Both host cells, leaving the host weakened. 1 S.Pneumoniae

Both viruses and bacteria can cause
respiratory tract illnesses. These pathogens can act on the tract alone or work
synergistically to cause possibly fatal disease. Streptococcus pneumoniae
(S.pneumoniae) and the influenza virus are two examples where disease can be
caused alone, but when infected simultaneously, cause extreme results.


S.Pneumoniae is a potentially highly
invasive, gram positive extracellular pathogen.1 It has been
intensely studied for the last 100 years and has finally been understood in
greater depth. The infection has attempted to be controlled through
polysaccaride vaccines and understanding of antibiotic resistance. The
inflammatory response to pnemococci is usually able to clear the infection but
damages host cells, leaving the host weakened. 1

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S.Pneumoniae infections predominantly
start through nasopharyngeal colonisation but can affect many body systems.

S.Pneumoniae usually causes asymptomatic colonies known as ‘carrier’ individuals.

Children are the highest carriers of S.Pneumoniae, averaging at 37%, and up to
58% in nursery environments.2 As well as children, individuals with
compromised immune systems and the elderly are most at risk. 3 Crowding
is the main factor that allows rapid transmission of S.Pneumoniae through
coughing and sneezing. After the nasopharyngeal colonisation, pneumococci
progress down into the respiratory tract, ultimately causing a full systemic
disease.4 The pneumococci enter the extracellular space around the
alveoli of the lungs. This stimulates an inflammatory response; causing plasma,
erythrocytes and leukocytes to fill the alveoli. 5 This condition is
called pneumonia. However, S.Pneumoniae can also cause various other serious
infections such as bacterial meningitis, enocarditis, otitis media,
peritonitis, septicaemia and sinusitis. 3The pathogenicity including the high
mobidity and mortality caused by S.Pneumoniae have been widely researched and
yet, are still largely unknown. The main
virulence factor of S.Pneumoniae is its capsule
and other surface structures. It has antiphagocytic activity and is made from
polysaccharides. 4 The capsule enables the pneumococci to evade
phagocytosis, and therefore the host’s immune system. It does this by
sterically inhibiting opsonisation of C3b which is a complement component. 6
Cell wall components and the intracellular toxin, pneumolysin are
involved in causing the inflammation response. Inflammation is thought to cause
most of the symptoms of pneumonia, therefore suggesting this could be responsible
for the morbidity and mortality of the disease. Experimental data has suggested
that the capsule is the most virulent factor. Encapsulated strains of
S.Pneumoniae were found to be 105 times more virulent than
uncapsulated strains. 3  Adherence to bronchoepithelial cells is
considered the first step in pathogenesis. The pneumococci bind to
nasopharyngeal buccal epithelial cells, lung vascular endothelial and lung
resting pneumocytes via lectin- like interactions, or protein-protein
interactions. 4 The pathogenesis of s.pneumoniae
is different whether it is infecting the lung or nasopharynx. The
platelet-activating factor receptor (pafR) serves as a lung ligand, whereas the
polymeric immunoglobulin receptor (pigR) serves as the nasopharynx ligand. It
has been widely reported that pigR is upregulated by proinflammatory cytokines.4

PspC is also thought to play a
significant role in binding to endothelial lung tissue. It is part of the
choline-binding protein family and is present on the cell surface of S.pneumoniae.

