Holland: RNA Viral Repiratory Tract Infections Flashcards
Respiratory Tract Infections
Basics:
- Most common form of infectious disease
- ~80% of RTIs caused by viruses
- Most respiratory infections remain localized, but some viruses can initially infect the respiratory tract and spread systemically
Respiratory Tract Infections
Modes of Transmission: (2)
- Aerosolized infectious droplets
- Manual spread (direct contact or fomites)
Innate and Adaptive Immune Mechanisms of Protection of Respiratory Tract: (7)
- Reduced temperature in URT
- Mucous
- Mucins
- Ciliated cells
- Toll-like receptors
- Interferons
- IgA (secreted immunoglobulins in mucous)
Innate and Adaptive Immune Mechanisms of Protection of Respiratory Tract
Mucins:
Decoy receptors (prevent bacteria from attaching to normal host cells)
High viscosity (difficult for pathogens to spread)
Innate and Adaptive Immune Mechanisms of Protection of Respiratory Tract
Ciliated cells:
Move mucous, clear particles
Innate and Adaptive Immune Mechanisms of Protection of Respiratory Tract
Toll-like receptors :
Recognize general features of a large number of pathogens
Innate and Adaptive Immune Mechanisms of Protection of Respiratory Tract
Interferons:
Induce antiviral state
Innate and Adaptive Immune Mechanisms of Protection of Respiratory Tract
IgA:
Secreted immunoglobulins in mucous
Seasonal Variation
March-May:
December-January:
November-May:
Rubella: spring peak (March-May)
Influenza: winter peak (December-January)
Rotavirus: winter peak (November-May)
Influenza Virus
Family:
Subfamilies:
Family: orthomyxoviridae
Subfamilies: Influenza A, B and C
Influenza Virus
Physical Characteristics:
enveloped?
genome:
segmented?
o Enveloped
o –ssRNA genome (segmented)
• A and B have 8 segments
• C has 7 segments
Influenza Virus
- Medical Significance:
o Frequent cause of severe respiratory disease
o Epidemics occur in the winter
o New strains can lead to world-wide epidemics (pandemics)
11 proteins encoded by 8 RNA segments:
- HA (hemagglutinin)
- NA (neuraminidase)
- M1 (matrix)
- M2 (ion channel)
- PB1 (RNA-dependent RNA polymerase component)
- PB1-F2 (may modulate viral replication and host responses, not found in all strains)
- PB2 (RNA-dependent RNA polymerase component)
- PA (RNA-dependent RNA polymerase component)
- NP (associated with RNA-dependent RNA polymerase)
- NS1 (blocks IFN-induced RNaseL pathway
- NS2 (viral ribonucleoprotein transport- RNA from nucleus to cytoplasm
Influenza A Replication
Attachment:
Attachment: HA binds to sialic acid moieties on cell surface glycoproteins and glycolipids
Influenza A Replication
Penetration/Entry:
- Virion internalized (receptor mediated endocytosis)
- Reduced pH in endosome triggers a conformational change in HA, which induces fusion between the virion envelope and endosomal membrane
Influenza A Replication
Uncoating:
Uncoating: M2 ion channel allows protons to enter into virion interior, freeing ribonucleoprotein complex (RNP); RNPs then transported to the nucleus (transcription takes place here- unusual for RNA virus)
Influenza A Replication
Ribonucleoprotein Transcription:
- mRNA for viral protens
- cRNA (+sense copy of vRNA) to be used as a template to produce more vRNA (genomes)
Influenza A Replication
Assembly and Release
RNP assembly where?
RNPs interact with:
How do they acquire envelopes?
