have the There is an acute inflammation of the sensory nerves characteristic vesicular rash and ganglia, often involving only a single ganglia Cell culture may be done but requires confirmation by Distribution of lesions in the skin corresponds to the areas DNA of innervation of the individual dorsal root ganglion, TREATMENT & PREVENTION producing a dermatomal distribution of lesions Neonates and immunocompromised patients with severe It is presumed that waning immunity allows virus infection should be treated replication in a ganglion, causing intense inflammation Varicella-zoster immune globulin is used to prevent the and pain development of the illness in patients exposed to Varicella → The virus travels down the nerve, to the skin, and who are at high risk of developing severe disease induces vesicle formation → It has no therapeutic value after varicella has started Cell-mediated immunity is the most important host Acyclovir, Valacyclovir, Famciclovir, and Foscarnet defense against VCV may be used for treatment Reactivations are sporadic and infrequent → Acyclovir: Prevents the development of systemic HZ usually occurs in the immunocompromised but may disease in immunosuppressed patients and halts the occur in healthy patients, beginning with severe pain in progression of HZ in adults an area of skin/mucosa supplied by a group of sensory ▪ Adults with HZ can be treated with oral Acyclovir at nerves and ganglia and is open unilateral a dose of 800 mg 5x daily Within a few days, a crop of vesicles with surrounding Live attenuated varicella vaccine is available for redness appear over the skin, supplied by the affected varicella nerves usually in a dermatomal distribution → 95% effective in preventing severe disease → Trunk, head, and neck are usually affected Herpes Zoster (Shingles Vaccine) is also available → Ophthalmic division of CN V is involved in 10-15% of → 14x more potent version of the varicella vaccine cases → Effective in older adults at reducing the frequency of Post herpetic neuralgia is the most common complication outbreaks of zoster and the disease severity in the elderly → Recommended for people with chronic medical → Causes protracted pain lasting for months conditions and persons older than 60 years old → Especially common after ophthalmic zoster Visceral disease, especially pneumonia, causes death in Table 2. Treatment regiments immunosuppressed patients with zoster. Dosage and Frequency of Drug administration DIAGNOSIS OF VARICELLA ZOSTER VIRUS (HHV-3) Acyclovir 800 mg five times daily for 7-10 days Famciclovir 500 mg three times daily for 7 days Valacyclovir 1 g by mouth three times daily for 5-7 ❗️ days Antiviral therapy should be started as soon as possible (within 24-48 h of symptoms) Space intentionally left blank Figure 32. Tzanck Smear [Lecturer’s PPT] MICROBIOLOGY - LEC DNA Viruses PAGE 14 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP D. EPSTEIN-BARR VIRUS / EBV / HHV-4 ADDITIONAL INFORMATION ON EBV PATHOGENESIS Also known as Human herpesvirus-4 (HHV-4) In normal individuals, most virus infected cells are Commonly spreads through bodily fluids primarily saliva eliminated. The small number of latently infected → It contains virus during both primary infection and in lymphocytes persist for the lifetime of the host repeated episodes of asymptomatic shedding Primary infections in children are usually subclinical Causes Infectious mononucleosis (also known as Infections in young adults usually results in acute “mono” or “the kissing disease”) infectious mononucleosis Also associated with the following malignancies: The activation of EBV latent infections can occur and will → Nasopharyngeal carcinoma produce an increased level of virus in saliva and of DNA in → Burkitt’s Lymphoma blood cells, which are usually clinically silent → Hodgkin’s and Non-hodgkin’s lymphoma Immunosuppression can cause a reactivation of infection, → Gastric Carcinoma sometimes with serious consequences → Lymphoproliferative disorders in immunodeficient individuals Figure 34. Human Herpesvirus 4 [Lecturer’s PPT] Two major strains of EBV: Type A & Type B Initial site of virus replication: oropharyngeal epithelium → Some of the progeny viruses would then infect the lymphocytes EBV major target cells: B-lymphocytes → Complement component C3D receptor in B-cell is the specific target of EBV → During B-cell infection only a limited number of early Figure 35. EBV Pathogenesis [Lecturer’s PPT] proteins are synthesized INFECTIOUS MONONUCLEOSIS (IM) → Expression of gene products result in latency and IM occurs after an incubation period of 4-7 weeks immortalization of the B-cell Classical triad of infectious mononucleosis The early genes of EBV induce cell multiplication and → Fever immortalization rather than cell death → Pharyngitis → Infection induces a polyclonal B-cell proliferation and → Lymphadenopathy (usually enlargement of anterior a non-specific increase in total IgM, IgG, and IgA and posterior cervical lymph nodes) Latency can be disrupted by a variety of stimuli including Presents splenomegaly and increased liver enzymes in chemical agents or cross-linking cell surface the blood → headache and malaise ensue that would last immunoglobulin → EBV genome activation for several weeks EBV can replicate in vivo, in epithelial cells of the Complete recovery may take much longer oropharynx, parotid gland, and uterine cervix The number of circulating white blood cells increases with It is found in the epithelial cells of some nasopharyngeal the predominance of lymphocytes carcinomas → Many of these are large atypical T-lymphocytes called PATHOGENESIS OF EBV Downey cells 1. In primary infection, EBV is commonly transmitted by infected saliva → infection in the oropharynx 2. Virus replicates in the epithelial cells or surface B-lymphocytes of the pharynx and salivary glands → Infected people shed low levels of virus for weeks to months after infection 3. Infected B-cells from the oropharynx spread infection throughout the body Figure 36. Infectious Mononucleosis [Lecturer’s PPT] MICROBIOLOGY - LEC DNA Viruses PAGE 15 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP CANCERS ASSOCIATED WITH EBV BURKITT’S LYMPHOMA Immunohistochemistry (IHC) or In situ hybridization (ISH) to detect virus in tissues A B-cell lymphoma presenting as a tumor of the jaw in → GOLD STANDARD: ISH targeting the non-coding African children and young adults EBV encoded RNA (EBER) as it is more sensitive than Most african tumors contain EBV DNA IHC since EBER is produced regardless of the stage of EBV may be involved at an early stage in Burkitt’s infection or latency of the virus lymphoma by immortalizing B cells Quantitative nucleic acid amplification test Malaria and parasitic disease may foster enlargement of → Useful to obtain viral loads the pool of EBV infected cells → Higher viral loads correlate to an increased probability of post transplant lymphoproliferative disorder (PTLD) Figure 37. Burkitt Lymphoma [Lecturer’s PPT] NASOPHARYNGEAL CARCINOMA A cancer of the epithelial cells common in males of Chinese and Southeastern asian descent EBV DNA is regularly found in nasopharyngeal carcinoma cells and patients have high levels of antibody to EBV Immunodeficient patients and transplant patients are Figure 39. Antibodies for EBV Testing [Lecturer’s PPT susceptible to EBV-induced lymphoproliferative diseases which may lead to monoclonal B-cell TREATMENT AND PREVENTION OF EBV INFECTIONS lymphomas Acyclovir 800 mg p.o. given 5 times daily for 10 days + AIDS patients: susceptible to EBV-associated lymphomas Prednisolone 0.7 mg/kg daily for 4 days and oral hairy leukoplakia (wart-like growth that develops → Acyclovir reduces oropharyngeal shedding of EBV on the tongue) during the period of drug administration but it does not affect the number of EBV immortalized B-cells HODGKIN AND NON-HODGKIN LYMPHOMA → Acyclovir has no effect on the symptomatology of IM All CNS non-hodgkin lymphomas are associated with EBV and has no proven benefit on the treatment of EBV EBV is associated with classic hodgkin’s disease wherein associated lymphomas in immunocompromised patients the viral genome of EBV is detected in the malignant Treatment caused no significant benefit on duration of Reed-Sternberg cells general illness, sore throat, weight loss and absence from DIAGNOSIS OF EBV school or work Diagnostic test: serology in most cases of EBV infection E. CYTOMEGALOVIRUS / CMV / HHV-5 → Heterophile antibody detection uses red blood cells or aka Human Cytomegalovirus or Human Herpes Virus 5 latex agglutination to detect anti-erythrocyte A member of the Betaherpesvirinae subfamily antibodies that are produced as a result of polyclonal Cytomegalovirus has a worldwide distribution with a zero B-cell expansion seen in mononucleosis prevalence of nearly 100% in the elderly population → Anti-VCA IgG and IgM antibodies Infections are typically asymptomatic with most children → Anti-EA IgG antibody and adults infected at an early age → Anti-EBNA IgG antibody Infection in immunocompromised host is common and → sometimes severe High prevalence in children and adults in developing nations and in low socio-economic groups Has the largest genetic content among the human herpes viruses as its DNA genome is significantly larger than that of herpes simplex virus (HSV). CMV can bind to the Fc portion of immunoglobulins which allows infected cells to evade immune elimination Human CMV infection is spread primarily from cell to cell CMV are species specific and cell type specific. Animals cannot be infected with human cytomegalovirus. There is a characteristic cytopathic effect that is produced by cytomegalovirus Figure 38. EBV- Specific Serology [Lecturer’s PPT] MICROBIOLOGY - LEC DNA Viruses PAGE 16 of 28 MICROBIOLOGY | LE 2 DNA Viruses | Januario E. Sia-Cunco MD, MHSE, FPASMAP → Perinuclear cytoplasmic inclusions and intranuclear ADDITIONAL INFORMATION ON CMV inclusions PATHOGENESIS → Many of the affected cells become greatly enlarged Initial replication of the virus in epithelial cells of the or cytomegalic. respiratory and GI tract is followed by viremia and → They become multinucleated and it contains inclusions infection of all organs of the body. called owl’s eye inclusions → In symptomatic cases, the most commonly affected CMV is endemic worldwide but epidemics are unknown organs are: kidney tubule epithelium, liver and CNS Oral and respiratory spread are probably the dominant Causes systemic infections and has been isolated from roles of CMV transmission, other transmission modes may lung, liver, esophagus, colon, kidney, monocytes and T occur as it may be shed in urine, saliva, semen, breast and B lymphocytes milk, and cervical secretions and is carried in WBCs and Can manifest as mononucleosis-like syndrome sero-positive transplant organs Can establish life-long latent infection CMV primary infection can cause depression of cell-mediated immunity and can lead to persistence of viral infections → CMV primary infection in immunosuppressed hosts are much more severe → Reactivated infections: immunocompromised patients