PspC non-covalently binds to phosphorylcholine present on the cell wall of
teichoic acid and the membrane-bound lipoteichoic acid. Once bound to
epithelial cells, phosphocholine can activate platelet factors. 8 Structurally similar to PspC, PspA is also a protein that resides
on the S.pneuomoniae surface. Recent studies have shown that PspA also adheres
to epithelial cells through interacting with E-cadherin. 6, 8  PspC also interacts with the
secretory component portion of polymeric Ig receports and secretory IgA. 7
Biofilms can start to form after the epithelial attachment, and it is thought
the pneumococci gain nutrients through manipulation of ABC transporters like
Piu iron transporters.Pneumolysin
is an intracellular protein belonging to the family of thiol-activated toxins. 3
It is not secreted by pneumococci, but is released upon lysis of
pneumococci under the influence of autolysin. Pneumolysin induces apoptosis and
destruction of the sub epithelial layer. This is achieved by stimulating the
production of cytokines involved in the inflammatory response such as TNF- a and IL -1b. It inhibits the ciliated epithelia and therefore, disrupts the
monolayers of cultured epithelial cells, stifling their ability to beat and
waft mucus. It decreases bactericidal activity and migration of neutrophils
used by the immune system for destruction of pathogens. Inhibition of
lymphocyte proliferation and Ab synthesis also occurs. The final stage is the
activation of the classical complement pathway as there is no anti-toxin AB
present. 3  Another
proposed mechanism to ensure adherence to epithelial cells is the exposure of
the receptor N-acetylgucosamine whereby neuraminidase cleaves sialic acid from
mucins enabling the pneumococci to bind with greater ease. 9 After
adherence and the subsequent outcome of the virulence factors, fluid from the
capillaries enter into the alveoli. The lung lobe begins to appear red and
swollen, much like hepatisation of the liver. Thereafter, grey hepatisation
occurs. This is when oedema in the lung occurs, and leukocytes fill the
interstitial gaps between the alveoli. During the final stage, macrophages
enter and attempt to clear the infection, termed ‘resolution’. Pneumonia
induced by S.Pneumoniae has many symptoms
including; mucus production, crackling chest, dyspnoea, and pleurisy pain.  Influenza viruses are enveloped
negative-stranded RNA viruses. There are three types of influenza virus, A, B
and C, which differ in morphology due to their surface glycoprotein structure. Influenza
is transferred between humans through infected surfaces, direct contact with
infected individuals and inhalation of virus-infected aerosoles. Influenza
pandemics are a regular occurrence and have been reported throughout history. Pandemics
arise from novel virus subtypes of influenza A, generated through reassortment
of the segmented genome known as antigenic shift. Annual epidemics arise due to
mutations in the surface antigens of influenza A and B, known as antigenic
drift. 11 It is the mutations in the surface
glycoprotein’s-haemagglutinin that ensure the virus is recognised by the host’s
immune system as a new pathogen. 11, 12

Influenza A and B are the most virulent in humans, whereas
influenza C only causes mild symptoms. The structure of influenza A and B are
very similar. They consist of 8 segments, 6 of which encode for viral
polymerase, membrane glycoproteins such as haemagglutinin and neuraminidase and
proteins PB1 and PB2.  The external
layer has approximately 500 projections, HA (rod shaped) and NA (mushroom
shaped). The major envelope of glycoprotein HA is synthesized inside the host
cell as a single polypeptide chain (HA0) and cleaved into two subunits; HA1 and
HA2. These are covalently linked with disulphide bonds. An enzyme named trypsin
protease is responsible for cleaving HA into its subunits and is found in the
Clara cells of the respiratory epithelium. HA1 is responsible for binding the
virus to the cellular sialic acid receptors. It is also the major antigentic
epitopes and therefore, the primary antigen that triggers the immune response. 12
The HA2 subunit forms the fibrous stem of the spike. It is often referred to as
the ‘fusion peptide’ as it is liable for fusing the viral envelope and host
cell membrane. The final notable protein is neuraminidase. Neuraminidase
cleaves sialic acid from viral proteins to ensure exposure of N-acetylgucosamine.

Thus allowing viral particles to attach to infected epithelial cells. 12


After the influenza virus binds to sialic acids they are linked
via a galactose alpha 2,6 glycosidic bond. 13 HA is bound to the
sialic acid residues found on epithelial cell glycoproteins, triggering
mediated receptor endocytosis. Particles of the virus are taken up by host cell
and further packaged into vesicles, which fuse to endosomes. The exact
mechanism that the virus evades lysosomal degradation is still unknown.

However, it appears that the acidification of the endosome triggers a low pH
and a conformational change in HA2 commencing the fusion process. The timing of
this release has impacts downstream in steps of viral replication. It has been
suggested that there is a ‘critical window’ in which the genome must be
transported into the nucleus. If it is too early, the likelihood of it reaching
the perinuclear region is significantly decreased, and if it is too late, the
cytosolic environment could inactivate it. 15 Once the viral genes
are transported into the nucleus, negative sense viral RNA is used as a
template, ensuring synthesis of new viral particles via the use of the host’s
cytosol and ER. The viral DNA is replicated thousands of times, causing cell
lysis and death. Neuraminidase
activates TGF – b which usually remains latent in cells. This
stimulates apoptosis in infected cells and affects lymphocyte activity. 16

Influenza is considered an acute respiratory
disease and is characterized by a sudden onset of symptoms including; coryza,
cough, headache, high fever, inflammation, malaise, prostration and upper and
lower respiratory tract problems. Acute symptoms usually persist for 7-10 days
and are most prevalent during January and February in temperate climates.

