Immune System Evasion Mechanisms in Staphylococcus

Malak et al.
| J Pure Appl Microbiol | 14(4):2219-2234 | December 2020

Article 6792 | https://doi.org/10.22207/JPAM.14.4.01
Print ISSN: 0973-7510; E-ISSN: 2581-690X
REVIEW Article OPEN ACCESS
Immune System Evasion Mechanisms in

Staphylococcus aureus: Current Understanding
Hesham A. Malak1,2, Hussein H. Abulreesh1,2*, Sameer R. Organji1,2,

Khaled Elbanna1,2,3, Mohammed R. Shaaban1.2,4, Samreen5, Iqbal Ahmad5,
Ashwag Shami6, Wafa A. Alshehri7, Ashjan Khalel8, Hiyam H. Abureesh9,
Fatimah H. Asiri9, Mohammad S. Aldosari9 and Meshal H.K. Almalki1,2
1
Department of Biology, Faculty of Applied Science, Umm Al-Qura University, Makkah, Saudi Arabia.
2
Research Laboratories Unit, Faculty of Applied Science, Umm Al-Qura Univeristy, Makkah, Saudi Arabia.
3
Department of Agricultural Microbiology, Faculty of Agriculture, Fayoum University, Fayoum, Egypt.
4
Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt.
5
Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh
- 202 002, India.
6
Biology Department, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
7
Department of Biology, College of Science, University of Jeddah, Jeddah, Saudi Arabia.
8
Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
9
King Abdulaziz Hospital, Makkah, Saudi Arabia.
Abstract
Staphylococcus aureus is a major human pathogen that may cause a wide range of infections and is a
frequent cause of soft tissue and bloodstream infections. It is a successful pathogen due to its collective
virulence factors and its ability to evade the host immune systems. The review aims to highlight how
S. aureus destroys and damage the host cells and explains how immune cells can respond to this
pathogen. This review may also provide new insights that may be useful for developing new strategy
for combating MRSA and its emerging clones such as community-associated methicillin-resistant S.
aureus (CA-MRSA).
Keywords: Staphylococcus aureus, pathogenesis, immune system, virulence, immune evasion
*Correspondence: hhabulreesh@uqu.edu.sa
(Received: November 30, 2020; accepted: December 15, 2020)
Citation: Malak HA, Abulreesh HH, Organji SR, et al. Immune System Evasion Mechanisms in Staphylococcus Aureus: Current
Understanding. J Pure Appl Microbiol. 2020;14(4): 2219-2234. doi: 10.22207/JPAM.14.4.01
© The Author(s) 2020. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License which
permits unrestricted use, sharing, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons license, and indicate if changes were made.
Journal of Pure and Applied Microbiology 2219 www.microbiologyjournal.org

Malak et al. | J Pure Appl Microbiol | 14(4): 2219-2234 | December 2020 | https://doi.org/10.22207/JPAM.14.4.01
Introduction these infections complicated and more challenging

