CASE 1: IMPETIGO

CASE 1: IMPETIGO
What could be the culprit? Based on the signs and symptoms that
Stephanie presents with, particularly the characteristic red sores found around
her mouth and nose as well as her rash and lack of fever (afebrile), she
potentially has a skin disease called impetigo (Figure 1A).[1][2] Certain groups
within a population are especially more likely to develop this disease, including
children who are aged two to six.[6] Stephanie falls into this category as well. The
two bacterial pathogens that are most commonly identified in clinical isolates
from patients afflicted with impetigo are 1) Streptococcus pyogenes (or Group A
Streptococcus) (Figure 1B) and 2) Staphylococcus aureus.(Figure 1C)[3]
A)
B)
C)
Figure 1- Presentation of Impetigo and Causative Agents
A) A child with the characteristic red sores in the perioral region[34]. B)
Streptococcus pyogenes or Group A Streptococcus[35] C) Staphylococcus
aureus[36]
Bacterial Pathogenesis
I. ENCOUNTER
Streptococcus pyogenes: Geographical Distribution and Mechanisms for Survival
S. pyogenes is a prevalent human specific pathogen that exists around
the world.[7] It has been estimated that this bacterium is responsible for more than
600 million cases of throat-related infections and more than 100 million cases of
skin diseases in children in developing countries annually.[8] It can be found in
both temperate and warm/humid climates, but more specifically, manifestations
of disease differ from country to country depending on these conditions.[4][5] It is
more common to find streptococcal pharyngitis in temperate areas and impetigo
in warm and humid areas.[5] Additionally, there are seasonal differences in some
countries, whereby pharyngitis predominates during the wintertime and impetigo
emerges during the summer.[7]
Survival of S. pyogenes outside of the host and in the environment is likely
in part facilitated by the presence of a bacterial capsule (it is a gram positive
bacterium).[9] It was initially believed that this bacterium rapidly dies once it is no
longer in contact with the human host as a result of desiccation and rapid loss of
infectivity.[10] Of note, it has been found that it has the ability to form a biofilm
outside of the host, allowing for the bacterium to remain viable for extended
periods of time, while remaining infectious.[10] This was not the case when the
bacteria were in a planktonic state, where they rapidly loss viability on both biotic
(hands) and abiotic (plastic) surfaces.[10]
Staphylococcus aureus: Geographical Distribution and Mechanisms for Survival
S. aureus is a bacterial pathogen not limited to humans that has a global
distribution.[11] It is one of the most common sources of skin and soft-tissue
infections.[11] To put this in perspective, it is believed that roughly 20% of people
are considered persistent carriers of this bacterium (with children being more
likely to belong to this category) and 60% are considered intermittent carriers.[11]
Although incidence is increasing, methicillin-resistant S. aureus is less prevalent
than methicillin-susceptible S. aureus.[12] The presence of a bacterial capsule
likely enhances survival outside of the host (the bacterium is gram positive).[13]
Streptococcus pyogenes: Normal Host Tissue Residence and Mechanisms for
Survival
S. pyogenes does not normally reside on the skin.[14] The throat and skin
are the primary reservoirs of S. pyogenes.[7] Additionally, S. pyogenes can also
exist in asymptomatic carriers in a quiescent commensal-like state in the throat.[7]
As an example, it can be found in the throat of 15% of school-aged children.[14]
Other locations where these bacteria can be found in a carrier state include the
vagina and the anus.[5]
Staphylococcus aureus: Normal Host Tissue Residence and Mechanisms for
Survival
S. aureus is a commensal of the human body, whereby it is believed that
close to 30% of the human population is colonized with it.[16] As an opportunistic
bacterium, S. aureus may transiently colonize the skin of certain susceptible
populations such as newborns.[14] It typically resides on skin surfaces of the
body, especially openings.[15] Some examples of such locations include the nose,
the mouth, the genitals, and the rectum.[15]
Streptococcus pyogenes: Transmission
S. pyogenes is a microbe that is highly communicable and people can
come in contact with it in many different ways. Bacteria can be spread through
contact with mucus originating from the nose or throat of someone who is
infected on both biotic and abiotic surfaces.[17] Additionally coming in contact with
infected wounds or sores also has a similar effect.[17] Methods in which the skin is
broken allows the bacterium to enter the body and these include animal bites,
insect bites, and trauma to the skin.[6][18] Waterborne and foodborne transmission
