Pathology Ch8 - Infectious Diseases - PARTIAL pp354-362 (Viral Infections)
Viral Infections
 Acute (Transient) Infections
o All elicit effective immune responses > limit duration of infection
o Variable genetic diversities impact susceptibility to re-infection by viruses of the same type
 Mumps > only once
 Influenza > repeatedly infect same individual due to new genetic variants
o Measles (rubeola)
 Acute viral infection that affects multiple organs, causing wide range of disease (mild to severe)
 Pathogenesis:
 Single-stranded DNA virus
 Paramyxovirus family (mumps, resp syncytial v., parainfluenza v., human metapneumovirus)
 Transmitted by respiratory droplets
 Three cell-surface receptors:
o CD46 (complement regulatory protein that inactivates C3 convertase)
 Expressed on all cells
o SLAM (signaling lymphocytic activation molecule)
 Expressed on cells of immune system
o Nectin 4 (adherens junction protein)
 Expressed on epithelial cells
o All receptors bind viral hemagglutinin protein
 Can replicate in a variety of cell types
 Virus initially multiple within the respiratory tract > spreads to local lymphoid tissues
 Replication in lymphatic tissues > viremia and systemic dissemination to many tissues
 Malnourished children can develop "black measles"
o Croup, pneumonia, diarrhea, protien-losing enteropathy, keratitis, encephalitis,
hemorrhagic rashes
 Antibody-mediated immunity protects against reinfection
 Can cause immunosuppression > secondary bacterial/viral infections > morbidity/mortality
 Morphology:
 Blotchy, reddish brown rash on face, trunk, and proximal extremities
 Koplik spots = ulcerated mucosal lesions in oral cavity near Stensen ducts
 Warthin-Finkeldey cells = multinucleated giant cells found in hyperplastic lymphoid organs
o Mumps
 Acute systemic infection associated w/ pain and swelling of salivary glands
 Member of paramyxovirus family
 Two types of surface glycoproteins
 Hemagglutinin and neuraminidase activities
 Cell fusion and cytolytic activities
 Enters upper respiratory tract via respiratory droplets > to lymph nodes > replicate in lymphocytes >
spreads through blood to salivary and other glands
 Results in desquamation of ductal epithelial cells, edema, and inflammation
 Morphology:
 Mumps parotitis = bilateral in most cases, enlarged, doughy, moist, glistening, reddish-brown
 Mumps orchitis = testicular swelling
 Mumps encephalitis = perivenous demyelination and perivascular mononuclear cuffing
 Infection/damage to acinar cells of pancreas > release digestive enzymes > parenchymal and fat
necrosis and inflammation
o Poliovirus Infection
 Acute systemic infection > range from mild symptoms to paralysis of limb and respiratory muscles
 Spherical, unencapsulated RNA virus of enterovirus genus
 Three serotypes of poliovirus, all included in:
 Salk formalin-fixed (killed) vaccine
 Sabin oral, attenuated (live) vaccine
 Limited genetic variability > virus nearly eradicated by vaccines
 Transmitted via fecal-oral route
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 Virus binds CD155 (epithelial adhesion molecule)
 Ingested > replicates in mucosa of pharynx/gut > spreads through lymphatics > blood > viremia/fever
 Antiviral antibodies control the disease in most cases
 Diagnosis via viral culture of PCR of throat secretions or stool
o West Nile Virus
 Acute systemic infection > ranges from mild symptoms to neuroinvasive disease (long-term sequelae)
 Arthropod-borne virus (arbovirus) of flavivirus group
 Transmitted by mosquitoes > birds (major reservoir for virus) & mammals
 Replicates in skin dendritic cells > moves and replicates further in lymph nodes > blood > maybe BBB
 If it reaches CNS > infects neurons
 Chemokine receptors CCR5 contributes to resistance to neuroinvasive infection
 80% asymptomatic, but can lead to fever, headache, myalgia, fatigue, anorexia, and nausea
 Meningoencephalitis (1 in 150)
o Viral Hemorrhagic Fever (VHF)
 Severe life-threatening multisystem syndrome > vascular dysregulation and damage > shock
 Enveloped RNA viruses of 4 different genera (Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae)
 Ranges from mild disease (fever, headache, myalgia, rash, neutropenia, and thrombocytopenia) to severe
disease (sudden hemodynamic deterioration and shock)
 Humans typically infected from rodents or insect vectors
Latent Infections (Herpesvirus Infections)
o Latent = persistence of viral genomes in cells that do not produce infectious virus
o Herpes Simplex Viruses (HSV)
 HSV1 & HSV2 differ serologically but are closely related genetically > similar primary/recurrent infections
 Large encapsulated double-stranded DNA viruses
 Replicate in skin and mucous membranes at site of entry (usually oropharynx or genitals)
 Spread to sensory neurons that innervate these primary sites
 During latency, virus remains within nucleus of neuron
 Produce latency-associated viral RNA transcripts (LATs) that confer resistence to apoptosis
 Reactivation results in virus spreading from neuron back to skin or mucous membranes
 HSV1 can also lead to corneal blindness and fatal sporadic encephalitis
 Mutations in TLR3 or components of its signaling > increased susceptibility to HSV encephalitis