Initially described in 1878, staphylococci, to achieve7. This review aims to provide and
Gram-positive cocci that have been implicated in updated literature survey on epidemiology,
infections involving multiple systems of the human virulence and pathogenicity as well as interaction
body, including the skin and soft tissue, the skeletal mechanisms with host immune system by S.
system, the respiratory system, the bloodstream, aureus.
and more recently, infections involving implanted Staphylococcus aureus Epidemiology
medical devices 1,2. Staphylococci are further S. aureus infections may not be all
classified as being coagulase-positive, primarily reported, given the wide variety of community
identifying Staphylococcus aureus (S. aureus), and hospital-acquired of infection, however, the
or coagulase-negative (CoNS)3. Staphylococcus number of reported cases is increasing worldwide,
epidermidis (S. epidermidis) is the most important for instance, in the USA around 80461 cases of
and best-studied member of the CoNS group4. MRSA infections in 2011, resulting in a 11000
S. aureus is facultative, non-spore- deaths6. Reported MRSA infections in Australia
forming, and non-motile bacteria that have the increased from 10.3% in 2000 to 16% in six years8.
ability to grow well on most cultural media. S. In Taiwan, dramatic increase of MRSA infection rose
aureus is a common inhabitant of the human from 9.8% in 2000 to 56% in 2005, similar increases
and animal body, particularly the nasal cavity of S. aureus infections were also reported in Saudi
and the skin4. Despite being a commensal in Arabia, Lebanon, England, India6,8,9. It is important
human and animals, S. aureus is a virulent to mention that these figures represent over all
bacterium that are able to produce number of infections, the epidemiological data of every type
toxins and enzymes which allow this bacterium of Tong et al.5 has well documented S. aureus
to be able to invade human body and cause infections concluding that there is an increase
wide range of infections, some of which may be of hospital-acquired infections particularly in
considered as life-threatening diseases (Table 1) the cases of infective endocarditis and infections
in immunocompromised and immunocompetent related to prosthetic devices, moreover, an
individuals5, 6. Moreover, some strains of S. aureus epidemic of community-associated skin and soft
are resistant to a wide range of antibacterial tissue infections controlled by certain virulence
agents, some of which show multiple resistance factors and resistance to antibiotics particularly
(resistant to three or more classes of antibacterial β-lactam group5. Molecular epidemiology of S.
agent), The most clinically important strains are aureus infections showed diversity of clones
the methicillin-resistant Staphylococcus aureus responsible for infections in every content, with
(MRSA) which are implicated in a large number the existence of predominant clones such as ST-80
of hospital and community acquired infections. which was found in North and South America and
The resistance towards antibacterial agents and at Europe. In Asia, high heterogenecity in terms of the
times multiple resistance make the treatment of clones associated with infection was highlighted.
Table 1. Human infections caused by Staphylocccus aureus
Infection site Clinical syndrome
Skin and soft tissues Boils, abscesses, impetigo, wound infection, scalded skin syndrome, necrotizing
fasciitis, cellulitis
Bone Osteyomyelitis
Joints Septic arthritis
Blood Bacteremia, Toxic shock syndrome, septic thrombophlebitis
Lung Pneumonia
Brain Brain abscess, meningitis
Heart Endocarditis
Urinary tract Urinary tract infection
Intestine Food poisoning
In general, it was suggested that low restrictions the peptidoglycan pentaglycine bridges of the
in the sales of antibiotics and/or prescribing bacteria. It is also known as an IgG-binding protein
antibiotics with proper laboratory analysis in some which combines with the Fragment crystallisable
countries aided the increase of S. aureus infections (Fc) region of the antibody in order to cover the
as well the diversity of clones responsible for these surface of the bacterium with IgG antibody to
infections8. make the recognition of this organism by the
Staphylococcus aureus virulence factors immune cells difficult and hard to detect11,12.
S. aureus infections occur when the The clumping factor A (ClfA) is another
mucosal or skin barriers are breached, following S. aureus virulence factor that is expressed by
the successful invasion of the bacterium into the surface of the bacteria cells. Also, it is known
the host tissues and its ability to escape the as fibrinogen binding protein that promotes the
defensive barriers of the immune system to enter clotting process of blood cells and the damage
the bloodstream. S. aureus have an arsenal of process of tissues13. In addition, the polysaccharide
virulence factors that play significant roles in the capsule is considered as one of the most essential
wide variety of infections and diseases in humans virulence factor which can contribute to assist
including animals. These factors can also support the S. aureus surviving within the host cells by
and provide protection for S. aureus to evade the inhibiting the phagocytosis process by macrophage
host immune system recognition and their actions. and dendritic cells10, moreover, S. aureus cells are
One of the most important virulence factors is capable of secreting several important toxins and
surface proteins which promote and encourage enzymes such as; coagulase; DNAase; leukocidin;
the binding and the attachment processes of hemolysins; exfoliative toxin in order to promote
this bacterium to the host cells surfaces. To bacterial penetration and help the bacterium to
avoid recognition from the host immune cells, evade in to the host tissues (Table 2)10.
the surface proteins combined with the blood Moreover, S. aurues can generate
proteins that lead to aid the bacterium to survive another harmful type of toxins such as Panton-
and cause damage to host tissues10. Another vital Valentine leukocidin (PVL) which cause pneumonia
factor is protein A, which is located in the cell in children and Toxic Shock Syndrome Toxin-1
wall of S. aureus which accurately anchored to (TSST-1) which is associated with some cases of
Table 2. Staphylococcus aureus virulence factors
Factor Effect / function
Cell surface proteins Helping attachment to host tissues

Polysaccharide microcapsule Resist phagocytosis
Protein A Limits the host immune response
Panton-Valentine leukocidin (PVL) Forming porins in cell membrane of host cells,
resulting in cell death by leakage ot its contents
Alpha hemolysin Red blood cells lysis
Chemotaxis inhibitory proteins Inhibit the chemotaxis of neutrophil and monocytes
Extracelleular adherence protein Play a role in adherence and invasion of host tissues
and also has immune-modularity activity
Proteases, lipases, nucleases, These enzymes contribute to host tissue destruction that facilitate
hyaluronatelyase, phspholipase C, the invation and penetration of the bacterium into host tissues
elastase and Staphylokinase
Toxic shock syndrome toxin-1 (TSST-1) Causes toxic shock syndrome particularly in menstrual women
Exfoliative toxin Causes scalded skin syndrome particularly affecting infants
Enterotoxins Several types pf enetrotoxins (SEA, SEB, SEC, SED, SEG, SEH & SEI)
causes food poisoning
Clumping factor Clots blood plasma
Adapted from10, 11, 12, 13

