Disease and Defense Unit 3 Flashcards
Define and describe infection, infectious disease, pathogenicity, and virulence
Infection: process where a microbe enters into a relationship with a host. It may or may not cause disease (can be good or bad). usually stable, can be transient
Infectious disease: disease caused by infection with microbe. may be COMMUNICABLE, or not (transmitted from patient to patient, is not the case for all microbial bugs, e.g.: rabies). relationship that results in disease state.
Pathology: the ability (of a microbial species) to cause disease. Microbes that can cause disease are FRANK PATHOGENS. microbes that cause disease in compromised hosts but less in normal host are OPPORTUNISTIC PATHOGENS
Virulence: degree of pathogenicity (of a specific strain or species). a highly virulent microbe is likely to cause disease when introduced into host in small numbers.
- note: both microbial and host factors contribute to the outcome of an infectious disease. “damage response” framework.
- etiologic agents: organism/something that is directly or indirectly responsible for the disease state
Explain how a microbe is shown to be the cause of a specific disease.
-Koch’s Postulates: criteria for a bacteria/microorganism/etc. that causes disease
- microbes are present regularly in characteristic disease lesions
- specific microbes can be isolated and grown in vitro
- injection of cultured microbes into animals reproduces disease seen in humans
- specific microbes can be re-isolated from lesions of the disease in animals
limitations:
- some do not have a characteristic/pathogenic lesion
- some microbes cause specific infectious diseases but can’t be grown in vitro
- traditional concepts of pathogenicity focus on properties of microbe vs. hosts
- characteristics of infectious diseases usually reflect complex interactions btw microbes and their hosts
Describe typical stages in pathogenesis of an infectious disease and explain their importance.
(EESMDO)
- Encounter: how agent and host meet. when contracted endogenously (from flora) or exogenously (from environment). need to ask what is route and dose of infection.
- source, route, dose
- modes of spread are among people and from animals to people - Entry: how the agent enters the host. what does it need to cross? is it actively (invasion) or passively (injection, bites, transfusion, transplant, etc.)
a) colonization of body surfaces is an important 1st step
b) adherence, by specific binding of microbial surface components (pili, non-pilus adhesions) to receptors on host tissues
- colonization of body surfaces, adherence - Spread: how agent spreads from entry site. microbial products can promote or inhibit spread
a) hyaluronidase, elastase, collagenase, facilitate spread of microbes through tissues (spreading factors)
b) coagulase inhibits spread of microbes by promoting deposition of fibrin to wall off and localize infections
- crossing mucosal surfaces, spreads in tissues - Multiplication: how agent multiplies in host. normal flora and pathogens must replicate the host at rates that exceed clearance by defense mechanisms. growth rate in vivo may be slower than in lab (in vitro)
- Damage: how tissue damage is caused by agent/host response, and are there virulence factors
a) some microbial products cause direct damage to host
b) some products cause damage to host via blocking or interfering with defense mechanisms
c) most of products causing direct damage to host interfere with host defense mechanisms. they are surface components of microbes, products that can be secreted, products that can be injected into a target cell. can be used as protective antigens for vaccine development - Outcome: does the microbial agent or host win the battle or do they coexist? what would be consequences?
Compare mechanisms of innate and acquired host defense against infections.
- **add in table from notes
- Rhinovirus: same virus can range 200 fold based on route of infection (nasal cavity vs. pharynx)
- route of infection and effect and determine the effective dose
- Cholerae: depending on route of infection, but what also is taken with it, has a 10,000 fold difference in infectivity. EG: take with bicarb, neutralizes stomach pH, and makes the oral route more effective since not as much destroyed in stomach.
- genetic differences in host: mouse pox example. route of infection was the same (injected footpad), mice were genetically different. Based on strain, the dose needed was huge.
Look at table to grasp idea but do not memorize it!!!
Describe the composition and importance of the microbiome of the body.