 HSV2 increases risk of HIV transmission by 4x and HIV acquisition by 2-3x
 Morphology:
 Intranuclear inclusions = large, pink/purple = viral replication proteins and virions > push host cell
chromatin out to edges of nucleus
 Fever blisters or cold sores (facial skin around mucosal orifices)
 Gingivostomatitis (from HSV1) = vesicular eruption, tongue to retropharynx > lymphadenopathy
 Genital herpes (mostly from HSV2) = genitalia vesicles converted into superficial ulcerations
 Corneal lesions:
o Herpes epithelial keratitis = cytolysis of superficial epithelium
o Herpes stromal keratitis = neovascularization, scarring, opacification of cornea
 Herpes simplex encephalitis
 Herpes esophagitis
 Herpes bronchopneumonia
 Herpes hepatitis
o Varicella-Zoster Virus (VZV)
 Acute infection causing chickenpox > reactivation causes shingles (aka herpes zoster)
 Infects mucous membranes, skin, and neurons
 Evades immune responses and establishes latent infection in sensory ganglia
 Transmitted by respiratory aerosols > widespread vesicular skin lesions
 Morphology:
 Chickenpox: macule > vesicle > rupture > crust over > heal by regeneration (no scars)
 Shingles: lesions associated w/ intense itching, burning, or sharp pain (due to radiculoneuritis)
o Cytomegalovirus (CMV)
 β-group herpesvirus > variety of manifestations depending on age and immune status
 Latently infects monocytes and their bone marrow progenitors
 Asymptomatic or mononucleosis-like infection in healthy individuals
 Fever, atypical lymphocytosis, lymphadenopathy, hepatitis, hepatomegaly, abnormal liver fxn
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Devastating systemic infection in neonates and immunocompromised people
 Was most common opportunistic infection in AIDS patients
 Primarily affect the lungs and GI tract > necrosis and ulcerations
 Transmission via:
 Transplacental transmission (congenital CMV): from mother who doesn't have antibodies to it
o 95% asymptomatic
o 5% symptomatic > resembles erythroblastosis fetalis
o Infants that survive usually have permanent deficits (intellectual disability, hearing loss)
 Neonatal transmission (perinatal CMV): cervical or vaginal secretions at birth, or breast milk
o Usually asymptomatic due to protective maternal anti-CMV antibodies
 Transmission through saliva: especially during preschool years
 Transmission by genital route: dominant mode after 15yo
 Iatrogenic transmission: organ transplants or blood transfusions
 Acute CMV induces transient but severe immunosuppression
 Can infect dendritic cells and impair antigen processing
 CMV can evade immune defenses by downmodulating MHC I and II molecules and producing homologues
of TNF receptor, IL-10, and MHC class I molecules, and can evade NK cells by producing ligands that block
activating receptors and engaging inhibitory receptors
 Morphology:
 Infected cells are strikingly enlarged
 Intranuclear basophilic inclusions (set off from nuclear membrane by clear halo "owl's eye")
Chronic Productive Infections
o Immune system unable to eliminate virus > continued viral replication > persistent viremia
o High mutation rate of viruses (ex. HIV and HBV) may contribute to their escape from immune control
Transforming Viral Infections
o Can transform infected cells into benign or malignant tumor cells
o Epstein-Barr Virus (EBV)
 Causes infectious mononucleosis (benign, self-limited lymphoproliferative disorder)
 Most commonly associated w/ lymphomas and nasopharyngeal carcinoma
 Fever, sore throat, generalized lymphadenopathy, splenomegaly, and atypical activated T cells
 EBV-specific CD8+ cytotoxic T cells, CD16+ NK cells
 Pathogenesis:
 Transmitted by close human contact, esp. through saliva
 Infects B cells and possibly epithelial cells of oropharynx
 EBV envelope glycoprotein binds CD21 (receptor for C3d complement) on B cells
 Establishes latent infection where it persists as an extrachromosomal episome
 Important EBV-encoded proteins:
o Epstein-Barr nuclear antigen 1 (EBNA1): binds EBV genome to hsot cell chromosomes
during mitosis
o Latent membrane protein 1 (LMP1): drives B-cell activation and proliferation
o EBNA2: promotes B-cell activation and replication
o vIL-10 (homolog of IL-10): inhibits macrophages and dendritic cells, suppresses antiviral
T cell responses
 Morphology:
 Peripheral blood shows lymphocytosis (60% WBC are lymphocytes)
 Atypical lymphocytes (5-80% of ^^) sufficiently distinct to suggest the diagnosis
 Lymph nodes are discrete and enlarged throughout the body
 Spleen enlarged in most cases
 Liver is usually involved to some degree (hepatomegaly is, at most, moderate)
 Clinical Features:
 Young children present w/ fever, sore throat, lymphadenitis
 Young adults present w/ malaise, fatigue, and lymphadenopathy
 Diagnosis depends on: (1) lymphocytosis w/ atypical lymphocytes, (2) positive heterophil
antibody reaction (Monospot test), and (3) rising titer of specific antibodies for EBV antigens
 Usually resolves within 4-6 weeks, but fatigue may last longer
 Burkitt lymphoma: caused by EBV
 Serious complications w/ Duncan disease (X-linked lymphoproliferation syndrome)