Pathology Ch8 - Infectious Diseases - PARTIAL Pp354-362 (Viral Infections)

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 . 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 . 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)