Respiratory Infections Flashcards
Upper Respiratory Tract (URT)
-everything above the larynx
Lower Respiratory Tract (LRT)
- site of bronchitis, bronchiolitis, pneumonia
- everything below the larynx
Common Pathogens of the nasopharynx
- rhinovirus
- coronavirus (except SARS)
Oropharynx
- adeno
- EBV-not a typical respiratory virus but is transmitted by respiratory/oral contact route
Larynx-trachea
parainfluenzaviruses
Bronchi
-influenzaviruses
Bronchioles
-respiratory syncytial viruses (RSV), SARS
alveoli
-influenza, parainfluenza, RSV, SARS
LRT pathogens
2 major virus families-orthomyxo and paramyxo
Orthomyxo-segmented, H+N surface glycoproteins
paramyxo-HN+F (G+F for RSV)
Antigenic Shift
- reassortment of genome segments
- primarily bird viruses, humans are accidental host
Major Flu pandemics
H1N1-spanish flu: 1918, severe H2N2-asian flu: 1957, severe H3N2-hong kong flu: 1968, moderate H5N1-hong kong, 1997 H1N1-mexico swine flu, 2009
Antigenic Drift
-random mutations affecting antigenicity
Pigs as carrier of flu
- pigs are hosts to both human and avian strains of flu
- pigs come in contact w/ birds and humans
- reservoirs for different strains of flu
Influenza Virus Evolution
- H1N1 (spanish)-arose directly from birds
- H2N2 (asian-1957)-3 of the RNAs derived from new source, antigenic shift
- H3N2-(hong kong-1968)-PB1, HA derived from new source
Avian Influenza Virus
1997-H5N1 strain: found in poultry markets and spread to small numbers of humans w/ high mortality
2007-outbreak from southeast asia westward, virus is endemic in birds
H5N1 transmitted inefficiently from birds to humans
Human and avian influenza virus
flu virus receptors are glycoproteins containing sialic acid
- human flu virus prefer alpha-2,6 gal linkages b/w sialic acid and galactose
- avian flu viruses prefer alpha-2,3 gal linkages
- humans possess alpha 2,6 gal in URT, but alpha 2,3 gal in alveoli
- 10 consistent aa’s implicated in differentiating birds and humans (none in H)
- fear that new mutations will lead to increased virulence in humans
- all H5N1 isolates show no more than 1 of these 10 mutations
H1N1 2009 swine flu
- origin in mexico, rapid spread worldwide
- despite initial rapid spread and virulence, the global epidemic was not severe:
- vigilant screening
- voluntary crowd avoidance, quarantines
- immunization programs
Factors in influenza pathogenesis (4)
- receptor binding (HA and sialic acid)
- HA proteolytic cleavage
- virulence/host range aa determinants (esp. HA, PA, PB1, PB2 genes)
- cytokine storm
HA proteolytic cleavage in flu pathogenesis
-cleavage of HA0 to HA1 and HA2 by host protease to activate virus mediated cell fusion
LPA1 (low pathogenic influenza)-proteases localized in respiratory and intestinal organs
HPA1-ubiquitous proteases
Cytokine Storm
- potentially fatal immune rxn involving a positive feedback loop b/w cytokines and immune cells
- highly pathogenic strains trigger higher levels of pro inflammatory cytokines than less pathogenic strains
- TNF-alpha
- CCL5 (RANTES)
- CCL3
- CCL4
- CCL2 (MCP-1)
Influenza Vaccines (6)
- succesful, formalin inactivated, fertilized egg grown virus trivalent vaccine (A/california/7/2009 H1N1, A/perth/16/ 2009 H3N2, B/Brisbane/60/2008)
- successful H1N1 immunization program in Canada in 2009
- live attenuated (nasal) available as of 2003
- constant surveillance required to detect new strains
- depends on good growth new strains in embryonated eggs
- worldwide production-just a few companies in a few countries
Immune Modulation of flu
- NS1 (segment 8) has immunomodulatory activities
- antagonism of host immune response
Paramyxo Viruses-2 groups
- parainfluenza
- RSV
Parainfleunzaviruses (types 1-4)
- types 1-3 major cause of croup (infection of larynx and upper trachea)
- type 3 assoc. w/ pneumonia and bronchitis
- type 4 mild upper RT infections
Paramyxo C and V proteins in suppression of IFN signalling
- paramyxoviral genome gives rise to multiple mRNAs, one of which is the C/P/V mRNA
- polycistronic, leaky scanning, atypical mechanisms to access C and V genes
Viral Suppression of IFN-activated signalling
C, V inhibits Jak-1/Tyk-2
C, V, P (Rabies), VP24 (Ebola) inhibits STAT-1-2
-pathway involved in antiviral response
Respiratory Syncytial Virus (RSV) (7)
- most children by age 2 yrs have been infected w/ RSV
- major LRT pathogen in infants, children, elderly and immunocompromised
- generally mild cold like symptoms in adults
- A and B subgroups (differ mostly in G protein)
- A subgroup more severe
- envelope glycoproteins F and G induce neutralizing Ab’s
- occurs every year like flu, never completely protected even though infected over and over again
RSV Envelope Spikes (3)
G -attachment -neutralization and protective antigen -antibody decoy (secreted G) -fractalkine mimic -TLR agonist F -fusion and entry -neutralization and protective antigen -TLR4 agonist SH -putative viroporin -inhibits apoptosis
RSV Nucleocapsid-associated proteins (4)
N-RNA-binding
P-phosphorylation
L-polymerase
-M2-1-Tc processivity factor
RSV Inner Envelope Face proteins (1)
M-assembly
RSV Regulatory Protein
M2-2
- decreases viral Tc
- increases RNA rep.
