Influenza Virus and Respiratory Tract Illness
Influenza, part of the Orthomyxoviridae
family is a negative sense,
single-stranded virus which can lead to respiratory tract illness, both upper and lower
respiratory tract infections (URTI and LRTI). Influenza can be found in three
different types, A, B and C. Types A and B are the main reason behind yearly
epidemics, whilst C is mainly sporadic. Sub-types of type A can be further characterized
by their neuraminidase (NA) and hemagglutinin (HA) surface
glycoprotein composition and are responsible for variations between strains. Infections
can lead to greater consequences, such as morbitiy and mortality. Such diseases
which result from influenza infection are acute Bronchitis, bronchiolitis and viral pneumonia1.
The body’s immune system mediates this infection through
detecting and directing neutralizing antibodies to the HA’s of the virus. Influenza
A viruses can undergo rapid change and have highly variable HA’s on their
surface, due to antigenic drift. This means that the virus can evade
neutralizing antibodies more effectively, due to the reduced ability to bind and
recognise this HA glycoprotein and successfully reduce viral numbers. Negative
selection occurs and consequently, evolution. The result of this is populations
who are immune to some strains of influenza, may not be to these variant
strains, and not only themselves get infected but are vectors of transmission
to other individuals, thus leading to new, yearly epidemics2. In
addition to antigenic drift, another mechanism of evolution can occur,
re-assortment. It is possible two differing strains or types of a virus can be
infecting the same host, and gene segments are interchanged between the two;
most notably occurring between Type A and B. This change in sequence, coupled
with type A’s ability to rapidly change glycoprotein HA (type B can also
change, but at a lesser rate), can lead to antigenic shift. Bird species have
been documented to have an abundance of variant strains which may be
potentially devastating to human populations because of such antigenic shifts
and drifts2. An example of this is the H5N1 avian influenza A virus
which in Southeast Asia is becoming an increasing problem, as it has infected
considerable populations of poultry and transmission to humans has grown.
Due to such variation, the continuous ability for influenza
to cause respiratory tract infection remains. Several mechanisms are utilized
by influenza to bring about such infections, for example rapid replication of virus at target area, reduction
in important immune cells and increased susceptibility to other pathogens.
Transmission occurs from the inhalation of airborne particles/droplets, into respiratory tract
· The receptor binding sites
of the virus are long chain glycans with sialic acid terminals, which are
linked to galactose through alpha-2, 6 linkage.
· The locality of these
receptors can be found on epithelial cells of the respiratory tract i.e.
bronchioles, nasal mucosa, alveoli, pharynx, bronchi, trachea, and paranasal
sinuses4. Influenza viruses
typically attach themselves mainly to ciliated bronchial and tracheal epithelial
cells, additionally to type 1 pneumocytes. However, other ciliated and non-ciliated epithelial cells
can also be targeted, for example alveoli macrophages and type II pneumoctyes,
but to a lesser degree.
· The result of this
uncomplicated viral infection is damage to respiratory epithelium, varying from
absence of cilia and edema to significant desquamation of the epithelial cells.
In addition, histiocytes and lymphocytes infiltrate affected areas. However,
the degree of infiltration of inflammatory cells was relatively small in
relation to the epithelial damage extent.
· The effect of the virus is short-lived
on the bronchial epithelial, as epithelial repair starts to undergo around 2
days after symptom onset. The only, if any long lasting difference between
healthy and influenza infected individuals was that surface epithelium was
thickened and infiltration of lymphocytes was increased marginally.
· Characteristic symptoms of
infection can be, systemic and local. Systemic being fevers, migraines, anorexia,
and muscle pain, whereas local symptoms are coughs, obstruction of the nasal
cavity, and sore throat. These symptoms are a result of physical damage at the
target site due to viral replication. In addition, they are also due to cytokine and inflammatory
mediator release at a systemic and local level.
· Bronchitis can be
characterised as inflammation of the bronchial passages (tree) and is often a
result from infection of the upper respiratory tract.
Upon acute bronchial infection, mucosa starts to become both edematous
and hyperemic and results in bronchial secretions. The degree of mucosal damage
can vary from significant depletion of respiratory epithelium to a small
reduction in mucociliary function1. Chronic forms of bronchitis involve
a substantial increase in cells which produce mucus (of the airways), in
addition to loss and inflammation of the bronchial epithelium (although this form
is often in co-infection with bacterial pathogens). Infection of influenza which can lead to
bronchitis in infants can be severe, this is due to potential respiratory
epithelium necrosis, inflammation and sloughing.