NA removes ____ from cell surface
- RNP assembly in nucleus → transport to cytoplasm
- RNPs interact with M1 (matrix) and acquire envelopes by budding through plasma membrane
- NA removes sialic acid from cell surface to facilitate release
Influenza Virus
Hemagglutinin (HA):
Key to both infection and immunity
- Functions in viral replication (attachment and penetration)
- Major target of neutralizing Abs (NA is secondary target)
Influenza Virus
Synthesis and Cleavage
Made as a:
Activated by:
HA1 binds to:
HA2 contains:
- Made as a single polypeptide (HA0)
- Activated by proteolytic cleavage → HA1 and HA2 (which remain bound to each other)
• HA1 binds receptors (sialic acid)
• HA2 contains transmembrane domain and fusion peptide (FP located at N-terminus of HA2)
Influenza Virus
HA Fusion Mechanism
Neutral pH (~7.4):
Neutral pH (~7.4):
- HA1+HA2 extends from virion envelope
- HA1 binds to cell surface receptors
- Fusion peptide not exposed to aqueous environment due to trimer configuration
Influenza Virus
HA Fusion Mechanism
Acidic pH (~5.3):
Acidic pH (~5.3):
- Low pH induces conformational shift in HA
- Fusion peptide is exposed, and inserts into target membrane
- Membranes are drawn close together, are locally disrupted, and fuse
Influenza Virus
Neuraminidase (NA)
Removes sialic acid from cell surface:
Removes sialic acid from cell surface
- Facilitates release of virus from the cell surface (without it, newly budded virions could bind back to the infected cell from which they were just released)
Influenza Virus
Neuraminidase (NA)
Removes sialic acid from mucins:
Removes sialic acid from mucins
- Destroy decoy receptors (normally inactivate virus)
- Lowers viscosity of mucous (helps virus to spread)
Influenza Virus
Target of Antiviral Drugs:
- Oseltamivir (Tamiflu): oral
• Note: cannot be used against seasonal influenza A (H1N1) as most strains are resistant - Zamanivir (Relenza): inhalation
Other Antivirals Against Influenza:
- Amantidine and Rimantidine:
o MOA: target M2 ion channel to block uncoating
o Issue: widely overused and misused; many (if not all) influenza strains have become resistant
Influenza Immunity and Vaccine Composition
Immunity:
Key Antigens:
Immunity: provided mainly by virus neutralizing Abs (Abs to HA better neutralizers than those against NA)
Key Antigens:
• HA: 9 subtypes
• NA: 15 subtypes
Major Influenzas Infecting Humans:
- H1N1 (1977 and 2009 strains)
- H2N2
- H3N2
Influenza
Vaccine:
Vaccine: against 2 influenza A strains and 1 influenza B
2010-2011 Vaccine:
• A/California/7/2009 (H1N1)
• A/Perth/16/2009 (H3N2)
• B/Brisbane/60/2008
Influenza Pandemics:
- 1918: H1N1 Spanish flu
- 1957: H2N2 Asian flu
- 1968: H3N2 Hong Kong flu (still in circulation today)
- 1977: H1N1 Russian flu (still in circulation today)
- 2009: H1N1 swine flu
o Formed from the combination of 3 different preexisting strains
• Eurasian swine (H1N1/H3N2)
• Swine (H1/N2)
• Triple Reassortment Swine (formed from segments of 3 previously known viruses)
Influenza
Antigenic Variation
Antigenic Drift:
Driven by:
Results in:
Antigenic Shift:
Occurs via:
Results in:
Antigenic Drift: minor antigenic changes in HA and NA, resulting from mutations
o Driven by selection for resistance to Abs
o Results in a need to change vaccine composition annually
Antigenic Shift: major change in HA or NA, sometimes both
o Occurs via genetic reassortment after infection of a cell with 2 different Influenza A viruses
o Results in a virus for which there is little pre-existing immunity in the human population (results in a pandemic)
1918 H1N1 Virus Pathogenicity:
- Excellent genetic synergy (individual genome segments worked well together)
- High replication potential in bronchial epithelium (high Pathogenicity potential)
- Broad cell tropism (not trypsin dependent)
o Most influenza virus trains require trypsin-like enzyme to cleave HA to HA1 and HA2
o This virus could be cleaved by enzymes found in most cell types - Dysregulation of immune responses (cytokine storms)
- Inhibition of IFN responses via NS1 protein
Avian Influenza H5N1
Basics:
Transmission to humans:
What limits its ability to replicate in humans?
How does it have a high pandemic potential?