septicaemia due to the use of particular types proteins and proteolytic molecules that are found
of tampons (Table 2)13,10. A number of S. aureus and circulate in the blood (Table 3). With S. aureus,
strains have the ability to produce a pigment complement employs some significant molecules
that known as staphyloxanthin which acts as an to: (1) mark the microbe with C3b and iC3b to make
important virulence factor. This strain has an its parts ready for phagocytosis through important
antioxidant role against reactive oxygen species immune cells such as; neutrophil and macrophage,
used by the host immune cells, in order to help and also to (2) seize the attention of phagocytes by
the bacterium to escape from killing action small chemoattractant molecules such as: C3a and
of immune cells14. Furthermore, S. aureus are C5a which are produced during the activation of
capable of forming biofilms of various surfaces complement to facilitate phagocytosis as well15,17.
which associated generally with most indwelling This system is initiated and activated by
medical devices problems such as heart valves and three significant pathways: (a) the classical, (b) the
knee replacements and via this biofilm community alternative and (c) and the lectin pathways (Fig.
resistance can be acquired to antibacterial agents 1). All the three pathways come together at the
through horizontal gene transfer12. formation of a surface bound biomolecular enzyme
How Does S. aureus subvert immune responses? known as C3 convertases. This enzyme stimulates
When S. aureus invade the host tissues, and enhances the activation of complement
the innate immune system responds rapidly as system by cleaving the complement protein C3 to
an early defense against the bacterial invasion. form C3a and C3b which are required to promote
This system consists of three important parts; and facilitate any additional essential activation
(i) the complement system, (ii) phagocytes and events such as; opsonization and phagocytosis15-17.
(iii) antimicrobial peptides. It also play many S. aureus Complement avoidance mechanisms
significant roles against the pathogen for instance; It has been shown that S. aureus
it summons the immune cells to the infection sites developed different mechanisms to avoid the
by producing chemical signaling molecules called action of the complement system by producing
cytokines, activates the complement system to a number of proteins that can change and affect
recognize the microbe to encourage the clearance the stages of the complement cascade, these
process of dead cells, and it activates the second mechanisms include; preventing complement
line of the host defense which is known as the identification; cleavage of complement proteins;
adaptive (specific) immune system through and/or inhibit the interaction of complement
antigen presentation process, in order to help the receptors on phagocytes18,19.
body to eliminate the microbe and to generate Although, the classical pathway C1
long lasting immunity against it to prevent any complex has the ability to recognize the microbe
challenge in the future by the same organism15,16. bound IgG and IgM antibodies and the lectin
The Complement System pathway (mannose-binding lectins and ficolins)
The complement system is a group of bind the saccharide elements of microbe, S.
Table 3. Functional protein classes in the complement system
Types of protein classes Examples
Binding to antigen: antibody complexes C1q

and pathogen surfaces
Binding to mannose on bacteria MBL
Activating enzymes C1r, C1s, C2b, Bb, D, MASP-1 and MASP-2
Membrane-binding proteins and opsonins C4b and C3b
Peptide mediators of inflammation C5a, C3a and C4a
Membrane-attack proteins C5b, C6, C7, C8 and C9
Complement receptors CR1, CR2, CR3, CR4 and C1qR
Complement-regulatory proteins C1INH, C4bp, CR1 and MCP
Adapted from25
aureus produce two surface proteins that can located on the surface of the bacterium that
damage and harm the IgG function (Fig 2.a), consists of four or five immunoglobulin binding
the first protein is the Staphylococcal protein A domains. Every domain is able to combine with
(SpA) and the second protein is known as the the Fc parts of IgG antibody, thus inhibiting the
Staphylococcal immunoglobulin binding protein interaction with Fc receptors on neutrophils in
(Sbi). Staphyloccocal protein (SpA) is a protein vitro17-19.
Fig. 1. Complement activation pathway: (A) The classical pathway is initiated by the binding of the C1 complex to
antibodies that are bound to antigens on the surface of bacteria. The C1 complex consists of C1q and tow molecules
each of C1r and C1s. The binding of the recognition subcomponent C1q to the Fc portion of immunoglobulins results
in autoactivation of the serine protease C1r. Then C1r cleaves and activate C1s. which translates the activation of
the C1 complex into complement activation through the cleavage of C4 and C2 to form C4bC2a enzyme complex.
C4bC2a acts as a C3 convertase and cleave C3 which results in products that bind to, and cause the destruction
of, invading bacteria.
(B) The lectin pathway is initiated by the binding of either mannose binding lectin (MBL) or ficolin -associated with
MBL-associated serine protease1 (MASP2), MASP2, MASP3 and small MBL-associated protein (sMAP) – to an array
of carbohydrate groups on the surface of a bacteria cell. Similar to C1s, MASP2 is responsible for the activation
of C4 and C2, which leads to the generation of the same C3 convertase (C4bC2a). As in the classical pathway, C3
convertase cleaves C3 to C3b and the chemo attractant peptide C3a. The C3b-C2a-C4b complex then cleaves C5
to C5a and the chemo attractant peptide C5b, which stimulates assembly of factors C6, C7, C8 and C9. MASP1 is
able to cleave C3 directly.
(C) The alternative pathway is initiated by the low grade activation of the C3 by hydrolysed C3 (C3(H2O)) and
activated factor B (Bb). The activated C3b binds factor B (B), which is then cleaved into Bb by factor D (D) to form the
alternative pathway C3 convertase, C3bBb. Once C3b is attached to the cell surface, the amplification loop consisting
of the alternative pathway components is activated, and the C3 convertase enzyme cleaves many molecules of C3
to C3b, which bind covalently around the site of complement activation [15, 17,48, 49].