Complications of influenza can be further detrimental to the lung and
well-being of the infected individual. Viral pneumonia involves alveolar epithelium damage, thus the
infection has spread deeper into the lung. This disease is particularly
dangerous because of the reduced gaseous exchange being carried out from the
respiratory tract4. Type I and II pneumocyte
(alveolar epithelium) damage is attributed to both the host indirectly
responding to the infection and also from viral infection stimulating direct
Type I and II pneumocytes
serve critical roles to alveoli; type I ensures fluid does not leak between the
alveolar- capillary barrier. Whilst type II reabsorbs alveolar lumen fluid, in
addition to lung surfactant production (plays an imperative role in moderating
surface tension of the alveoli). Thus, substantial damage to these pneumocytes can
result in fluid overwhelming the alveolar lumina, leading to respiratory
dysfunction which is potentially fatal4.
pneumoniae and respiratory tract illness
Streptococcus pneumoniae, is a Gram-Positive
bacterial pathogen with exotoxin releasing abilities- which is one of the
leading agents contributing to pneumonia. Pneumococci serve a role as a human
commensal, colonizing the nasopharynxes of healthy children (20-50%) and
healthy adults (8-30%). Pneumonia is the inflammation of the parenchyma in the
lungs, affecting the alveoli2.
Although S.pneumoniae has many
serotypes only a small number can actually lead to infection, with the 10 most abundant
being responsible for upto 62% of invasive pneumococcal disease (IPD) 5.
A few most notable serotypes leading to IPD are 9V, 4, 14, 19F and 6B. However
treatments such as antibacterials and polysaccharide vaccines which are
effective against 23 known serotypes S.pneumoniae have been developed1.
Factors which can
lead to increased prevalence of IPD amongst populations are colder climates
such as during winter seasons, over-populated environments, and amongst young
children, nursery and day care institutions.
The means in
which transmission occurs from individuals is through airborne droplets and is
particularly an issue in closed populations, i.e. schools.
A key evolution
adaption of S.pneumoniae is the outer polysaccharide capsule which plays a fundamental
role in the virulence of a particular strain. The thicker the capsule layer,
the greater potential it has to be more virulent. The importance of the capsule
is to reduce the effect of classic complement pathways with aims to destroy
bacterium, in addition to macrophage and neutrophil phagocytosis. Furthermore,
the ability of this pathogen to go undetected by the immune system and
reproduce rapidly is also a property of pneumococci5.
Pneumonia is a
significant cause of mortality and morbidity globally, with a fifth of deaths
of over 65 year olds in the US due to this disease.
to disease occurs as colonization of the bacteria spreads from the nasopharynx
into the lower respiratory tract i.e. bronchioles and alveoli. However replication does occur at a slower
rate in the nasopharynx compared to in the lung, with doubling rates of 161 and
108 minutes respectively. This suggests conditions are less favourable for
growth in the nasopharynx as nutrients are less accessible opposed to the lungs9.
start from the common cold consequently lead to more conditions such as Sinusitis
and lastly pneumonia.
Sinusitis is the acute
inflammation of the paranasal sinuses and S.pneumoniae can be a causative
agent. Initial damage to the cilia, weakens
the respiratory tracts ability to sweep bacterial-colonized mucus. This is
through impairment of sinus epithelial lining ciliary, and increasing
concentrations of mucous secretions. The result is the paranasal sinusal ostia
becomes obstructed, reducing drainage ability. Continual replication of the
bacteria in these cavities, and increased secretion of mucus, the mucus
eventually is reformed into mucopurulent exudents. These mucopurulent exudents
cause mucosomal lining irritation, consequences include further destruction of
the epithelium, increased levels of edema and ostial obstruction1. This weakened state allows for bacterium to
further replicate and lead to more serious states of infection.
Depending of the
locality of S.pneumoniae infection, so will the disease for example in the
lung, pneumonia can result whereas in the blood can lead to the fatal systemic
infection- pneumococcal sepsis8. Furthermore, Bacteraemia can also
occur if lung infection becomes advanced, with one result being spread across
the blood-brain barrier, resulting in infection of the meninges and
One feature of
upper respiratory infection, is inflammation such as
b is a lead cause for this inflammation.
coinfection leads to more severe disease
caused by viruses can result in opportunistic pneumonia, for example in AIDS
· Influenza and streptococci pneumoniae together can form or lead to a
superinfection; together both have resulted in worldwide pandemics and led to the death of more
than 50 million in year 1918 alone3.
· The reason
behind this is both pathogens work in unison (co-symbiosis), complementing each
other when targeting the lower respiratory tract.
· The Initial
viral infection weakens the immune defences by inhibiting innate antibacterial
defences of the lungs and allows for greater bacterial adherence6.