Basics: highly pathogenic H5N1 virus circulating in avian populations in many parts of the world
Not easily transmitted to humans, but could adapt to be
Mutation of viral genes that currently limit its ability to replicate in humans
Reassortment with viruses that replicate well in humans
- Have a high pandemic potential
Avian Influenza H5N1
Determinants of Pathogenicity:
Only transmissible to humans on exposure to:
Hemagglutinin H5 contains:
Preference for avian influenza receptors:
What allows HA cleavage by enzymes present in many cell types?
Only transmissible to humans on exposure to high doses
• Little to no ability to transmit from person to person
Hemagglutinin H5 contains 2 key pathogenicity determinants:
Preference for avian influenza receptors (sialic acid with alpha 2,3-linkage)
- Humans have sialic acid with alpha 2,6-linkage
- May also have avian-like receptors deeper in the human respiratory tract (not easy for the virus to access)
Multibasic amino acid sequence at HA cleavage site allows HA cleavage by enzymes present in many cell types
Paramyxoviridae
Family:
Subfamilies:
Family: Paramyxoviridae
Subfamily: Paramyxovirinae, Pneumovirinae
Paramyxoviridae
Paramyxovirinae
Genus: Paramyxovirus:
Genus: Paramyxovirus:
➢ Human Parainflueznavirus 1 (HPIV-1)
➢ Human Parainfluenzavirus 2 (HPIV-3)
Paramyxoviridae
Paramyxovirinae
Genus: Rubulavirus:
Genus: Rubulavirus
➢ Mumps Virus
➢ HPIV-2
➢ HPIV-4
Paramyxoviridae
Paramyxovirinae
Genus: Morbilivirus:
• Genus: Morbilivirus
➢ Measles Virus
Paramyxoviridae
Pneumovirinae
Genus: Pneumovirus:
Genus: Pneumovirus
➢ Respiratory Syncytial Virus (RSV)
Paramyxoviridae
Physical Characteristics:
Genome:
Enveloped
RNA genome:
• -ssRNA (only one segment)
Paramyxoviridae
Enveloped
How many glycoproteins?
Exceptions:
Most have 2 glycoproteins:
- HN (has both HA and NA activities)
- F (fusion activity; activated by proteolytic cleavage of F0 → F1 and F2)
Exceptions:
- Measles (has H, with HA activity only, and F)
- RSV (has G, which binds receptor but has no HA and NA activity, and F)
Laryngitis/Croup
Cause:
Human Parainfluenza Viruses
Croup
Seen in what pop.?
Infection and inflammation of:
Croup: seen in infants and young children
Infection and inflammation of larynx and upper airway (may also involve trachea and bronchi)
Croup
Narrows airway, resulting in:
Other symptoms include:
Narrows airway, resulting in: • “Barking” cough • Stridor (characteristic sound on inhalation) • Hoarseness • Respiratory distress
Other symptoms include:
• Fever
• N/V
Laryngitis
Seen in what pop.?
Life threatening?
Can also be caused by:
Laryngitis: seen in adults and older children
Respiratory tract is wider and therefore it is not life-threatening (swelling does not restrict airway as much)
Can also be caused by other infectious agents and conditions
Tracheobronchitis
Lower Respiratory Tract Infection:
Major Symptoms:
Lower Respiratory Tract Infection: infection of the trachea and bronchi
Major Symptoms: coughing and wheezing
Tracheobronchitis
Most cases due to viral causes
Adults: (2)
Children: (2)
- Adults: influenzavirus, adenovirus
- Children: parainfluenzavirus, influenzavirus
Tracheobronchitis
Nonviral causes:
- Pertussis
- Other bacterial infections
Bronchiolitis
Infection/inflammation of the bronchioles:
Adults:
Children:
Infection/inflammation of the bronchioles: small airways between bronchi and alveoli
o Adults: rarely seen
o Children: life-threatening (especially in those under one year of age)
Bronchiolitis
Symptoms:
Cause:
Symptoms: dyspnea and cough
Cause: Respiratory Syncytial Virus (RSV
Pharyngitis
Sore throat: usually also accompanied by other symptoms
Pharyngitis
Sore throat