Staphylococcal Sbi is made of four parts is an anti-opsonic protein, in order to stimulate

of Sbi-I and Sbi-II which are also able to bind and encourage surface bound plasminogen
with IgG. Besides blocking Fc-receptor-mediated into plasmin, which make the bacteria able to
phagocytosis, Sbi has been shown to play some invade and infect the host tissues17. In fact, the
roles in blocking the binding of C1q and subsequent presence of the C3 convertases is significant for
activation of the complement classical pathway18. the activation of complement system and for the
Furthermore, S. aureus uses another approach to response of host immune cells. S. aureus uses
evade the recognition of the complement system three ways to affect and change this vital step in
by removing and degrading the opsonic molecules the complement cascade (Fig. 2.b)17,18.
(the molecules that are able to bind with both The Cleavage of C3 convertase
antigen and receptors of phagocytic cells like The S. aureus clumping factor A (ClfA) is
C3b component of complement system) from it a surface protein which can join the human C3b
surface through proteolytic process. In addition, protease factor I (fI), thereby enhancing cleavage
S. aureus produce a staphylokinase (SAK) which of surface-bound C3b into iC3b in vitro20.
Fig. 2. Staphylococcus evasion of complement recpgnition: (A)- S. aureus produce two surface proteins that can
damage and harm IgG function; Staphylococcal protein A (SpA) and Staphylococcal immunoglobulin binding protein
(Sbi). (B)- Presence of the C3 convertases is significant for the activation of complement system and for the response
of host immune cells. S. aureus use three ways to affect and change this vital step in the complement cascade [17, 18, 19].

Direct inactivation of C3 convertases S. aureus produces five unlike molecules which

Convertases are the major complement work directly to prevent the action of these
target among S.aureus immune evasion strategies. important enzyme mixtures. Staphylococcal
complement inhibitor (SCIN) and its homologues
Fig. 3. Phagocyte extravasation: (a) for phagocytes to reach infection sites, they need to extravasate from the blood
vessels into the tissue. The successful recruitment of circulating immune cells depends on the productive interaction
of leukocytes with the endothelial cells lining the vessel wall and it is a multistep process. Phagocytes tether and
roll on activated endothelium through transient interactions of PSGL-1 and selectins. Following stimulation of
the cells by endothelium bound chemokines, integrins are activated that mediate the firm cellular adhesion to
intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) presented by the vessel
wall. The phagocytes then transmigrate through the endothelium into the underlying tissue .The cells are directed
to the site of infection through the sensing of chemoattractant gradients by GPCRs. Here, chemokines and bacteria
and complement derived products are important. The pathogen is cleared by phagocytosis upon recognition of the
bacterium opsonized by antibodies and/or complement components. (b) At the infection site, infected cells and the
surrounding tissues release chemoattractants. These secreted chemoattractants form a concentration gradient and
attract leukocytes, which move through the gradient towards the higher concentrations, a process called chemotaxis.
Leukocytes move through the gradient toward the higher concentrations, a process called chemotaxis [25, 26, 17].
SCIN-B and SCIN-C are extremely efficient C3 Phagocytosis

