Herpes Viruses affecting hematolymphoid system PDF

G A L A L A U N I V E R S I T Y T H E F U T U R E S TA R T S H E R E Herpes Viruses affecting hematolymphoid system D r. R a s h a S h a l a by T H E F U T U R E S T...

G A L A L A U N I V E R S I T Y T H E F U T U R E S TA R T S H E R E Herpes Viruses affecting hematolymphoid system D r. R a s h a S h a l a by T H E F U T U R E S T A R T S H E R E Outline Intro about Herpes viruses Epstein-Barr virus Cytomegalovirus Members of Herpes viruses Classified into alpha, beta and gamma herpes viruses based on: 1-Type of cell most often infected (tropism) and 2- The site of latency. Alpha-herpesviruses infect epithelial cells primarily and cause latent infection in neurons. Beta-herpesviruses infect and become latent in a variety of tissues. Gamma-herpesviruses infect and become latent primarily in lymphoid cells. Herpes viruses; an introduc1on Each has an icosahedral core surrounded by a lipoprotein envelope. The genome is linear double-stranded DNA. (All are structurally related!) The virions possess a tegument located between the nucleocapsid and the envelope which play a role in viral replicaDon. Herpes viruses; an introduction Herpesviruses cause life-long latent infec@ons Acute disease is followed by an asymptomaDc period during which the virus remains in a quiescent (latent) state. When immunosuppression occurs, reacDvaDon of virus replicaDon and disease can occur.  G A L A L A U N I V E R S I T Y T H E F U T U R E S T A R T S H E R E Part I: Epstein-Barr Virus T H E F U T U R E S T A R T S H E R E Outline Dis:nc:ve characteris:cs of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complica:ons Immunity Diagnosis Preven:ons and treatment Distinctive characteristics of EBV Epstein-Barr virus (EBV); cause of infec6ous mononucleosis Enveloped DNA virus A member of the family Herpesviridae. The most important an6gen is the viral capsid an,gen (VCA), because it is used most oFen in diagnos6c tests. Outline Distinctive characteristics of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complications Immunity Diagnosis Preventions and treatment Transmission and epidemiology Transmission Natural hosts: Humans. EBV cellular tropism: - Infects mainly lymphoid cells, primarily B lymphocytes. - EBV also infects the epithelial cells of the pharynx, resulting in the prominent sore throat. Transmission: Direct oral contact and contamination with saliva (principal modes of transmission) Transfer through blood transfusions, sexual contact, and organ transplants is possible. Transmission and epidemiology; con>nued Epidemiology: EBV infec*on is one of the most common infec*ons worldwide. More than 90% of adults in the United States have an*body. Not for memorization Outline Dis:nc:ve characteris:cs of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complica:ons Immunity Diagnosis Preven:ons and treatment Pathogenesis EBV causes infec*ous mononucleosis The infec*on first occurs in the oropharynx and then spreads to the blood, where it infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B cells. Pathogenesis (Life cycle) EBV enters B lymphocytes at the site of the complement C3 receptor. There are three types of viral genes: immediate-early, early and late. The immediate-early genes are transcribed immediately aMer infecDon and ensure the transcripDon of early genes, which encode the proteins necessary for the viral replicaDon. The late genes mostly encode structural proteins. Pathogenesis; con1nued Virulence factors: Latency (no progeny viruses produced) Ability to integrate into host DNA The latency of the virus and its ability to integrate its DNA into host cell DNA enable it to avoid the host’s immune response. EBV switches between 2 infection cycles within the host: Latent infection (no progeny viruses) Lytic infection (intense viral replication and progeny production) Switching of EBV cycles Outline Distinctive characteristics of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complications Immunity Diagnosis Preventions and treatment Signs and Symptoms Incubation period: long (30 to 50 days). The symptoms are sore throat, high fever, and cervical lymphadenopathy. Many patients also have a gray- white exudate in the throat, a skin rash, and enlarged spleen and liver. Fatigue is a hallmark of the disease. Patients remain fatigued for a period of weeks. Gray-white exudate in the throat  Complica>ons Oral hairy leukoplakia—a whitish, nonmalignant keratinized lesion with hairy like appearance on the lateral side of the tongue. It occurs in immunocompromised individuals, especially AIDS patients. EBV infection is associated with several cancers e.g., Burkitt’s lymphoma, some forms of Hodgkin’s lymphoma, and nasopharyngeal carcinoma.  