This allows for opportunistic bacterium such as streptococci pneumonia to
overwhelm the respiratory tract and uncontrollably colonize and spread to the
lower respiratory tract.
· Influenza virus
is more readily removed from the lungs due to their glycoprotein coat, by the
mucocilliary escalator, thus bacteria are more responsible for deep lung infection.
The glycoprotein, neuraminidase (NA) of influenza, necessary for replication of
the virus and plays a role in disrupting and stripping sialylated mucins found
on host cells. The latter is beneficial for S.pneumoniae growth and
colonization, because sialylated mucins act as decoy receptors for which
bacteria (or other microbes) bind too and can be targeted by immune cells such as
neutrophils. Bacterial lectins attach themselves to carbohydrate
surfaces, more specifically exoglycosidase bgaA becomes increasing more able to
bind to these host surface carbohydrates as the sialic acid layer becomes further
diminished, exposing these sites9.
· In addition,
the viral infection increases production of mucus and sloughed host cells,
providing a more nutrient rich environment for bacterial growth, enhancing
colonization potential. Furthermore, viral damage to the epithelial layer
exposes more sites in the extracellular matrix proteins of the basement
membranes for S.pneumoniae attachment7.
· The effect of a
‘cytokine storm’ plays a role in the severity of co-infection, which can cause
significant tissue damage, and is responsible for many early deaths from severe
lung damage resulting in hypoxia and anorexia.
· Damage to the
lower respiratory tract, resulting in loss of barrier function can cause acute
respiratory distress syndrome (ARDS).
· Viral infection
of the respiratory system causes extensive damage to the lungs, this is further
heightened by the influx of myeloid cells such as mononuclear phagocytes, which
secrete TRAIL, a lytic molecule, killing alveoli epithelial cells.
also have key prowess in initiating mediating inflammatory molecules through
the release of vast amounts of pro-inflammatory cytokines post necrotic cell
(and other lysed cell product) encounters. Interleukin-6, 8 (IL-6, IL-8) and
TNF-? are the pro-inflammatory cytokines playing roles in immune protection.
However, over-expression of these cytokines can be toxic; for example IL-8
although important in the regulation of bacterial replication, it can also
cause excessive neutrophil responses in ARDS patients. Consequently significant
damage to the alveoli is caused and vast build-up of dead cells in protein-rich
fluid, inhibiting effective oxygen diffusion7.
co-infection, substantial suppression of the innate immune cells occurs,
regardless of the considerable cytokine activity.
· From animal studies it was found greater
susceptibility to S.pneumoniae has been linked to high concentrations of Type 1
interferon (IFN??) and the negative regulation of ?? T
cells ; a source of IL-17 and aid in recruitment of neutrophils to the
lung region. Neutrophil count was typical low post-influenza virus infection,
partly because of the prolonged desensitization and exposure to TLRs (play a
role in bacterium recognition).
adaptive immune cells aid in the control of bacterial infections (of healthy
individuals), such as specific forms of CD4+ T cells producing IL-17/ Th17
infection of influenza virus, Th17 is developed and transformed through the use
of growth factors, TGF-? and IL-6. A mild pathogenic form of Th17 is
formed, and further initiated the production of IL-10, TGF-? and IL-21
– promoting auto-proliferation. When IL-1 and IL-23 are present, the mildly
pathogenic Th17 response is amplified, as a consequence IL-21 and IL-10
expression is down-regulated.
· A state of anti-inflammation is induced, through
the action IL-10, returning to a normal homeostatic state (negative feedback),
however, this may also make the host more susceptible to bacterial
co-infection. After the consumption of host cells, a change in cytokine response
occurs from macrophages to regulate apoptosis through the production of TGF?
and IL-10 (pro-inflammatory). This process occurs rapidly to prevent the
exposure of danger associated molecular patterns (DAMPS), which restart the
inflammatory response. Throughout the recovery period from influenza virus ,
suppression of macrophage activity occurs, due to up-regulation of CD200
(inhibitory receptor) and lack of sensitivity to bacterium from TLRs.
· Viral infection induces greater concentrations
of T cell derived interferons i.e. IFN-?;
consequentially, the clearance of bacterial infections is reduced from alveolar
macrophages. One reason for this is the lack of expression from scavenger
receptors, used to clear debris of dead cells and extracellular bacteria
components via phagocytosis. Conversely, IL-22 and IL-17 aids in reducing the
severity of lung damage and promotion of wound healing during co-infection10.
Furthermore, damage to surface proteins during wound healing, can expose
specific cryptic sites to which bacteria can adhere too and resist the mucociliary
The impact of
co-infection is not only that bacterial growth is heightened but also develop
the virus’s immunity and resistance7.