RSV Non-structural Protein
NS1 and NS2
- inhibit type 1 IFN induction
- inhibit type 1 IFN signalling
- activate P13K and NF-kappaB
- inhibit apoptosis
- at 3’ end of genomic RNA
The search for a safe and effective RSV vaccine
- formalin killed vaccine
- non protective and worsened the disease
- lung inflammation of neutrophils and eosinophils
- induced non-neutralizing antibodies
- mouse studies show formalin killed RSV vaccine and RSV G protein primes harmful Th2 response w/ eosinophil recruitment
- use subunit (F or G protein) or DNA vaccines
- aim to stimulate Th1 but not Th2 response
Immune Evasive Mechanisms Used by RSV (5)
- interference w/ type I IFN signalling (NS1/2 proteins degrade STAT2, block Tc activation)
- interference w/ TNF signalling (SH protein)
- tilting Th1/Th2 balance (G protein)
- TLR4 interaction/signalling (F protein)
- interference w/ leukocyte chemotaxis (G protein CX3CR-binding motif)
Chemokine mimicry by RSV G protein
- G protein has chemokine (CX3CL/fractalkine) activity, allowing binding to CX3CR thereby affecting leukocyte trafficking
- -> delayed viral clearance, enhanced infectivity of cells
RSV and asthma
- correlation b/w severe RSV disease in early childhood and asthma/recurrent wheezing later in life
- polymorphisms of TLR4 assoc. w/ susceptibility to RSV infection and later development of asthma
Emerging Respiratory Virus Pathogens (4)
- new strains of flu
- hantavirus (member of bunyavirus fam)
- SARS
- MERS
Hantavirus Structure
- lipid enveloped virion
- 3 ss (-) RNA segments
Hantavirus Pulmonary Syndrome
- transmitted by rodents and their droppings, virus spread to humans via inhalation
- acute respiratory distress syndrome (ARDS)
- virus remains in interstitial tissue rather than airspaces
Hantavirus Pulmonary Syndrome Pathogenesis
- viral antigens within the endothelium of capillaries in various tissues
- EM confirms infection of endothelial cells and macrophages in the lungs of HPS patients
- disease severity correlates w/ elevated levels of virus specific CD8+ T cells
- endothelial cells separate blood vessels from surrounding tissues
SARS (coronavirus)
- severe acute respiratory syndrome
- 1st outbreak in 2003
- interstitial pneumonia
- may be spread from animals (bats, civet cats) to humans
Mechanism of Immunopathogenesis in SARS
- hyperactive immunopathological response (cytokine storm)
- virus uses ACE2 (angiotensin converting enzyme 2) as receptor, resulting in its downreg
- as a result there is accumulation in lung of angiotensin II which is damaging to lung tissue
- > fluid accumulation in lung tissue
SARS interference w/ host immune functions
- most things target IFN response
- nsp-16 disguises the cap of v mRNA to make look like cell mRNA
MERS (coronavirus)
- Middle East Respiratory Syndrome
- emerged 2012 in countries in or near arabian peninsula, also spread by air passenger travel
- origin unknown
RIsks for Severe RSV
- host determined risk factors
- early age of infection
- viral factors blocking IFN responses and apoptosis
- high infectitvity and viral pathogenesis