EBV-associated BurkiJ lymphoma Outline Distinctive characteristics of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complications Immunity Diagnosis Preventions and treatment Immunity Specific EBV antibodies: The immune response to EBV infection consists first of IgM antibody to the VCA. IgG antibody to the VCA follows and persists for life. The IgM response is therefore useful for diagnosing acute infection, whereas the IgG response is best for revealing prior infection. Nonspecific heterophil antibodies: - These antibodies do not react with any component of EBV. - Not specific for EBV infection - Heterophil antibodies usually disappear after recovery. Immunity; con>nued The term heterophil refers to anDbodies that are detected by tests using anDgens different from the anDgens that induced them. The heterophil anDbodies formed in infecDous mononucleosis aggluDnate sheep or horse red blood cells in the laboratory. A Proposed mechanism: EBV infecDon modifies a cell membrane consDtuent such that it becomes anDgenic and induces the heterophil anDbody. Outline Dis:nc:ve characteris:cs of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complica:ons Immunity Diagnosis Preven:ons and treatment Laboratory diagnosis Healthcare providers can test for anGbodies to the following EBV-associated anGgens by ELISA: Viral capsid anGgen (VCA) AnG-VCA IgM appears early in EBV infec*on and usually disappears within four to six weeks (sign of early ac*ve infec*on). AnG-VCA IgG appears in the acute phase of EBV infec*on, peaks at two to four weeks aYer onset, declines slightly then persists for the rest of a person’s life.  Laboratory diagnosis; continued Early anGgen (EA); non-structural protein An*-EA IgG appears in the acute phase of illness and generally falls to undetectable levels aYer 3-6 months. In most people, detec*on of an*body to EA is a sign of ac*ve infec*on. EBV nuclear anGgen (EBNA); non-structural protein An*body to EBNA is not seen in the acute phase of EBV infec*on but slowly appears 2-4 months aYer onset of symptoms and persists for the rest of a person’s life [marker of past infec*on and latency]. Interpreta>on of EBV an>body tests Primary (new or recent) infection If they have anti-VCA IgM but do not have antibody to EBNA. High or rising level of anti-VCA IgG and no antibody to EBNA after at least four weeks of illness. Past/Prior infection The presence of IgG antibodies to both VCA and EBNA suggests past/prior infection (from several months to years earlier).  Laboratory Diagnosis; con0nued Differen@al blood count: absolute lymphocytosis occurs. Stained blood smear: Atypical lymphocytes are enlarged, have an expanded nucleus, and have an abundant, oMen vacuolated cytoplasm (check the figures). They are cytotoxic T cells that are reacDng against the EBV- infected B cells. As many as 30% abnormal lymphocytes are seen on a stained smear. Outline Dis:nc:ve characteris:cs of EBV Transmission and epidemiology Pathogenesis Signs, symptoms & complica:ons Immunity Diagnosis Preven:on and treatment  Prevention and treatment PrevenGon: there is no EBV vaccine. Treatment: The usual treatments for infec*ous mononucleosis is symptoma*c for relief of fever and sore throat. No an*viral therapy is necessary for uncomplicated infec*ous mononucleosis. Summary  G A L A L A U N I V E R S I T Y T H E F U T U R E S TA R T S H E R E Part II: Cytomegalovirus (CMV) T H E F U T U R E S T A R T S H E R E  Human Cytomegalovirus Viral structure: refer to slide no. 3 Transmission & Epidemiology A. Transmission: CMV is transmiSed by a variety of modes. Early in life, it is transmiSed across the placenta, within the birth canal, and quite commonly in breast milk. In young children, its most common mode of transmission is via saliva. Later in life, it is transmiSed sexually; it is present in both semen and cervical secreDons. It can also be transmiSed during blood transfusions and organ transplants. B. Prevalence Es#mated global cytomegalovirus seroprevalences in women of reproduc#ve age https://core.ac.uk/download/pdf/199401111.pdf Replica9on cycle Refer to EBV replication cycle. Tropism: Able to infect diverse cell types such as epithelial cells, fibroblasts, lymphocytes, monocytes, and macrophages, and this characterization of broad tropism. Pathogenesis and clinical manifesta9ons: Cytomegalic inclusion disease: caused by transplacental infec*on. mul*nucleated giant cells with prominent intranuclear inclusions (check image). Widespread congenital abnormali*es more common when a fetus is infected during the first Colonic biopsy with intracellular cytomegalovirus inclusions trimester than later in gesta*on  Pathogenesis and clinical manifesta9ons: InfecGon of immunocompetent children and adults - Mostly asymptomaDc (latency) unless there is an immune suppression. - CMV can cause mononucleosis-like symptoms characterized by fever, and the presence of abnormal lymphocytes in peripheral blood smears (heterophil an@body-nega@ve). In immunocompromised paGents: systemic CMV infecDons, especially pneumonia, esophagiDs, and hepaDDs are common In AIDS paDents : coliDs with diarrhea, reDniDs can occur. Clinical manifestations are not for memorization Laboratory Diagnosis PCR-based assays for CMV DNA or mRNA in tissues or body fluids, such as spinal fluid and amniotic fluid. Fluorescent antibody and histologic staining of inclusion bodies (oval owl’s eye shape) (check Cytomegalovirus—owl’s eye inclusion body. Arrow image) points to an “owl’s eye” inclusion body in the nucleus of an infected cell Serologic tests to detect IgM in patient’s serum (recent infection). References Levinson, Warren E., et al. Review of Medical Microbiology and Immunology. McGraw Hill Professional, 2022 hSps://www.cdc.gov/epstein-barr/index.html