Viral Infections
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25/12/2018 Introduction to Microbiology for M.D. Students University of Jordan School of Medicine Department of Pathology, Microbiology and Forensic Medicine Section of Microbiology and Immunology Malik Sallam, MD, PhD What are viruses? 1 25/12/2018 General Characteristics of Viruses • Obligate intracellular parasites. • Extremely small size. • Genome is either DNA or RNA (never both). • Extremely variable. • Uncertain origin. Terminology 2 25/12/2018 Virus Taxonomy-ICTV Classification Order (-virales) Family (-viridae) Subfamily (-virinae) Genus (-virus) Species Baltimore Classification 3 25/12/2018 Virus Classification • Morphology (capsid symmetry, presence of an envelope, etc.). • Host organism (human, animal, plant, bacteria). • Type of disease (hepatitis viruses, respiratory viruses, etc.). Virus Classification 4 25/12/2018 Virus Classification Overview of Human Viruses-DNA Viruses • HHAPPPy viruses: Herpesviridae oReplicate in the nucleus (except Pox). Hepadnaviridae oDouble-stranded (except Parvo). Adenoviridae oNaked vs. Enveloped. Papovaviridae Parvoviridae Poxviridae 5 25/12/2018 Overview of Human Viruses-RNA Viruses Arenaviridae Picornaviridae Bunyaviridae Reoviridae Caliciviridae Retroviridae Coronaviridae Rhabdoviridae Filoviridae Togaviridae Orthomyxoviridae Paramyxoviridae Herpesviruses: An Overview o The outstanding property of herpesviruses is their ability to establish lifelong persistent infections in their hosts and to undergo periodic reactivation. o Their frequent reactivation in immunosuppressed patients causes serious health complications. 6 25/12/2018 Herpesviruses: An Overview o Double-stranded DNA virus. o Icosahedral symmetry. o Enveloped. o Envelope is acquired from the nuclear membrane. o Baltimore Class I. Herpes Simplex Viruses-Introduction o Hippocrates used the Greek word herpes to describe lesions that seem to creep or crawl along the skin. o ICTV designate the two species as human herpesviruses 1 and 2 (HHV-1) and (HHV-2). o The two species were first identified as two distinct serotypes; herpes simplex viruses 1 and 2 (HSV-1) and (HSV-2). 7 25/12/2018 Herpes Simplex Viruses Taxonomy Order (Herpesvirales) Family (Herpesviridae) Subfamily (Alphaherpesvirinae) Genus (Simplexvirus) Species (Human herpesvirus 1; HHV-1) Species (Human herpesvirus 2; HHV-2) Herpes Simplex Viruses-Important Features Natural Host: Human, mammals. Tropism: Epithelial mucosal cells. Latency: Sensory neurons (dorsal ganglia). Cellular receptors: Heparan sulfate among others. Geography: Worldwide. 8 25/12/2018 Herpes Simplex Viruses-Important Features o Transmission (HHV-1): Direct contact, saliva. o Transmission (HHV-2): Sexual contact, vertical. o HSV is transmitted by contact with an individual excreting virus. o The virus must encounter mucosal surfaces or broken skin in order for an infection to be initiated (unbroken skin is resistant). Herpes Simplex Viruses-Characteristic Lesions Vesicles are circumscribed epidermal elevations containing clear fluid and less than 1 cm in diameter. If the lesion has a diameter of greater than 1 cm, it is called a bulla. Vesicles and bullae are commonly called blisters. 9 25/12/2018 Herpes Simplex Viruses-Pathogenesis & Pathology . Primary infection o Viral replication occurs first at the site of infection. o HSV then invades local nerve endings and is transported by retrograde axonal flow to dorsal root ganglia. o After further replication, latency is established. o Oropharyngeal infections result in latent infections in the trigeminal ganglia. o Genital infections lead to latently infected sacral ganglia. Herpes Simplex Viruses-Pathogenesis & Pathology . Primary infection o Primary HSV infections are usually asymptomatic. o Most symptomatic primary infections are mild. o Only rarely does systemic disease develop. o Widespread organ involvement can result when an immunocompromised host is not able to limit viral replication and viremia ensues. 10 25/12/2018 Herpes Simplex Viruses-Pathogenesis & Pathology . Latent infection o Virus resides in latently infected ganglia with very few viral genes being expressed. Herpes Simplex Viruses-Pathogenesis & Pathology . Latent infection o Provocative stimuli can reactivate virus from the latent state, including: Axonal injury. Fever. Physical or emotional stress. Exposure to ultraviolet light. 11 25/12/2018 Herpes Simplex Viruses-Pathogenesis & Pathology . Latent infection o The virus follows axons back to the peripheral site, and replication proceeds at the skin or mucous membranes. o HSV-specific immunity limits local viral replication, so that recurrent infections are less extensive and less severe. o Many recurrences are asymptomatic, reflected only by viral shedding in secretions. Primary/Recurrent Oropharyngeal Disease . Gingivostomatitis. Pharyngitis. Mononucleosis-like syndrome. Herpes labialis (cold sores). 