-some prevalent bacteria of the normal flora of the skin, oropharynx, large intestine, vagina
- some factors that differ among people and affect micro biome: diet, suppression of flora by antibiotics, anatomic abnormalities, genetic differences between individuals
- examples of physiologic importance of micro biome: effects on tissue/organ differentiation, production of vitamins by gut flora, biochemical conversions, competition with pathogens for body surface colonizations
- growth rate doubling times vary between viruses
- slow doesn’t mean non-pathogenic
- growth can be intra or extra cellular
**add in table from notes (don’t memorize it!!! just be familiar with trends)
Compare several disease paradigms that illustrate selected mechanisms of pathogenesis.
- Cholera-toxin mediated disease
- pneumococcal pneumonia-acute inflammation by invasive, extracellular bacteria
- tuberculosis-infection by a facultative intracellular bacterium
- rheumatic fever-pathology mediated by immune response
Define the basic properties of viruses
- submicroscopic, obligate, intracellular parasites
- genetic material enters host cell and directs production of building blocks of new particles
- genome is encased in a capsid, and it hijacks the cell to create what it wants
- not alive, do not grow or divide
- genome is replicated and directs synthesis of viral components and will be assembled to form progeny viruses
- particles are produced from self assembly of newly synthesized components in a host cell
List the strategies viruses employ for survival.
-since not alive, one view is that they are chemicals.
- employ 3 part survival strategy:
1) house DNA/RN genomes in small, pertinacious particles (capsids)
2) genome contains all info they need to initiate/complete infectious cycle
3) establish a relationship in population of hosts that range from benign to lethal
-particle architecture, size/nature/topology of genomes, protein coding strategies, cell/tissue/host tropism, pathogenesis
Describe two means of classifying viruses.
- classical system: viruses are grouped according to shared physical properties
-nature of genetic material in iron (DNA/RNA)
-symmetry of capsid (helical or icosahedral)
-naked or enveloped
-dimensions of viron and capsid
-linnaen/biological categorization of verses governed by ICtV
-starts at level of order and continues as:
Order (-virales)
Family (-viridae)
Subfamily (-virinae)
Genus (-virus)
Species
-Species names generally take the form of [Disease] virus,
e.g. Hepatitis virus. - Baltimore system: based on central dogma, DNA–>RNA–>protein
- all viruses are parasites of the host mRNA translation machinery and therefore must produce mRNA to decode genome
- categorizes virus based on how they produce mRNA
-originally were classified based on the fact that they were filterable (below a certain size)
Describe basic methods for studying viruses. Electron microscopy animal models sequence analysis cell culture serology other
Electron microscopy: type of microscope that uses a beam of electrons to create an image of the specimen. It is capable of much higher magnifications and has a greater resolving power than a light microscope, allowing it to see much smaller objects in finer detail.
Animal models: allow for better understanding the disease process without the added risk of harming an actual human. The species chosen will usually meet a determined taxonomic equivalency to humans, so as to react to disease or its treatment in a way that resembles human physiology as needed.
sequence analysis: the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alignment, searches against biological databases, and others.
cell culture: the removal of cells from an animal or plant and their subsequent growth in a favorable artificial environment.
serology: study of serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum.
other:
- we can grow large amounts of viruses in eggs
Identify the main structural characteristics of virus particles. viral genomes protein capsids (helical, icosahedral) envelopes virus attachment proteins
Viral genomes: made of DNA or RNA
Protein capsids: the genome delivery device, can be helical or icosahedral
- Helical: simplest way to arrange identical subunits, use rotational symmetry and arrange around circumference to form a disk.
- icosahedral: arrange proteins in a hollow, quasi-spherical structure enclosing the genome inside. number of ways to do this depending on shape of subunits. Nature uses triangle as repeating unit. solid shape of 20 triangles with 12 vertices and faces with 2, 3, 5 fold symmetry. smallest is 60 identical subunits
Envelopes: lipid bilayers acquired during assembly of viral particles, typically have viral glycoproteins embedded in membrane. many are acquired via budding though host membrane. don’t have to kill cell during production.