Infants:
Infants:
• Adenovirus (involvement of tonsils and adenoids)
• HSV 1
Pharyngitis
Sore throat
Children:
Children:
• Adenovirus
• Coxsackievirus (herpangina)
Pharyngitis
Sore throat
Adults:
Adults:
• Adenovirus
• Coxsackievirus
Human Metapneumonvirus
- Discovvered in the the Netherlands in 2001, found worldwide
- Close relative of RSV
- Second-most common cause of LRT infections in young children, after RSV
- High rate of seropositivity (~100%) in older children
- Elderly, the immunocompromised, and persons with chronic obstructive pulmaonry disease are also at risk of severe human metapneumovirus infection
Pneumonia
Infection/inflammation of:
Common illness in all age groups:
Infection/inflammation of the lungs
Common illness in all age groups: chest pain, cough, fever, difficulty breathing, fatigue
o Common cause of death in the elderly
Pneumonia
Common viral causes
Young Children:
Young Children:
• RSV
• Influenzavirus
Pneumonia
Common viral causes
Older Children:
Older Children:
• Influenzavirus
• Parainfluenzavirus
• (Adenovirus)
Pneumonia
Common viral causes
Adults:
Adults:
• Influenzavirus
• Adenovirus
Paramyxovirus Zoonoses
Henipaviruses
Hendra Virus:
- Natural host fruit bats
- Hendra Virus
- Discovered in 1994 in Australia
- Human case fatality rate ~ 60%
Paramyxovirus Zoonoses
Henipaviruses
Nipah virus
IDed in 1999 in pigs in Malasia
>200 humancases with >100 deaths
Numerous additional outbreaks in SE Asia, New Guinea, Australia
Human fatality rate ~50%
Mumps
Basics:
Basics: common childhood disease o Humans only natural reservoir o Transmission by salivary or respiratory secretions o 14-24 day IP o Less infectious than measles
Mumps
Frequent Manifestations: (5)
- Painful swelling of parotid gland
- Swelling of cheeks and jaws
- Ear pain
- Fever
- Headaches
Mumps
Less Common Manifestations: (3)
- Viral meningitis
- Inflammation of testes (orchitis; more likely in older individuals and can cause sterility)
- Rash
Mumps
Prevention:
Dosing:
MMR vaccine
Dosing:
• 1st dose at 12-18 months (as early as 6 months in an epidemic)
• 2nd dose at 4-6 years
Measles, Mumps and Rubella trivalent vaccine
Measles:
Mumps:
Rubella:
o Measles, Mumps and Rubella trivalent vaccine
• Measles: Attenuvax (Enders’ attenuated Edmonton strain)
• Mumps: Mumpsvax (Jeryl Lynn B level strain)
• Rubella: Meruvax II (Wistar RA 27/3 strain of live attenuated rubella virus)
Measles (Rubeola)
Basics:
Best known for causing:
infectious?
Basics:
o Best known for causing a skin rash, although it is a respiratory pathogen
o Highly infectious
o Still an important disease in many parts of the world (prevented by MMR vaccine in US)
• Although 156 cases in 2011 is the highest number seen since 1996
• Most of these were in people who were unvaccinated and traveling abroad
Measles (Rubeola)
Death Rate:
Transmission:
IP:
- Death Rate: low in developed countries, but can be significant in people who are malnourished
- Transmission: respiratory spread
- IP: 14-18 days
Measles (Rubeola)
Manifestations: (6)
o High fever
o Malaise
o Cough and coryza (symptoms of head cold)
o Headache
o Conjunctivitis
o Rash (5-7 days; begins on face and spreads to trunk and limbs)
Measles (Rubeola)
Complications:
Prevention:
Complications: o Diarrhea o Pneumonia o Encephalitis o Corneal ulceration
Prevention: MMR vaccine
Rubella
Family:
Genome:
IP:
- Family: Togaviridae
- Genome: +ssRNA genome (one segment)
- IP: 12-23 days
Rubella
Symptoms: (4)
o LN swelling
o Maculopapular rash
o Fever
o Risk of congenital infection in pregnant women is greatest concern
Rubella
Birth defects include:
➢ Deafness ➢ Mental retardation ➢ Motor control deficits ➢ Heart, brain or eye malformations ➢ Enlarged liver and/or spleen ➢ Encephalitis ➢ Meningitis
