Questions and Answers
What is a characteristic of survivors of viral infections?
They are usually immune to subsequent infections
What is the primary mechanism by which viral proteins block the Adaptive Immune Response?
By blocking the production of proteasome-derived viral peptides
What is a persistent infection?
A long-term viral infection that is not cleared by the immune system
What happens to viral genomes in a persistent infection?
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What is a characteristic of latent infections?
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What is the primary site of infection for Herpesviruses?
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What is a characteristic of acute infections?
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How are Herpesviruses transmitted?
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What is antigenic variation?
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What is antigenic drift?
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What is the role of latent infections in the viral life cycle?
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What type of viral genome do Herpesviruses possess?
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What is a characteristic of well-adapted pathogens?
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What is the function of viral gene products in latent infections?
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Why may acute infections be inapparent?
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What is the outcome of viral modulation of the Adaptive Immune Response?
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What is the primary characteristic of an acute viral infection?
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What occurs during the incubation period?
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What is the term for the adverse physiological consequences of viral infection?
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What is the characteristic of persistent-latent infection?
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What is the duration of an acute viral infection?
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What is the characteristic of persistent-asymptomatic infection?
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What is the characteristic of persistent-pathogenic infection?
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What is the purpose of the incubation period?
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What type of cells does HSV-1 primarily infect?
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What is the direction of transport of nucleocapsids in sensory neurons?
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What is the role of LAT in HSV-1 infection?
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What triggers the reactivation of HSV-1?
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Where does the HSV-1 genome persist in a latent state?
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What is the outcome of the immune response to HSV-1 infection?
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How does the virus travel from sensory neurons to epithelial tissues?
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What event marks the reactivation of HSV-1?
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What is the primary reason why mice infected with Lymphocytic Choriomeningitis Virus congenitally or immediately after birth do not develop encephalitis and edema?
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During latent infection, what is the primary function of LATs?
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What is the characteristic of HIV infection during the asymptomatic phase?
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What is the outcome of persistent infection with Lymphocytic Choriomeningitis Virus on the cognitive abilities of mice?
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What is the duration of the acute phase of HIV infection?
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What is the primary mechanism by which the immune response controls HIV infection during the acute phase?
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What is the characteristic of HIV infection during the acute phase?
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What is the primary difference between the asymptomatic phase of HIV infection and the acute phase?
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What type of receptors are expressed in certain cell types such as macrophages and dendritic cells?
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What is the outcome of MAMP-PRR engagement?
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What type of RNA can act as a MAMP?
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What is the function of adaptor proteins in PRR signaling?
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What is the outcome of activation of NFkB and IRFs?
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Where are cell surface PRRs located?
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What is the function of RIG-1-like receptors (RLRs)?
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What type of cytokines are expressed as a result of PRR signaling?
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What occurs upon binding of viral RNA to PRRs?
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What is the role of RIG-1 and MDA5 in their active conformations?
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What is the function of specific phosphatases in the viral response?
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What is the role of MAVs in the viral response?
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What is the outcome of RIG-1 and MDA5 activation?
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What is the mechanism by which viruses evade RIG-1 and MDA5 responses?
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What is the function of IKK and TBK1 in the viral response?
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What is the outcome of the interaction between RIG-1 and MAVs?
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What is the outcome of PKR activation through dsRNA binding?
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What is the effect of RIG-1, MDA5, and MAVS cleavage?
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What is the consequence of viral RNA ligand sequestration?
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What is the mechanism of translational arrest induced by PKR?
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What is the outcome of post-translational modifications on RIG-1, MDA5, and MAVS?
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What is the effect of RIG-1, MDA5, and MAVS relocalization?
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What is the consequence of PKR dimerization and autophosphorylation?
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What is the outcome of viral manipulation of RIG-1, MDA5, and MAVS?
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What is the primary function of RIG-1 in the cytoplasm?
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What is the main difference between RIG-1 and MDA5?
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What is the function of protein kinase R (PKR) in the context of viral infections?
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What is the result of cGAS binding to viral dsDNA in the cytoplasm?
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What is the state of CARD domains in uninfected cells?
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What is the role of Ubiquitin Ligases in the activation of CARD domains?
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What is the outcome of the dephosphorylation of CARD domains?
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What is the common feature of RIG-1 and MDA5?
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What is the result of inactive GDP-bound eIF-2?
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Which of the following is not a mechanism used by viruses to evade PKR responses?
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What is the function of cGAS in the detection of viral infections?
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What is the outcome of eIF2α phosphorylation by PKR?
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Which of the following is a mechanism used by viruses to counteract the antiviral response mediated by PKR?
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What is the consequence of PKR-mediated eIF2α phosphorylation on viral protein synthesis?
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What is the role of STING in the detection of viral infections?
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What is the outcome of the interaction between cGAS and viral dsDNA?
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What is the primary function of cilia in the upper respiratory tract?