-glycoproteins are integral membrane proteins with 1 or 2 membrane spanning domains
Virus attachment proteins:
- Virus attachment involves specific binding of a virus-attachment protein with a cellular receptor molecule.
- Many examples of virus receptors are now known. Target receptor molecules may be:
a) proteins (usually glycoproteins)
b) carbohydrates (found on glycoproteins or glycolipids) - Carbohydrate receptors tend to be less specific than protein receptors because the same configuration of carbohydrate side-chains may occur on many different glycosylated membrane bound molecules.
Describe the seven basic virus genomes, protein expression strategies and replication strategies of each.
7 classes of viral genome configuration: dsDNA gapped circular dsDNA ssDNA dsRNA ss(+)RNA ss(-) RNA ss(+)RNA with DNA intermediate
- if dsDNA genomes are grouped with gapped circular dsDNA, then 6 types of genomes correspond to the classification in the Baltimore system.
- Viruses are obligate intracellular parasites they rely on the host cell biosynthetic machinery to varying degrees for their propagation.
Describe the typical, generalized replication cycle of a virus. Double stranded Single stranded Gapped circular Viruses with RNA
-exact copies of viral genome must be produced and packaged
Double stranded strategies:
- replication in nucleus, dependent on cellular factors. may involve viral polymerase and accessory factors
- replication in cytoplasm (poxviruses) occurs when they have all the factors necessary for replication of genomes and are independent of cellular machinery
Single Stranded DNA:
-replication in nucleus with formation of double stranded intermediate as template for synthesis of single stranded genome
Gapped circular double stranded DNA:
-virally encoded reverse transcriptase to copy viral genome from mRNA transcribed from template genome
Viruses with RNA genome:
-transcription and genome replication is highly integrated for RNA viruses. genome is replicated using anti-genome as template. production of anti genome is done by RdRp.
Basic Steps:
1) Attachment of virus to the cell.
2) Entry of virus into the cell and uncoating of the viral genome.
3) Viral gene expression.
4) Viral genome replication.
5) Assembly of new viruses and egress of new virus particles from the cell.
Compare and contrast acute local disease versus acute systemic disease in incubation periods, virus shedding and transmission, host responses, and likelihood of re-infection.
** add in table from notes
Acute infection: high viral replication rate and the production of large number of progeny. persistent lasts for longer.
Acute Local: infections of epithelial cells at body surface (gut, respiratory tract, eyes). short incubation times, include many serotypes (rapidly mutating and result in short lived immunity, via IgA). re infections common. cold and diarrhea
Acute Systemic: primary infection also in epithelium. viremia and systemic infection result in secondary replication at various sites, lifelong immunity and includes IgA and IgG. Measles and smallpox
Describe the expected outcome of viral infection and disease in a healthy host versus an immune compromised host, including symptoms, shedding and transmission, and length of primary infection.
-The expected outcome of viral infection and disease in an immune compromised host (relative to a healthy individual) is: worse and longer. The point is that when you are diagnosing someone or considering impact on community health, you must be aware that the textbooks symptoms and times have to be adjusted for certain cases.
Detail two differences between persistent and latent infection.
- Persistent - usually refers to virus infections that continue to produce new virus over a long period of time, it never completely settles down.
- Latent - refers to virus infection in which the virus genome is relatively silent, there is little gene transcription in most infected cells, and there is little to no disease in a healthy host for a long time, in many cases for life.
List the potential outcomes and types of virus diseases, with the contributing factors.
acute viral and acute systemic
chronic viral (persistent, latent)
transforming
- *** add in photo from slides
- acute viral infection: local/systemic depends on initial events of infection/virus tropism
- acute local: infections in epithelial cells at body surface. re-infection common.
- acute systemic: primary infection also in epithelium, viremia and systemic infection result of secondary replication at various sites. lifelong immunity IgA,G.