12 25/12/2018 Primary/Recurrent Oropharyngeal Disease . The incubation period ranges from 2-12 days, with a mean of 4 days. The duration of clinical illness may be from 2-3 weeks. Primary/Recurrent Genital Disease . Genital herpes: o Symptomatic primary genital infection is the most severe, lasting about 3 weeks. 13 25/12/2018 Primary/Recurrent Genital Disease . Genital herpes o In females: Excruciatingly painful lesions in the vulva, perineum, buttocks, cervix, and/or vagina associated with inguinal adenopathy and dysuria. o In males: Lesions involving the glans penis or the penile shaft with extragenital lesions of the thigh, buttocks, and perineum. o Proctitis can occur in male homosexuals. o Recurrences of genital herpetic infections are common and tend to be mild. Primary/Recurrent Genital Disease . Genital herpes o Recent evidence documented the increase in the frequency of genital (HSV‐1) compared with genital (HSV‐2) infection. This trend has been seen both in Europe, Australia and in the US. o Oral shedding of HSV-2 is infrequent. 14 25/12/2018 Neonatal Herpes Simplex Virus Infection • The estimated incidence of neonatal HSV infection is 1 in 3,000 to 1 in 5,000 deliveries per year. • May be acquired in utero, during birth, or after birth. • Neonatal herpes infections are almost always symptomatic. • The overall mortality rate of untreated disease is 50%. • Many survivors of severe infections are left with permanent neurologic impairment. Herpes Simplex Keratoconjunctivitis HHV-1 infections may occur in the eye, producing severe keratoconjunctivitis. Recurrent lesions of the eye are common and appear as dendritic keratitis or corneal ulcers or as vesicles on the eyelids. Keratitis may end up in blindness. Pathognomonic Dendritic Ulceration 15 25/12/2018 Herpetic Skin Infections o Usually manifest as eczema herpeticum in patients with underlying atopic dermatitis. o Disseminated HSV infections have been also reported among wrestlers (herpes gladiatorum). Herpetic Skin Infections o Rarely, the infection may be spread to the distal phalanx via direct inoculation and cause pain, swelling, erythema, and vesicles in an entity known as herpetic whitlow. 16 25/12/2018 Infections of the Immunocompromised Host o Immunocompromised patients are at increased risk of developing severe HSV infections. o These include patients immunosuppressed by disease or therapy. o Patients with deficient cellular immunity suffer more frequent and more severe HSV infections. o Herpes lesions may spread and involve the respiratory tract, esophagus, and intestinal mucosa. o In most cases, the disease reflects reactivation of latent HSV infection. Infections of the Central Nervous System o HSV encephalitis is one of the most devastating of all HSV infection. o HSV-1 (HHV-1) is considered the most common cause of sporadic, fatal encephalitis. o The disease carries a high mortality rate. o Aseptic meningitis is a common occurrence in individuals with primary genital HSV infections. 17 25/12/2018 Diagnosis o Clinical diagnosis. o Virus isolation is a definitive diagnostic method (samples include: skin scrapings, throat swab, CSF). o PCR detection of viral DNA. o Cytopathology with Giemsa stain of scrapings (Tzanck smear). o Serology. Treatment o Nucleoside analogues: acyclovir, valacyclovir, penciclovir and famciclovir. o All nucleoside and nucleotide analogues must be activated by phosphorylation usually to the triphosphate form to exert their action. o Mechanism of action: Inhibition of viral genome replication through inhibiting the viral polymerase. 18 25/12/2018 Treatment o The virus thymidine kinase is much more potent compared to the cellular kinases in activating the drug, ∴ it is more efficient in virus- infected cells. o Treatment is important in herpes encephalitis, neonatal herpes, and disseminated infections in immunocompromised patients. o Despite treatment, HSV remains latent in sensory ganglia. o Drug-resistant virus strains may emerge. Epidemiology In 2012, an estimated 3.7 billion people under the age of 50, or 67% of the world population, had HSV-1 infection (WHO). The overall prevalence of HSV-2 among 15–49 year olds world-wide in 2012 is estimated to be 11% (over 400 million people). 19 25/12/2018 Prevention and Control o Educational efforts must be developed for adolescents and those at greatest risk. o Surgical abdominal delivery. o Hospital staff: Temporary removal of personnel who have cold sores is advocated for clinical services. o Experimental vaccines. Varicella Zoster Virus (VZV)-Introduction o Zoster was derived from a Greek word meaning belt. o Shingles was derived from a Latin word meaning