convertase inhibitors which inhibit the alteration Phagocytosis is a common mechanism
of C3, later phagocytosis and C5a formation in vitro that involved in the immune response to eliminate
at low concentrations18. pathogens or foreign particle may be a toxin
Besides that, the alternative pathway C3 invading the body. It is activated through the
convertase made of a vital cofactor called C3b which binding to pathogen-associated molecular patterns
connected to the protease subunit (Bb) loosely18. (PAMPS), which leads to the activation of nuclear
The action of SCIN on the classical pathway factor kappa B (NF-κB) that is important to control
convertase remains to be resolved but seems to and regulate the response of the immune system25.
be caused by a stabilizing mechanism as well21. In Furthermore, there are types of the immune cells
addition, the alternative pathway convertase can that have the ability to engulf microbial pathogens
be changed via the extracellular fibrinogen-binding in order to remove them from the host, these cells
protein (Efb) and the extracellular complement- include; neutrophils, macrophages and dendritic
binding protein (Ecb) by binding the convertase to cells26. Moreover, complement system plays an
the C3b particle directly20. The crystal structures of important role in phagocytosis by facilitating the
both molecules in complex with the C3d domain uptake of the pathogen by phagocyte cells. This
of C3 have revealed their exact binding sites21. process occurs through specific complement
Modulating human convertase regulators receptors (CRs) such as; CR1 and CR2 (Table 4),
In order to protect from unnecessary these receptors bind the microbe to make it ready
action of the complement system, humans for phagocytosis25,26.
produce complement regulators which reduce and In addition, at the early stage of the
decrease the activity of the convertase22. On the immune response to the site of infection, the
other hand, a large number of microbes generate pathogen and its fragments are engulfed by
molecules which interfere with the function of antigen-presenting cells and other immune
theses regulators. In addition to its two IgG binding cells such as macrophages and neutrophils and
fragments, Sbi-III and IV that can also bind to the transferred to the lymph nodes. This leads to
C3, the staphylococcal IgG-binding molecule Sbi the activation of the B cells to discriminate and
plays several important roles in the alteration of to produce antibodies in order to reduce the
the complement23. Moreover, Sbi has the ability effects of the bacterial toxins and to encourage
to bind the human complement regulators such and promote the phagocytosis of the pathogen26.
as; factor H (FH) and factor H-related proteins in Furthermore, following the entry of S. aureus
order to make a constant tripartite compound with to the host tissue, the response of neutrophils
FH and C3. In general, these actions lead to inhibit and macrophages initiate which is critical and
the activity of the alternative pathway in vitro24. essential to promote and assist the body in
Table 4. Types and functions of complement receptors
Receptor Specificity Function Target cells
CR1 (CD35) C3b, C4b, Promotes C3b and C4b decay Erythrocyte, macrophage, monocytes,
iC3b Stimulates phagocytosis Erythrocyte leukocytes, B cells
transport of immune complexes
CR2 (CD21) iC3b Part of B-cell co-receptor B cells
CR3 (Mac-1) iC3b Stimulates phagocytosis Macrophages, monocytes,
(CD11b/CD18) leukocytes
CR4 (gp150,95) iC3b Stimulates phagocytosis Macrophages, monocytes,
(CD11c/CD18) leukocytes, dendritic cells
C5a receptor C5a Binding of C5a activates G Endothelial cells, mast cells,
protein phagocytes
C3a receptor C3a Binding of C3a activates G protein Endothelial cells, mast cells, phagocytes
Adapted from 25
removing and eliminating the pathogens during formed through activated host cells and some
the phagocytosis21. (Fig. 3.a). of them produced as an activated component
These cells are called via an important of the complement system (C5a) at the time of
chemoattractants such as C5a; leukotriene B4; and identification of a preserved structure present
chemokines such as CXCL8 which also known as on the bacterium28. All these chemoattractants
interleukin-8 (IL-8) in order to direct their actions trigger phagocytes by attaching to membrane
to the site of infection27. This chemoattractants bound receptors called G protein-coupled
Fig. 4. Inhibition of the neutrophil response to infection: (a) the chemotaxis inhibitory protein of staphylococci
(CHIPS) and the extracellular adherence protein (Eap) interfere with neutrophil chemotaxis and extravasation.
Resistance to killing by antimicrobial peptides in the neutrophil phagosome is promoted by D-alanine and L-lysine
modifications to cell-wall components (indicated by +), by secretion of staphylokinase (Sak) and aureolysin (Aur),
and by the creation of ‘spacious’ phagosomes in which bacteria can survive. The pore-forming leukotoxins are shown
by the mushroom-shaped insertion in the neutrophil membrane. (b) Model for interactions between CHIPS and
the formyl peptide receptor (FPR) and C5a receptor. Two distinct but closely linked binding domains in CHIPS are
indicated, one for the extreme N terminus of FPR involving residues F1 and F3, the second for a domain located
between residues10–20 of the C5a receptor. FMP, N formyl-methionyl peptide; ICAM-1, intercellular adhesion
molecule-1; LFA-1, lymphocyte function associated antigen [19, 30, 48].
receptors (GPCRs). Both chemoattractants and Resistance to phagocytosis