- chronic viral: ongoing virus infection/replication with mild inapparent disease in healthy host. coincident with immune suppression
- persistent: continue to produce new virus
- latent: vires is silent for a long time (even for life). may be reactivated/ recrudescence
-transforming viral: integrate into host genome and activate oncogenes. cause ongoing inflammation and contribute to tumerogenesis
List effects of viruses on infected cells, such as CPE, syncytia, growth, apoptosis.
Cytopathic effects (CPE) of virus infection: Direct cell damage and death from viral infection may result from diversion of the cell's energy, shut off of cell macromolecular synthesis, competition of viral mRNA for cellular ribosomes, competition of viral promoters, and enhancers for cellular factors inhibition of the interferon defense mechanisms. -- any detectable morphologic changes in the host cell.
Indirect cell damage can result from integration of the viral genome, induction of mutations in the host genome, inflammation, and host immune response.
Syncytia are multinucleate masses of cytoplasm that have not separated into individual cells.
Growth and apoptosis.
Explain the interferon response and “anti-viral state”.
- Infection of cells with viruses induces the production of proteins that are known as interferons because they were found to interfere with viral infection of neighboring cells.
- The anti-viral state is a state that can be induced in neighboring cells to prevent the virus from spreading.
Mediators of the IFN-induced anti-viral state:
1) PKR- protein kinase that phosphorylates and thereby inactivates a cellular translation initiation factor, resulting in decreased protein synthesis.
2) OAS- 2’-5’Oligoadenylate synthetase activates a cellular ribonuclease (RNAseL) that degrades mRNA.
3) others, many unidentified
IFNs bind to specific receptors on cells & induce transcription of genes = antiviral state.
-PKR and OAS are made as inactive precursors and are activated by dsRNA.
-Once activated, these gene products shut down translation of both cellular and viral mRNAs.
IFNs can also induce the synthesis of gene products that arrest the cell cycle (blocking virus replication), or induce a pro-apoptotic state.
-IFNs can induce the synthesis of proteins that are involved in the presentation of virus proteins to cytotoxic T lymphocytes.
Distinguish between innate and adaptive anti-viral responses.
Innate defenses : natural barriers, cells, soluble factors.
-Natural barriers: skin, mucus, ciliated epithelium, gastric acid, tears, and bile.
-Cells: macrophages, neutrophils, dendritic cells, and NK cells.
-Soluble factors: interferons, cytokines, complement, chemokines.
-Innate immunity is non-specific (responds to infection) and immediate (within hours of infection).
-Innate immunity and the inflammatory response are critical
precursors to the adaptive immune response to viruses. Innate responses are triggered in many ways.
-Interferons (IFN)
What does the adaptive immune response recognize?
- All viruses encode proteins- these are foreign antigens that can elicit specific/adaptive immune responses.
- Viral antigens may be found on virions, surfaces of infected cells, debris from infected cells, or as peptide fragments bound to host MHC molecules on infected cells or phagocytic cells.
- recognizes cell mediated or humoral immunity
- recognizes antigens in a more specific way than TLRs
- Viral pathogens are recognized by the cells in which they replicate, leading to the production of interferons that serve to inhibit viral replication and to activate NK cells. The induced innate responses either succeed in clearing the infection or contain it while an adaptive response develops.
- Adaptive immunity harnesses many of the same effector mechanisms used in the innate system, but is able to target them with greater precision. Thus antigen-specific T cells activate the microbicidal and cytokine-secreting properties of macrophages harboring pathogens, while antibodies activate complement, act as direct opsonins for phagocytes, and stimulate NK cells to kill infected cells. In addition, the adaptive immune response uses cytokines and chemokines, in a manner similar to that of innate immunity, to induce inflammatory responses that promote the influx of antibodies and effector lymphocytes to sites of infection.
Compare antibodies produced in primary and secondary responses.
-Antibodies produced during primary virus infections are usually of lower affinity than those produced later, and are often of the IgM isotype (unswitched).