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What is the site of gas exchange in the lungs?
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What is the primary function of goblet cells in the respiratory tract?
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What is the approximate volume of air inhaled by a resting human every minute?
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What is the structure that increases the surface area of the epithelium in the small intestine?
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What type of cells are present in the alveoli of the lungs?
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What is the primary portal of entry for viruses into the human body?
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What is the characteristic of the mucosal surfaces of the respiratory tract?
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What is the primary function of the placenta during pregnancy?
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What determines the pattern of systemic illness produced during a viral infection?
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What is the term for the presence of viruses in the blood?
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What is the mechanism by which some viruses evade the immune response?
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What is the primary requirement for a virus to cause a disease?
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What is the term for the process by which viruses disseminate within the host?
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What is the primary route of viral dissemination within the host?
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What is the term for the adverse physiological consequences of viral infection?
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What is the difference between viral virulence and cytopathogenicity?
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What is the term for the process by which viruses cross the placenta during pregnancy?
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What is the term for the site where viruses primarily replicate after entering the host?
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What is the primary site of infection for viruses that enter the body through the respiratory tract?
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What is the function of goblet cells in the epithelium of the upper respiratory tract?
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What is the term for the process by which a virus spreads from the initial site of infection to other parts of the body?
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What is the outcome of the host immune response to viral infection?
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What is the final step in the viral pathogenesis process?
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What is the primary route by which PV invades the CNS?
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What is the primary mechanism of HPV transmission?
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What is the primary site of viral replication for HPV in the skin?
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What is the term for the transmission of viruses from parents to their offspring?
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What is the consequence of vertical transmission of viruses?
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What is the primary mode of HBV transmission?
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What is the primary site of viral entry for HIV?
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What is the primary mechanism of viral replication in the skin?
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What is the primary mechanism by which the host's immune response contributes to disease development?
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What is the primary function of anatomical barriers in the host's defense against viral infections?
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What is the primary difference between humoral immunity and cell-mediated immunity?
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What is the primary function of phagocytes in the host's defense against viral infections?
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What is the term for the shedding of infectious virus into the environment?
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What is the primary function of lysozymes in the host's defense against viral infections?
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What is the primary function of cytokines and inflammatory mediators in the host's defense against viral infections?
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What is the primary difference between innate and adaptive immune responses?
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Study Notes
Patterns of Viral Infection
- Relative virus particle production plotted as a function of time after initial infection, showing symptoms and clearance
- Acute infection: virus particles produced, symptoms appear, and infection is cleared (7-10 days)
- Persistent infection: divided into latent, asymptomatic, and pathogenic types
- Latent infection: periodic episodes of acute infections followed by quiescent phase
- Asymptomatic infection: virus production continues for the life of the host or in tissues where immune cells do not often patrol
- Pathogenic infection: fatal appearance of symptoms after a period of years, with continuous or undetectable virus production
Incubation Period
- Time before symptoms of disease appear following initial infection
- During this period, viral genomes may be replicated and innate immune responses initiate production of cytokines
Viral Pathogenesis
- Adverse physiological consequences of viral infection in the host organism
- Acute infection: rapid virus production and resolution by the immune system (short-term infection)
- Persistent infection: not cleared by the immune system (long-term infection), with possible latent, asymptomatic, or pathogenic outcomes
Acute Infection
- Adaptive immune responses provide lasting protection to subsequent infections
- Infection may be resolved within a few days, but viral progeny may still be shed and transmitted to other hosts
- Inapparent (asymptomatic) acute infections may occur, with limited or no clinical symptoms detected
Antigenic Variation
- Accumulated mutation in viral genome, resulting in substantial change in genetic makeup
- May facilitate repeated acute infections by evasion of the adaptive immune response
Persistent Infections
- Viral proteins may block adaptive immune response by blocking presentation of viral peptides within MHC I complexes
- Latent infections characterized by:
- Viral gene products not synthesized (or synthesized in small quantities)
- Cells with the viral genome poorly recognized by the immune system
- Viral genome persists intact within the infected cell for later productive infection
Herpes Simplex Virus (HSV-1)
- Enveloped virus with dsDNA genome
- Transmission: saliva, sexual contact, maternal-neonatal
- Infection: primary site - epithelial mucosal cells; latency established in sensory ganglia
- Associated diseases: skin vesicles or mucosal ulcers
- Reactivation factors: bacterial infection, hormonal changes, environmental stress
- HSV-1 infects epithelial cells, spreads to sensory neurons, and persists in a latent state in the sensory neurons
Latency-Associated Transcripts (LATs)
- Expressed during latent infection, blocking transcription of lytic genes
- Suppresses viral lytic gene expression, allowing the virus to maintain latency
Cytoplasmic RNA Helicases
- RIG-1 (Retinoic acid-inducible gene 1) and MDA5 (Melanoma differentiation-associated gene 5) are cytoplasmic RNA helicases that function as RNA sensors.