The “Common Cold”:
Viral infection of nose and throat
The “Common Cold”
Symptoms:
Duration: 1-2 weeks
- Symptoms: o Sneezing/runny nose/nasal congestion o Watery eyes and drooping eyelids o Cough o Pharyngitis o Mild/no fever
Duration: 1-2 weeks
Coronavirus characteristics
Enveloped:
Nucleocapsid:
Genome:
- Enveloped virion
- Nucleocapsid has helical symmetry
- RNA genome, single-stranded, positive sense, single segment
- Genome is 30 kb, very large for an RNA virus
Coronavirus
Viral glycoproteins:
- Spike (S) glycoprotein - responsible for attachment and entry
- Envelope (E) glycoprotein - multiple functions, including roles in assembly and egress and modulating the host cell stress response
Emerging Coronaviruses
SARS and MERS
The “Common Cold”
Most common viral causes: (4)
o Rhinoviruses (picornaviridae)
o Coxackieviruses (picornaviridae)
o Coronaviruses
o Adenovirus
Rhinoviruses (picornaviridae):
Pleconaril:
Rhinoviruses (picornaviridae): cause at least 50%; over 100 serotypes
Pleconaril: anti-rhinoviral drug that prevents uncoating of capsule
Coxackieviruses (picornaviridae)
o Coxackieviruses (picornaviridae): most common in infants and kids (herpangina and hand, foot and mouth disease)
Coxackieviruses (picornaviridae)
Symptoms:
• Symptoms: fever, sore throat, headache, anorexia, vomiting, convulsions
Coxackieviruses (picornaviridae)
Lesions:
• Lesions: develop after 2 days of symptoms; small papulovesicular lesions on the tonsils, soft palate and tongue
➢ Heal in 1-5 days
➢ Can also occur on hands, feet and in diaper area (Hand, Foot and Mouth Disease)
•
Coxackieviruses (picornaviridae)
Resolution:
Resolution: more rapid than HSV (can look similar)
Coronaviruses:
Adenovirus:
Coronaviruses: SARS
Adenovirus: over 50 serotypes
Picornavirus and Infections of the Skin and Mucous Membranes
Picornavirus size:
Enveloped?
Genome:
What cause infections of the skin/mucous membranes?
- Picornavirus are very small, nonenveloped viruses with single-stranded, plus-sense RNA genomes
- Certain Picornaviruses, esp. certain Coxsackieviruses, as well as Echoviruses and Enterovirus 71, cause infections of the skin/mucous membranes
Picornavirus Virus
Spread by:
- Spread by saliva, mucous, or feces
- Coxsackievirus infections tend to occur in epidemics
Hand, Foot, and Mouth Disease
Associated with Coxsackie A Virus, esp. type A16, Enterovirus 71
- Recently, an outbreak of severe HFMD was caused by Coxsackie A Virus A6 in Alabama
- Outbreaks in the US tend to be small, some larger outbreaks in Asian countries with thousands affected
Herpangina (mouth blisters and ulcers)
Associated with certain types of Coxsackie A Virus, Coxsackie B Virus, and Echoviruses
Viruses causing Common Cold:
Rhinoviruses and other Picornaviruses, Coronaviruses,
Parainfluenzaviruses, Adenovirses
Viruses causing Pharyngitis:
Parainfluenzaviruses, Rhinoviruses and other
Picornaviruses, Influenza A and B Virus, Cytomegalovirus, Epstein-
Barr Virus, Herpes Simplex Virus, Adenoviruses
Viruses causing Bronchitis:
Parainfluenzaviruses, Respiratory Syncytial Virus,
Influenza A and B Viruses, Metapneumovirus
Viruses causing Bronchiolitis:
Parainfluenzaviruses, Respiratory Syncytial Virus,
Metapneumovirus
Viruses causing Croup:
Parainfluenzaviruses, Respiratory Syncytial Virus,
Metapneumovirus
Viruses causingInfluenza:
Influenza A and B Viruses
Viruses causing Bronchopneumonia:
Influenza A and B Viruses, Respiratory Syncytial
Virus, Parainfluenzaviruses
Viruses causing Pneumonia:
Pneumonia - Influenza A and B Viruses, Adenoviruses, Novel
Coronaviruses (SARS-CoV, MERS-CoV), Parainfluenzaviruses