List and describe major cell types involved in anti-viral responses.
Innate: phagocytes, dendritic cells, NK cells, granulocytes
Adaptive: T and B cells
Compare the efficacy of antibody versus cell-mediated immunity in the anti-viral response.
All viruses multiply in the cytoplasm of infected cells. Once inside cells, viruses are not accessible to antibodies and can be eliminated only by the destruction of the infected cells on which they depend. This role in host defense is fulfilled by cytotoxic CD8 T cells. The elimination of infected cells without the destruction of healthy tissue requires the cytotoxic mechanisms of CD8 T cells to be both powerful and accurately targeted.
However, when outside the cells, antibodies can act as effector molecules
- IgA (secretory Ab) inhibits virion/host attachment, neutralizes toxins and enzymes
- IgG inhibits fusion of enveloped viruses with host membranes
- IgG and IgM opsonize virions to enhance phagocytosis
- IgM can coat and agglutinate some virions
- IgG and IgM can facilitate complement lysis of enveloped viruses
Explain means of virus evasion/manipulation of host defenses by various viruses.
A. Antigenic variation- mechanisms include point mutations in antigenic drift (e.g. HIV, influenza A) and genome shuffling in antigenic shift (e.g. influenza A)
B. Inhibition of the IFN pathway (e.g. influenza NS1).
C. Inhibition of apoptosis and cell cycle control (e.g. SV40 large T Ag and Adenovirus
E1A)
D. Immune tolerance (molecular mimicry or infection prior to competent immune system)
E. Infection of immunoprivileged sites such as the brain (e.g. HSV)
F. Direct infection of the immune system (e.g. HIV and EBV)
G. Restricted expression of viral genes- going invisible to the host defenses as in latent infections (e.g. HIV)
H. Production of viral molecules that act as inhibitors or decoys of host defense molecules such as TLRs, cytokines, receptors, and Ab’s (e.g. Pox and Herpesviruses)
I. Down-regulation of host proteins such as MHC class I or adhesion molecules (e.g. Pox and Herpesviruses)
Viruses can evade capture and death by:
having antigenic variation, mimicking host proteins, restricting the expresion of their genes, producing molecules that act as decoys or inhibitors of host defense molecules, down-regulating host proteins like MHC’s, infecting immunoprivelaged sites (brain), infecting the immune system, and inhibiting apoptosis.
For the following virus
Herpes simplex type 1 (HSV1)
be able to discuss:
a.Type of virus (DNA vs. RNA, double strand versus single strand);
b.Cells targeted for primary infection and latency;
c.Transmission and incubation period;
d.Disease entities and their clinical presentations;
e.Diagnosis and key diagnostic tests;
f.Treatments;
g.Prophylaxis-including vaccines.
a. DS DNA, protected by isocadedral capsid, alpha
b.Cells targeted for primary infection: mucosal epithelium
and latency: neuron (ganglia)
c.Transmission: close contact, penetrates through mucosal surfaces or cracks in the skin
incubation period: 2-12 days, average is 4
d. Disease entities and their clinical presentations:
- orofacial lesions and (sometimes) genital lesions, encephalitis, herpes whitlow, herpes keratitis, neonatal herpes
- most common presentation is painful mucocutaneous ulcers (orofacial, ocular)
- “above the belt”
e. Diagnosis and key diagnostic tests;
- viral culture, direct fluorescent antibody stain of lesions, PCR of lesions
f. Treatments;
- nucleoside drugs used to treat, take advantage of activation of drug by thymidine kinase (coded by HSV)
- acycloguanosine (acyclovir) and other similar agents
- IV acyclovir: treat severe patients, neonatal, immunocompromised, encephalitis, meningitis patients
- oral antiviral for oral or genital HSV outbreaks
g. Prophylaxis-including vaccines.