- RIG-1 detects 5' triphosphate RNA (without 5' cap) in the cytoplasm, while MDA5 detects long dsRNA (and RNA without 5' cap).
- RIG-1 and MDA5 contain tandem N-terminal CARD domains that are phosphorylated in uninfected cells, leading to an inactive conformation.
Signaling Events
- MAMP-PRR engagement leads to signaling events that activate transcription factors such as NFkB and the Interferon regulatory factors (IRFs), promoting the expression of IFNs and inflammatory cytokines.
- PRRs undergo conformational change, exposing CARD domains that are dephosphorylated by specific phosphatases, leading to an active conformation.
- In their active conformation, RIG-1 and MDA5 are translocated to bind with the mitochondrial antiviral signaling protein (MAVS).
Protein Kinase R (PKR)
- PKR is a sensor for viral dsRNA that inhibits cap-dependent translation by eIF2α (eukaryotic initiation factor).
- PKR is activated by binding to viral dsRNA, leading to dimerization and autophosphorylation.
- Activated PKR phosphorylates the α subunit of eIF-2, causing it to remain in an inactive GDP-bound form, leading to translation arrest.
cGAS
- Cyclic GMP-AMP synthase (cGAS) binds to viral dsDNA in the cytoplasm.
- Following DNA binding, cGAS generates cyclic GMP-AMP (cGAMP), which binds and activates STING (located on the ER).
Viral Evasion
- Viruses evade RIG-1 and MDA5 responses through sequestration or modification of viral RNA ligands, manipulation of post-translational modifications, cleavage of RIG-1, MDA5, and MAVS, and sequestration or relocalization of RIG-1 and MDA5.
- Viruses evade PKR responses by inhibiting the activation of PKR, using eIF2-independent translation mechanisms, activating protein phosphatase to remove the phosphorylated Protein, and activating RAS pathway to inhibit PKR.
Viral Pathogenesis
- Viral disease is a harmful abnormality resulting from viral infection of the host organism
- A virus is pathogenic for a particular host if it can infect and cause signs of disease in that host
- Viral virulence in intact animals should not be confused with cytopathogenicity for cultured cells
Steps in Viral Pathogenesis
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- Entry and primary replication
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- Viral spread
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- Cellular injury
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- Host immune response
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- Viral clearance or establishment of persistent infection
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- Viral shedding
Entry and Primary Infection
- A virus must attach to and enter cells of one of the body surfaces (skin, respiratory tract, gastrointestinal tract, urogenital tract)
- Respiratory tract is the most common portal of entry for viruses into the human body
- Most respiratory tract infections occur through inhalation of aerosolized droplets or particles containing viruses
Respiratory Tract
- Upper respiratory tract (URT): lined with cilia and mucus-producing goblet cells
- Lower respiratory tract (LRT): smaller aerosolized particles or liquids can travel into the lungs, where gas exchange occurs
- Alveoli of the lungs contain alveolar macrophages and lack ciliated cells
Gastrointestinal Tract
- A hollow tube stretching from the oral cavity to the anus
- Small intestine has finger-like projections called villi that increase the surface area of the epithelium
Urogenital Tract
- Refers to the organs involved in reproduction
- Viruses can be transmitted via the genital tract through sexual activity or breaks in the genital epithelium
- Examples: human papillomavirus (HPV), hepatitis B virus (HBV), human immunodeficiency virus (HIV)
Skin
- Composed of two layers of tissue: epidermis and dermis
- Viruses that replicate in the epidermis, such as HPV, can gain access through small cuts or abrasions in the skin
Placenta and Congenital Infections
- Congenital infections occur when a mother infects a fetus before birth
- Occur via vertical transmission (generational transmission of viruses from parents to their offspring)
- Can lead to long-term persistence of the virus within the child
Viral Spread
- Tropism determines the pattern of systemic illness produced during a viral infection
- Factors affecting viral tropism: many viruses produce disease at sites distant from their point of entry
- Mechanisms of viral spread vary, but the most common route is via the bloodstream or lymphatics
- Presence of virus in the blood is called viremia
Cell Injury and Clinical Illness
- Destruction of virus-infected cells in target tissues and physiological immune response contribute to disease development
- Clinical illness is an insensitive indicator of viral infection; inapparent infections by viruses are very common
Host Defense/ Recovery from Infection
- Innate (nonspecific) immune response: physical barriers, anatomical barriers, epithelial and phagocytic enzymes, phagocytes, and inflammation-related serum proteins
- Adaptive immune response (acquired/specific): carried out by lymphocytes (B cells, T cells) and humoral and cell-mediated immunity
Viral Shedding
- Pertains to the shedding of infectious virus into the environment
- Last stage in viral pathogenesis
- Occurs from the body surfaces involved in viral entry and at different stages of disease depending on the particular agent involved
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