The a cytokine storm, causing damage to

The human respiratory tract is a common target for bacterial
and viral infections as it presents an entry into the human internal
environment. To combat this the respiratory tract utilises a number of
mechanical defences to prevent infection, however pathogens have evolved to
evade or target these mechanisms through methods such as antigenic change and increasing
host susceptibility to superinfection. This review will focus on the context of
disease resulting from Influenza virus and streptococcus pneumoniae(influenza-strep)
co-infection. There are many reviews focusing on the infection trends of
influenza on the immunosuppressed, elderly, and weak which the review will
explore, however infection in the general population. Structure of the
respiratory tract and differing examples of respiratory co-infection are not
part of the review focus and so will only be referred to if in appropriate
context to influenza-strep co-infection. The review is sequenced to explore
respiratory defense mechanisms relevant to prevention of influenza-strep
co-infection, analysis of the methods in which Influenza and streptococcus
pneumoniae infect and thrive in the host respiratory tract, and the
consequences of influenza-strep co-infection.


Influenza Evasion of specialised
mucosal immune system and damage to immune system

Influenza targets host respiratory tract mucosa(ref) and can
evade respiratory defences. Invasion by an influenza virus is first targeted by
the innate immune system, induced through respiratory mucosa. N-acetylneuraminic
acid(NA)-containing receptors present in mucus secreted from mucous glands act
as decoy receptors for neuraminidase glycoproteins in influenza as seen in
Fig.1. Neuraminidase bypasses this by cleaving Neu5Ac in human salivary
mucus(ref).The mucosal immune system possesses pattern recognition receptors
able to recognise viral RNA in cells resulting in IFN secretion and stimulation
of IFN-stimulated gene expression which can result in a cytokine storm, causing
damage to the host through uncontrolled inflammation(Ref). IFN can be inhibited
by the Influenza NS1 protein which binds to RIG-1 complexes in host cells,
blocking downstream signalling(ref). This reduction in IFN can make the host
more susceptible to other pathogens. Susceptibility to coinfection with
pathogens such as SP is also increased through NS1 blocking of 3?-polyadenylation of IFN, and cytokine
mRNA(ref) which is particularly damaging in the immunocompromised.

The adaptive immune system makes key use of a hemagglutinin (HA)-specific
antibody secreted in the humoral immune which targets a surface HA glycoprotein
in Influenza cells seen in Fig.1 (ref). This drives the antigenic variation of Influenza
which results from amino acid changes on the HA, NA genes(ref). This variation
can be from genetic drift in which mutations reduce the ability for antibody
interaction and genetic shift in which a new HA subtype is gained through
reassortment of multiple Influenza strains.

Streptococcus Evasion
of specialised mucosal immune system and damage to immune system

The primary site of streptococcus pneumoniae colonisation is
the nasopharynx(ref). Streptococcus pneumoniae is characterised by its
polysaccharide capsule which prevents C3 opsonisation(ref).

Streptococcus pneumoniae is the increase in epithelial mucin
gene MUC5AC expression through binding to TLR4 through the virulence factor
Pneumolysin. This results in ERK1 signalling pathway activation as seen in
Fig.1 in host epithelial cells. Potential overproduction of mucus can result in
airway obstruction which could prevent function of the mucociliary escalator
resulting in increased build-up of streptococcus pneumoniae. This increase in
bacterial load over time can result in respiratory damage due to pneumolysin
release form autolysed bacterial cells which can result in movement of
streptococcus pneumoniae into the bloodstream(ref) and conductive hearing loss.



Influenza pathogenicity

Influenza B and C are isolated almost solely from humans, whereas
Influenza A is found in many mammals. Certain subtypes of influenza are capable
of increased damage due to antibiotic resistance which includes H5N1 which
favours binding to the alveoli due to differing sialic acid expression. Epithelial
binding of the influenza virus is facilitated by the cleavage of HA into linked
subunits HA1 and HA2 which bind to sialosaccharides
on host cells. (ref). Upon endocytosis into the cell the vRNP proteins
bind to cellular machinery and utilise nuclear localisation signals to gain
entry to the nucleus(ref). The viral RNA dependant RNA polymerase is
responsible for conversion to a positive sense RNA. The RNA polymerase has no
proof reading mechanism so mutations are common during replication which
increases the difficulty of treatment and host-defence. The PB2 viral protein takes
cellular mRNA 5′ caps which damages host cellular protein synthesis and
inhibits cellular function.

Influenza A is able to cause damage to the epithelial-endothelial
barrier of the pulmonary alveolus. This can occur through NS1 binding in H5N1 to
PDZ domain containing proteins which are required for epithelial tight junction
stability(ref). Disruption of these tight junctions floods the alveolar
lumen  with oedema fluid and inflammatory
cells which can result in acute respiratory distress syndrome where gas
exchange is prevented which can result in organ dysfunction(ref). Influenza A
and B are also able to damage epithelial cells by induction of apoptosis(ref)
through increasing expression Fas antigen in target cells(ref).
Endothelial-influenza interaction results in increased production of adhesion
molecules recruits non-specific leukocytes and cytokine production. Recruitment
of neutrophils can result in oxidative damage to alveolar or epithelial cells
in the respiratory tract through release of reactive oxygen species and
pro-oxidant cytokines such as TNF-a. This can result in membrane phospholipid
peroxidation resulting in disruption of cellular transport and cellular
respiration(ref).  Expression of TRAIL by
recruited macrophages can result in epithelial cell apoptosis by interacting
with epithelial death receptor. Influenza is also able to induce cell apoptosis
through activation of transforming growth factor beta (ref).

Over time
influenza is able to result in alveolar thrombosis due to the endothelial
dysfunction resulting in leukocyte adhesion to alveolar cells. This results in
an increased uptake of vascular lipids which can result in a fibrous cap
forming resulting in the formation of atheroma over time. Continued apoptosis
caused by Influenza can result in reduction in gas exchange through fibrous
thrombosis in the alveoli(ref) which can result in alveolar necrosis. High
levels of damage can result in hyperemia
of the alveolar capillaries which can be seen through a widening of the
alveolar septa.