- in compliant patients suppressive therapy considered for frequent painful oral/genital herpes
- must take 2x’s a day and not miss days
For the following virus
Herpes simplex type 2 (HSV2)
be able to discuss:
a.Type of virus (DNA vs. RNA, double strand versus single strand);
b.Cells targeted for primary infection and latency;
c.Transmission and incubation period;
d.Disease entities and their clinical presentations;
e.Diagnosis and key diagnostic tests;
f.Treatments;
g.Prophylaxis-including vaccines.
a. DS DNA, protected by isocadedral capsid, alpha
b. Cells targeted for primary infection: mucosal epithelium
latency: neuron (ganglia)
c.Transmission: close contact, usually sexually. penetrates through mucosal membranes or cracks in the skin
incubation period; 2-12 days, usually 4
d. Disease entities and their clinical presentations;
- genital lesions and (sometimes) orofacial lesions, encephalitis, herpes whitlow, herpes keratitis, neonatal herpes
- “below the belt”
e. Diagnosis and key diagnostic tests;
- most people with it have not been diagnosed, 50% or more of new cases are asymptomatic/unrecongized
- can often be diagnosed clinically, but always must make definitive diagnosis
- viral culture, direct fluorescent antibody stain of lesions, PCR of lesions
f. Treatments;
- nucleoside drugs used to treat, take advantage of activation of drug by thymidine kinase (coded by HSV)
- acycloguanosine (acyclovir) and other similar agents
- IV acyclovir: treat severe patients, neonatal, immunocompromised, encephalitis, meningitis patients
- oral antiviral for oral or genital HSV outbreaks
g. Prophylaxis-including vaccines.
- in compliant patients suppressive therapy considered for frequent painful oral/genital herpes
- must take 2x’s a day and not miss days
- used in patients without stable partner or who are sexually active
For the following virus
Varicella zoster virus (VZV)
be able to discuss:
a.Type of virus (DNA vs. RNA, double strand versus single strand);
b.Cells targeted for primary infection and latency;
c.Transmission and incubation period;
d.Disease entities and their clinical presentations;
e.Diagnosis and key diagnostic tests;
f.Treatments;
g.Prophylaxis-including vaccines.
a.DS DNA, protected by isocadedral capsid, alpha
b. Cells targeted for primary infection: mucosal epithelium. enters via respiratory tract, spreads to lymph nodes, then replicates in liver, spleen, spreads to particles of skin
latency: neuron (ganglia)
c.Transmission: contact or respiratory route
incubation period: 10-21 days
d. Disease entities and their clinical presentations;
- chickenpox, shingles (zoster)
- starts with fever, malaise, headache, cough
- rash in “crops”/waves
- lesions start as flat, become “dew drop on rose petal” (vesicle with erythematousus base)
- rash on face/trunk, spreads to extremities
- vesicles become pustules then rupture and scab. (usually you find various stages in a patient)
- takes about 7 days for the all lesions to scab, then they are not infectious
- adolescents/adults are higher risk
- pregnancy= risk of varicella pneumonia and death
e. Diagnosis and key diagnostic tests;
- clinically is done typically
- if unclear, can do: direct fluorescent antibody (swab lesion to look for antigens), VZV PCR, viral culture (HSV grows quickly, VZV grows slowly)
f. Treatments;
- self limited in children, doesn’t mandate therapy
- if antivirals given in first 48-72 hours, course is shortened
- acyclovir ot outpatients or IV if very sick
- immunocompromised, pregnant, or severe cases should be treated
- teenagers and adults= high rrisk
g. Prophylaxis-including vaccines.
- live attenuated vaccine (varivax) is recommended for prevention
- given to children as a 2 dose series via subQ injection
- initial dose 12-15 months, booster 4-6years
- can cause disease in immunocompromised
- for shingles, treat with acyclovir in 48-72 hours of onset to lesson lesions and pain
- if post-herpetic neuralgia occurs, you need to do pain control
- live attenuated vaccine for shingles but it has 14x’s more than the chickenpox dose (Zostavax)