GPCRs have an essential role which is directing S. aureus produces many significant
the innate defence cells against the invading factors to avoid and evade from phagocytosis.
microbe (Fig. 3.b). As a result S. aureus has a wide It expresses anti-opsonic proteins bound to the
range of strategies to evade and avoid phagocytic surface and a capsule of polysaccharides which: (a)
activity28,29. interfere with antibodies and with the formation
S. aureus phagocytosis avoidance mechanisms of complement through classical and alternative
Inhibition of neutrophil chemotaxis pathways, (b) inhibit their interaction to neutrophil
A large number of S. aureus strains (about complement receptor and Fc receptor. Therefore,
60%) secrete a chemotaxis inhibitory protein efficient phagocytosis by neutrophils that requires
(CHIPS) which can combine with the C5a receptor recognition of bound complement proteins and
(C5aR) and the formyl-peptide receptor (FPR) in antibody is compromised25. Moreover, S. aureus
order to block the binding of any related agonist has some mechanisms which help and assist the
(Fig. 4), the C5aR- and FPR-binding activities of organism to evade the killing of phagocytic cells,
CHIPS were separated by specific amino-acid including interference with endosome fusion and
substitutions and the specificity of blocking release of antimicrobial substances by factors that
monoclonal antibodies 19,30. The intercellular are dependent on the global regulator SarA31.
adhesion molecule-1 (ICAM-1) on the endothelial Protein A
cell surface is one of the several ligands recognized Is a surface protein that consists of four
by the extracellular adherence protein Eap (or else or five domains which can bind to the Fc region of
called the main histocompatibility class II analogue IgG antibody. Protein A interact with IgG in order
protein Map)30. to cover the cell surface with IgG molecules which
Fig. 5. Mechanisms by which Staphylococcus aureus avoids opsonophagocytosis: (a) the capsular polysaccharide,
which can compromise neutrophil access to bound complement and antibody; (b) the extracellular staphylokinase
(Sak), which activates cell-bound plasminogen and cleaves IgG and C3b; (c) protein A with 5 IgG Fc-binding domains;
(d) fibrinogen-binding protein (Efb), which binds complement factor C3 and blocks its deposition on the bacterial
cell surface. Complement activation beyond C3b attachment is prevented, thereby inhibiting opsonization. (e) ClfA,
which binds the γ chain of fibrinogen [19, 21, 30, 33, 34].
are in the incorrect orientation easy to recognize human neutrophils and that defense is at least
by the Fc receptor of neutrophil (Fig. 5).This action partly dependent on fibrinogen21,34. Furthermore,
can clarify the anti phagocytic role of protein A and ClfB and fibronectin-binding proteins can also bind
its effects on S. aureus infections32,33. fibrinogen, to shield the bacterium through the
Clumping factor A (ClfA) exponential phase of growth, when the expression
Is the dominant fibrinogen-binding of such proteins is larger than ClfA34.
protein present on the surface of S. aureus cells Capsule
in the stationary phase of growth. In the murine Is an important factor which expresses by
model the ClfA is a virulence factor for sepsis and S. aureus to inhibit the process of phagocytosis.
arthritis34. Virulence was thought to increase during The expression of type 5 and type 8 capsules
the bacteremic stage of the infection as well as is associated with increase virulence in animal
during the growth of infected joints, since bacterial infection models35. It has been considered that
cells were coated with fibrinogen (Fig. 5), which the presence of the capsule lead to reduce the
in turn inhibited deposition of, or accessibility ability of neutrophils to uptake the pathogen cells
to opsonins30,34. This notion is supported by the in the presence of normal serum opsonins (Fig. 5),
observation that ClfA protects S. aureus from meaning that capsule act as anti-opsonic19.
phagocytosis by murine macrophages46 and by
Fig. 6. Mechanisms of immunosuppression mediated by Staphylococcus aureus: This figure illustrates examples of
immunomodulatory molecules used by S. aureus to alter the host immune response, including the superantigens
(sAgs) enterotoxins and toxic shock syndrome toxin-1 that bind the MHC class II receptor to T-cell receptors; protein
A, which binds immunoglobulin M (IgM) VH3 on B cells; and the MHC class II analogue protein Map, which binds
the T-cell receptor (TCR) [36, 38, 39, 41].
Toxins that kill leukocytes the α-toxin, which is secreted as a monomer paired
S. aureus is a common pathogen that with a heptamer in the membrane, with β-strands
has the ability to secrete and produce toxins assembled in a 14-stranded β-barrel pore from
which contribute to the damage of host cells each monomer36,37.
membranes. The expression of cytolytic toxins that The two-component leukotoxins consist
damage leukocytes contributes to development of two subunits, which are separately secreted
of abscesses by the killing of neutrophils that and configured into hexameric or heptameric
are attempting to engulf and kill the bacteria36. oligomers with a great leukocyte affinity. There
Cytolytic toxins forming β-barrel pores in target are 4 different types of bicomponent leukotoxin,
cell cytoplasmic membranes cause leakage, and y-toxin (Hlg), Panton–Valentine leukocidin (PVL),
eventually lysis. The representative of this class is leukocidin E / D, and leukocidin close to M / F-PV.
Fig. 7. Role of SERAM in endovascular Staphylococcus aureus infection: During wound infection, S. aureus organisms
secreting and/or decorated by secretable extended repertoire adhesion molecules SERAM) (black triangles) gain
access not only to the intact vessel wall, but also to subendothelial matrix and activated platelets and will form a
bacteria-entrapped platelet clot (A). SERAM bind to various extracellular matrix components including fibrin (ogen)
(Fg), fibronectin (Fn) or thrombospondin (Tsp) that are present in this vegetation and thereby augment bacterial
attachment through molecular bridging mechanisms (Α). In addition, SERAM may facilitate bacterial binding to
Fn expressed on endothelial cells resulting in enhanced uptake of microorganisms (Β). Through interaction with
complement factor C3, the extracellular fibrinogen binding molecule (Efb) may interfere with opsono-phagocytosis
(C). Among other interactions with host factors, the extracellular adhesion protein (Eap) binds to ICAM-1 and
other ligands on endothelial cells thereby inhibiting leukocyte adhesion and preventing their extravasation (D).
After passaging through the endothelial cell layer and/ or the extracellular matrix stroma, S. aureus may gain
access to other capillaries, arterioles and venules, attach to the vessel wall and start disseminating from focal sites
of infection (E) Eap may inhibit vascular cell proliferation and angiogenesis possibly via direct interference with
agonist-stimulated endothelial functions (F), while Efb interacting both, with platelets and with fibrinogen, may
interfere with fibrin formation resulting in altered wound healing (G). Finally, Eap interferes with T-cells function
shifting towards a Th2-cell response and reducing delayed- type hypersensitivity reactions [42, 43].
The γ-toxin lyses both erythrocytes and leukocytes, ability to bind the host components or block some
whereas PVL is toxic only for leukocytes36,38. steps in wound healing process. Eap also known as
Other evasion mechanism of S. aureus a MHC class II analogous protein. It has a very wide