has also been reported.[19] Generally, hygiene is a very important issue and
fingernails and the perianal region have been cited as a common way of
dissemination.[19]
Staphylococcus aureus: Transmission
The most common way that S. aureus is transmitted is by coming in
contact with people who have contaminated hands.[20] This bacterium is also a
cause of food poisoning through the secretion of enterotoxins into food and its
subsequent ingestion.[21] Touching infected lesions or a carrier of the bacteria
can facilitate transmission between people.[11] Chances for exposure are
increased in environments or communities that are unsanitary and crowded.[11]
II. ENTRY
Streptococcus pyogenes: Adhesion, Invasion, and Site Specificity
S. pyogenes expresses various virulence factors anchored to the cell wall
in order to facilitate their attachment to human epithelial cells of the pharynx and
skin and subsequent invasion (Figure 2).[22] This includes fimbrial-like proteins,
fimbrial-like proteins that bind to extracellular matrix proteins such as fibronectin,
laminin, and collagen, and M proteins (which are used as a diagnostic for
identifying specific strains).[22][23][24][25] It was also reported that different M
serotypes of S. pyogenes corresponded to the tendency to cause infection in the
throat or the skin and not often simultaneously.[7][26] More specifically, the M
protein has been shown to interact with glycosaminoglycans found on the host
cell surface and extracellular matrix, which promotes adhesion.[32] This bacterium
is a predominantly extracellular pathogen and certain serotypes also encode
protein F1 (PrtF1/Sfbl), which not only aids in adhesion, but also inhibits the
deposition of C3 (a complement component) and prevents phagocytosis.[25]
Despite this, when it does get phagocytosed, many proteins involved in
adherence such as the M protein allows the bacterium to persist and survive
intracellularly.[25]
Figure 2- Virulence Factors of Group A Streptococcus
Schematic representation of some of the virulence factors that GAS uses and for
what purpose in the environment of the pharynx. Figure adapted from (Olsen,
2009)[25].
Staphylococcus aureus: Adhesion, Invasion, and Site Specificity
S. aureus employs various molecules to facilitate its adhesion and
invasion of host epithelial cells (Figure 3).[27] Of note, teichoic acids aid the
binding of nasal epithelial cells and fibronectin.[14] Virulence factors that mediate
the adherence to the extracellular matrix are collectively organized under the
term MSCRAMM (microbial surface components recognizing adhesive matrix
molecules).[14] Within this term, many proteins have been suggested to play
important roles for S. aureus adhesion, but the two most notable ones are
clumping factor B and the above mentioned teichoic acid.[27] It is believed that
this bacterium survives well both intracellulary and extracellularly.[27] Specifically,
upon activation of the immune response, the bacterium upregulates multiple
virulence factors such as clumping factor A on its surface capsule, which
functions to inhibit opsonization and phagocytosis.[27] It has also been shown that
S. aureus infection can occur post-viral infection with influenza, which damages
the mucosal lining of the upper airway, resulting in a predisposition to S. aureus
pneumonia.[27] This damaging likely exposes extracellular matrix components to
which the bacteria can bind.
Figure 3- Virulence Factors of Staphylococcus aureus
Schematic representation of some of the virulence factors employed by S.
aureus and their purpose. Figure adapted from (Todar, n.d.).[30]
III. MULTIPLICATION AND SPREAD
Streptococcus pyogenes: Multiplication and Spread
Starting as a superficial infection of the skin or the throat, S. pyogenes can
spread into deeper tissue.[28] This can result in necrotizing fasciitis.[28] Other
complications/secondary sites of infection include examples such as sepsis,
pneumonia, and meningitis.[28] More specifically, the colonization of the upper
respiratory tract or pharynx, may result in spreading to other locations of the
respiratory tract both upper and lower, which can ultimately cause infections of
the middle ear, sinuses, and lungs.[29] Meningitis can be a result of the spread of
the bacterium from middle ear or sinus infection or by way of the blood stream
after pneumonia.[29] As mentioned above, S. pyogenes generally stays
extracellularly, but in some serotypes, the bacterium has the ability to
successfully persist and survive intracellularly.[25]
Staphylococcus aureus: Multiplication and Spread
Once in the host, S. aureus has to fight the immune response and it
normally does this with a relatively high amount of difficulty.[30] As a result of this,
in humans, infection by this bacterium is generally localized at the site of entry.[30]