Children, the elderly and immunocompromised individuals are most seriously
afflicted. The most fatal cases usually climax by causing bronchitis,
broncholitis and pneumonia. During the acute stage, destruction and
desquamation of the pseudostratified columnar epithelium of the trachea and
bronchi are common. Usually, only a basal layer of the epithelium remains after
infection. The submucosa are often marked by oedema and congestion. Autopsies
carried out after the 1918 Spanish influenza involving H1N1 displayed reddened
and swollen mucosal surfaces and constant evidence of secondary bacterial
infections, making it hard to determine the exact cause of death from influenza
alone. 14 Neutrophils may contribute to acute lung injury after the
original influenza infection. They have been poorly studied in respect to viral
disease, however, as they are first-responders in the immune response, it is
plausible that insufficient or incorrect signalling may cause overstimulation
of type I interferons (IFN). This would cause phagocytic cells to hone into the
infected airways and cause destruction of the epithelium in response to the
inflammatory cytokines and chemokines. 17 During the final stages,
the epithelium can become necrotic. Necrosis during bronchitis caused by
influenza can cause build up of secretions in bronchial lumen, coupled with
bronchial wall thickening can culminate in serious breathing impairment. 18
Pneumonia caused by influenza results in thrombosis of vessels, interstitial
oedema from oxygen deficit and haemorrhage from mass infiltration of
inflammatory cells. 18



S.pneumoniae is a relatively harmless commensal bacterium that usually lies
dormant in healthy individuals. However, once co-infected with the influenza
virus, a lethal synergism between the two can arise. Damage to the respiratory
tract from the influenza infection will aid bacterial acquisition, however, progression
also depends on the host’s immune status, sequence and timing of infection and
pathogenic strain. 19 The characteristics of the separate infections
are changed when co-infection occurs. Firstly, influenza can decrease the
mucociliary clearance of pneumococci whilst the pneumococci themselves adhere
to epithelial cells with greater virulence

This could be due to viral neuraminidase
activity. This achieved by neuraminidase disturbing the sialylated mucin found
on the epithelium, which in turn exposes binding sites for the pneumococci to
adhere to. TNF- a from virally infected cells which indirectly upregulate PAFr
further enabling pneumococci adherence. 21 As adherence deepens
further into the lungs, the excess mucus sloughs off creating an optimum
environment for the bacteria to multiply in. 20


The severe immune response to destroy these
pathogens leads to further damage to the lung epithelium. Prior to and
throughout co-infection, inflammatory cytokines IFN-a,
IFN-b, IFN-g, TNF-a and IL-6 and anti-inflammatory cytokine IL-10 are released in a
significantly greater quantity, influencing downstream events. These include
macrophagre and neutrophil recruitment. The apoptotic immune cells express
CD200 on their surface.

In summary, the immune response is
desensitised. 19 The recovery period of influenza disables the
ability of alveolar macrophages to phagocytose the pneumococci that results in
an amplified but ineffective clearing of bacteria.

PB1-F2 is an influenza A protein that induces
apoptosis. Viruses with increased PB1-F2 result in more severe secondary
infections. In fact, truncated PB1-F2 strains have very low virulence with
bacterial infection suggesting the important role the protein plays in
co-infection. 22


Both S. pneumoniae and the influenza virus
can cause disease in the human body when singularly infecting. However,
together, they can form a lethal synergy through secondary bacterial
infections, resulting in overstimulation of the immune response components. The
influenza virus aids the pneumococci in adherence to the pulmonary endothelium.

In general, S. pneumoniae is commensual and only displays symptoms when the
immune response is already compromised. Co-infection is so virulent due to the
adaptive immune response inhibiting the innate immune system whilst trying to
destroy the pnemococci bacterium. Therefore, the endothelium is almost entirely
destroyed, allowing for a systemic infection of S. pneumoniae.