Immunomodulatory molecules spectrum of binding interactions to components of
Protein A the host. However, some strains of S. aureus loss
In addition to its immunoglobulin the ability to express Eap therefore these strains
binding ability, Protein A is an important cannot colonize or invade host tissues44,45. This
immunomodulatory molecule owing to its capacity protein can also combine with endothelial ICAM-
to combine with the VH3 region that is next to the 1 in order to inhibit the intraction between the
antigen-binding domain of IgM molecules located ICAM-1 and its integrins Mac-1 and LFA-1. Thus,
on the B lymphocyte surface (Fig. 6). Those cells Eap completely destroyed the adhesion systems
carrying VH3 IgM are induced to proliferate and of respective functional leukocyte, i.e. strong
undergo apoptosis, resulting in depletion of a large adhesion and endothelial transmigration42. In
proportion of potential antibody-secreting B cells addition to Eap anti-adhesive and anti-migratory
in the spleen and bone marrow39,40. function, it has been considered that Eap has an
Enterotoxins and TSST-1 anti-inflammatory role by inhibiting neutrophils
S. aureus produces toxins which work as and T cells to get to the site of infections to prevent
superantigens such as toxic shock syndrome toxin- their effects against the bacterium. It also has been
1(TSST-1), the expression of these antigens in the described that Eap has an immunomodulatory
host cell prevents the development of the immune activity by increasing the synthesis of interleukin
response such as activation of B and T cells or (IL)-4 syntheses which is vital for the differentiation
formation of antibodies (Fig. 6)36,38. Furthermore, of T-cells into Th2-cells in the response of the
Antigen-specific T cells are unable to reproduce in immune cells in order to down regulate and reduce
response to antigens that are normally presented the response of T-cells to facilitate the intracellular
by MHC class II due to a phenomenon called survival of S. aureus46-49.
anergy 41 . Therefore, immune- suppression
occurred due to the failure of the antibody Conclusion
response. This seems to be important to prevent It seems clear that S. aureus is a
the production of antibodies to superantigenic widespread organism that lives as a normal flora
toxins themselves36,38,41. in the nose and on the skin of humans and animals.
Secretable expanded repertoire adhesive It is a very successful pathogen because of its
molecules (SERAM) ability to express and produce virulence factors
S. aureus generates some bacterial to evade the recognition and the killing of the
proteins that anchored in the cell wall which host immune cells. The bacterium infection starts
has a significant role in mediating bacterial through its entry to the host tissue which leads to
adherence to host cells and to the components stimulate and induce the innate immune response.
of the extracellular matrix (ECM). The general The activation of this system occurred via specific
roles of SERAM (Fig. 7) can be described as: (1) pathways which lead to activate other important
to facilitate bacterial adhesion to host molecules, cells such as neutrophils and macrophages in
cells, or tissues, (2) to interact with a broad array order to eliminate and remove the pathogen from
of host ligands, thereby sharing diverse activities the host. The function of these cells initiated by
in that they typically interfere with host defense the complement system which plays a significant
mechanisms42,43. role by producing chemoattarctant (chemotactic
Other proteins involved in immune-evasions fators, chemokines, and complement factors etc.)
mechanisms in order to label and opsonise the pathogen for
Furthermore, some studies has shown phagocytosis.
new functions of some bacterial proteins such However, it has been shown that S.
as extracellular matrix binding protein (Emp) and aureus improved many ways to avoid the effects of
extracellular adherence protein (Eap) which play phagocyte cells by producing some proteins such
significant roles in S. aureus pathogenesis due to its as SpA and Sbi to inhibit and block the recognition
of complement and their receptors interaction on aureus and Staphylococcus epidermidis infections on
phagocytes. Also, S.aureus can inhibit neutrophil implants. J Hospital Infect. 2018;98(2):111-117. doi:
10.1016/j.jhin.2017.11.008
chemotaxis by producing CHIPS that can interfere 5. Tong SYC, Davis JS, Eichenberger E, Holland TL, Fowler
with some important receptors such as C5a VG. Staphylococcus aureus infections: epidemiology,
receptor protein to prevent the binding of any pathophysiology, clinical manifestations and
related agonist. This pathogen can also produce management. Clin Microbiol Rev. 2015;28(3):603-661.
doi: 10.1128/CMR.00134-14
super antigens toxins to make the response of 6. Li Z. A review of Staphylococcus aureus and the
the immune system difficult to achieve and hard emergence of drug-resistant problem. Adv Microb
to occur. Furthermore, it has been described Physiol. 2018;8:65-76. doi: 10.4236/aim.2018.81006
that S. aureus can kill the leukocytes directly by 7. Abulreesh HH, Organji SR, Osman GE, et al. Prevalence
of antibiotic resistance and virulence factors encoding
secreting important cytolytic toxins such as PVL genes in clinical Staphylococcus aureus isolates in Saudi
and leukocidin E/D. Moreover, SERAM, Eap and Arabia. Clin Epidemiol Glob Health. 2017;5(4):196-202.
Emp are ubiquitous proteins that can help and doi: 10.1016/j.cegh.2016.08.004
assist the bacteria to survive and cause infections. 8. Junie LM, Jeican II, Matros L, Pandrea SL. Molecular
epidemiology of the community-associated methicillin-
resistant Staphylococcus aureus clones: a synthetic
Acknowledgments review. Clujul Med. 2018;91(1):7-11. doi: 10.15386/
None. cjmed-807
9. Moghnieh R, Alothman AF, Althaqafi AO, et al.
Epidemiology and outcome of invasive fungal
Conflict of interest infections and methicillin-resistant Staphylococcus
The authors declare that there is no aureus (MRSA) pneumonia and complicated skin and
conflict of interest. soft tissue infections (cSSTI) in Lebanon and Saudi
Arabia. J Infect Public Health. 2017;10(6):849-854. doi:
10.1016/j.jiph.2017.01.013
Authors’ contribution 10. Gnanamani A, Hariharan P, Paul-Satyaseela M.
All authors have made substantial, direct, Staphylococcus aureus: Overview of bacteriology,
and intellectual contribution to the work and clinical diseases, epidemiology, antibiotic resistance
approve it for publication. and therapeutic approach. In: Frontiers in
Staphylococcus aureus. Enany S. Alexandar LC. (Eds.).
Intech Open. 2017:4-28. doi: 10.5772/67338
Funding 11. Bien J, Sokolova O, Bozko P. Characterization of
None. virulence factors of Staphylococcus aureus: novel
function of known virulence factors that are implicated
in activation of airway epithelial proinflammatory
Data availability response. J Pathog. 2011;2011:601905. doi:
All datasets generated or analyzed during 10.4061/2011/601905
this study are included in this manuscript 12. Shettigar K, Murali TS. Virulence factors and clonal
diversity of Staphylococcus aureus in colonization
and wound infection with emphasis on diabetic
Ethics STATEMENT foot infection. Eur J Clin Microbiol Infect Dis.
This article does not contain any studies 2020;39(12):2235-2246. doi: 10.1007/s10096-020-
with human participants, or animals performed 03984-8
by any of the authors. 13. Lacey KA, Geoghegan JA, McLoughlin RM. The
role of Staphylococcus aureus virulence factors
in skin infection and their potential as vaccine
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Immune System Evasion Mechanisms in Staphylococcus