One of the main and most serious complications/secondary site of infection to
infection is bacteremia, whereby the bacteria enter the bloodstream and this can
be potentially fatal.[30] As previously mentioned, this S. aureus can successfully
survive both intracellularly and extracellularly once it has properly colonized.[27]
IV. BACTERIAL DAMAGE TO THE HOST
Streptococcus pyogenes: Damage to the Host
Extracellular products and toxins produced by S. pyogenes play a major
role in cytotoxicity and the inflammatory response.[19] These can be broadly
categorized into hemolysins, pyrogenic exotoxins, nucleases, and other
products.[19] The two main hemolysins include Streptolysin S and Streptolysin
O.[19] Streptolysin S is oxygen-stable leukocidin that functions to damage
polymorphonuclear leukocytes and organelles, but is not in itself
immunogenic.[19][29] Streptolysin O is an oxygen-labile leukocidin, which is
cytotoxic to various cell types including the myocardium and is highly
immunogenic.[19][29] Reactivity to the myocardium has implications in the
generation of non-rheumatic myocarditis.[31]
S. pyogenes possess four main progenic exotoxins called streptococcal
pyorgenic exotoxins A, B, C, and F (SPE A, B, C, F).[19] These exotoxins are the
main cause of the rash present in scarlet fever (and potentially impetigo).[19] SPE
A, C, and F also have the ability to be superantigens, resulting in febrile
symptoms, induced T cell proliferation, and induced cytokine production
(including IL-1β, IL-6, and TNF).[19] It has been suggested that this is potentially
due to their ability to bind both the T cell receptor and MHC-II.[19]
S. pyogenes also has four nucleases (A, B, C, and D), which function in
the liquefaction of pus in order to generate substrates for growth.[19] Finally, this
bacterium also has the leukotoxic NADase, hyaluronidase (which can degrade
both its own hyaluronan capsule as well as the host connective tissue),
streptokinase (which acts in fibrinolysis), and Streptodornases A, B, C, and D,
which are deoxyribonucleases.[19][29] Proteases also play a key role in the
generation of soft tissue necrosis and toxic shock syndrome.[29] Of note,
proteolysis of the epidermis and subepidermal layers of the skin is the main
mechanism in which the bacteria employs to spread along skin layers, resulting
in the characteristic blisters and pus-containing lesions in impetigo.[19]
Staphylococcus aureus: Damage to the Host
In general, many toxins secreted by S. aureus are potentially the cause of
symptoms.[13] A variety of mechanisms are behind this, which are mainly as a
result of the release of toxins and this includes the following: disruptions to
cellular membranes, toxin-mediated septic shock, and toxin-mediated toxic
shock.[13] More specifically, the membrane damaging toxins include the α-toxin,
β-toxin, δ-toxin, γ-toxin, and leukocidin.[13] α-toxin forms a pore in target cells
allowing cations to enter.[13] Platelets and monocytes are especially susceptible
to α-toxin as a result of possessing high affinity sites.[13] This specific targeting
then results in the release of eicosanoids and cytokines and ultimately he
generation of the symptoms associated with septic shock.[13]
γ-toxin and Pantan and Valentine (PV) leukocidin act as a two-component
toxin system, which damages host cell membranes.[13] Three subunits come from
the γ-toxin, namely A, B, and C, with B and C forming a leukotoxin that is weakly
hemolytic, and A and B forming a hemolysin that is weakly leukotoxic.[13] On the
other hand, the PV leukocidin is potently leukotoxic, but non-hemolytic.[13] PV
leukocidin plays a major role in necrotizing fasciitis.[13]
S. aureus also produces a variety of superantigens including enterotoxins
(of which there are six serotypes, A, B, C, D, E, and G) and toxic shock
syndrome toxin (TSST-1).[13] The enterotoxins are one of the main causes of
staphylococcal food poisoning and the resulting diarrhea and vomiting.[13] When
systemically expressed, toxic shock syndrome can result.[13] TSST-1 is the
primary cause of toxic shock syndrome (at 75% of cases) and this is the result of
the lack of specific host neutralizing antibodies.[13] These superantigens may
stimulate T cells non-specifically by binding to both the T cell receptor and
MHCII, resulting in massive cytokine release and the subsequent symptoms of
toxic shock syndrome.[13]
This bacterium can also produce epidermolytic (exfoliative) toxin (ET),
which results in blistering and the loss of epithelium.[13] Two distinct forms of the
toxin exist, namely ETA and ETB.[13] Bullous impetigo is mainly caused by these
two toxins.[33] They cause the loss of adhesion between the cells of the
superficial dermis, resulting in blisters and skin being sloughed off.[33]
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