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Malak et al.

| J Pure Appl Microbiol | 14(4):2219-2234 | December 2020

REVIEW Article OPEN ACCESS

Immune System Evasion Mechanisms in

Hesham A. Malak1,2, Hussein H. Abulreesh1,2*, Sameer R. Organji1,2,

(Received: November 30, 2020; accepted: December 15, 2020)

Journal of Pure and Applied Microbiology 2219 www.microbiologyjournal.org

Introduction these infections complicated and more challenging

Table 1. Human infections caused by Staphylocccus aureus

Infection site Clinical syndrome

Table 2. Staphylococcus aureus virulence factors

Factor Effect / function

Cell surface proteins Helping attachment to host tissues

Adapted from10, 11, 12, 13

Types of protein classes Examples

Binding to antigen: antibody complexes C1q

Journal of Pure and Applied Microbiology 2223 www.microbiologyjournal.org

Staphylococcal Sbi is made of four parts is an anti-opsonic protein, in order to stimulate

Journal of Pure and Applied Microbiology 2224 www.microbiologyjournal.org

Direct inactivation of C3 convertases S. aureus produces five unlike molecules which

SCIN-B and SCIN-C are extremely efficient C3 Phagocytosis

Receptor Specificity Function Target cells

receptors (GPCRs). Both chemoattractants and Resistance to phagocytosis

Journal of Pure and Applied Microbiology 2232 www.microbiologyjournal.org

applications. J Innate Immun. 2018;10(5-6):455-464. 2016;5(1):32. doi: 10.3390/pathogens5010032

Journal of Pure and Applied Microbiology 2233 www.microbiologyjournal.org

Journal of Pure and Applied Microbiology 2234 www.microbiologyjournal.org

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