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*Corresponding author: E-mail: f.vanoverveld@ucr.nl; 
 
 
 

Asian Journal of Immunology 
 
1(1): 1-13, 2018; Article no.AJI.41198 
 

 
 
 

 

The Martyrdom of St. Julia: On Microbial Strategies 
to Evade the Immune System 

 
Thuc Anh Nguyen1, Angkarina Angkasuwan1, Claudia Rossi1,  

Frans J. Van Overveld1 and Ger T. Rijkers1,2* 
 

1
Department of Science, University College Roosevelt, Lange Noordstraat 1, 4331 CB Middelburg, 

The Netherlands. 
2
Laboratory of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein,  

The Netherlands.  
 

Authors’ contributions  
 

This work was carried out in collaboration between all authors. Author GTR designed the study and 
wrote the outline. Authors TAN, AA and CR each searched the literature and wrote the draft versions 

of sections of the manuscript. Author FJVO supervised the literature search and edited the lay-out. All 
authors read, commented on and approved the final manuscript. 

 
Article Information 

 
DOI: 10.9734/AJI/2018/41198 

Editor(s): 

(1) Jaffu Othniel Chilongola, Department of Biochemistry and Molecular Biology, Kilimanjaro Christian Medical University 
College, Tumaini University, Tanzania.  

Reviewers: 

(1) Tania Mara Pinto Dabés Guimarães, Federal University of Minas Gerais, Brazil. 

(2) Festus Otajevwo, Western Delta University, Nigeria. 

(3) M. Zamri Saad, Universiti Putra Malaysia, Malaysia. 

Complete Peer review History: http://www.sciencedomain.org/review-history/24615 

 
 
 

Received 19
th

 February 2018  
Accepted 4th May 2018 

Published 16th May 2018 

 
 
ABSTRACT 
 

Bacteria and viruses use an array of evasion mechanisms to escape from the host immune system. 
Due to antigenic variation, pathogenic micro-organisms can escape the immune system. Micro-
organisms can occur in different types, such as the 97 serotypes of Streptococcus pneumoniae. 
Influenza viruses change their antigenic make-up, in particular, the hemagglutinin molecule by 
antigenic drift and antigenic shift. Trypanosomes and malaria parasites use DNA programmed 
expression of highly variable surface antigens. Micro-organisms can also produce proteins that 
degrade (IgA protease) or inactivate antibody molecules (protein A and protein G). Some bacteria 
and viruses produce proteins that inhibit complement activation. Virus can become invisible for 
recognition by T-lymphocytes by interference with antigen presentation. Antiviral immunity can be 

Review Article 



 
 
 
 

Nguyen et al.; AJI, 1(1): 1-13, 2018; Article no.AJI.41198 
 
 

 
2 
 

suppressed by viral homologues of cytokines and cytokine receptors and other proteins. Despite 
the extensive immune evasion strategies used by viruses, bacteria and other micro-organisms, the 
immune system in most cases is ultimately able to control an infection. 
 

 
Keywords: Evasion mechanisms; IgA proteases; capsular polysaccharides; antigenic drift; antigenic 

shift; complement inhibitors; antigen presentation; cytokine homologues. 
 

1. INTRODUCTION 
 
Micro-organisms and parasites use a number of 
different ways to escape the immune system. The 
Christian religious history has the legend of Saint 
Julia, who tried to escape from her future 
husband. The story of this legend is that in the 
14

th
 century, Julia, the daughter of a heathen 

King in Portugal, was promised by her father to 
be the bride of the King of Sicily. Julia refused 
because she wanted to remain a virgin and in 
order to prevent she had to marry, she prayed to 
God for help. Soon thereafter she grew a beard 
and her husband-to-be then refused her. 
Unfortunately, Julia’s father became so mad that 
this prearranged marriage was cancelled that 
he had her crucified. Saint Julia has been 
popular through the ages and her crucifixion is 
depicted in many works of art, including statues, 
drawings and paintings [1]. The scene of her 
crucifixion is also depicted by Jheronimus Bosch 

in the Martyrdom of Saint Julia (Fig. 1). For the 
occasion of the 500

th anniversary of Jheronimus 
Bosch in 2016, the painting was loaned by the 
Gallerie dell'Accademia, Venice, Italy to the 
Noord-Brabants Museum in ‘s Hertogenbosch, 
The Netherlands, the home town of Jheronimus 
Bosch. As a part of the deal the painting was fully 
restored and only then the beard of Saint Julia 
became clearly visible. Growing a beard as a 
strategy to escape marriage. 
 
Various micro-organisms and parasites have 
evolved different strategies to escape the 
immune system of the host. This strategy is 
called evasion. Evasive mechanisms contribute 
strongly to the virulence and pathogenicity of 
these organisms. Different categories of evasive 
mechanisms can be distinguished, each with 
different targets on the immune system, which 
will be discussed in this review. 

  

 
 

Fig. 1. Detail of the painting The Martyrdom of Saint Julia by Jheronimus Bosch (around 1497). 
The painting is alternatively named Saint Wilgefortis Triptych, because Saint Julia had such as 

strong (fortis) will (wilge). Gallerie dell'Accademia, Venice, Italy. 
(http://boschproject.org/#/artworks/Saint_Wilgefortis_Triptych) 

 



 
 
 
 

Nguyen et al.; AJI, 1(1): 1-13, 2018; Article no.AJI.41198 
 
 

 
3 
 

2. IMMUNE EVASION MECHANISMS 
 

2.1 Due to Antigenic Variation Pathogenic 
Micro-organisms can Escape the 
Immune System 

 
One of the ways in which a micro-organism         
can escape elimination by the immune system            
is by altering its antigenic make up [2].                 
Such a makeover can occur in three different 
ways. 
 

First, a micro-organism can occur in different 
types. For example, the bacterium 
Streptococcus pneumoniae has ninety seven 
serotypes that differ in the structure of the 
capsular polysaccharide (Fig. 2) [3]. Infection 
with a given serotype leads to type-specific 
immunity, which, however, does not protect 
against infection with any of the other 
pneumococcal serotypes [4]. For the acquired 
immune system, every pneumococcal serotype is 
therefore a separate micro-organism. This means 
that Streptococcus pneumoniae can cause a 
primary infection several times in the same 
individual. 
 

The second way of antigenic variation is more 
dynamic and is found among others in the 
influenza virus, the cause of influenza. There are 
three different types of influenza virus, A, B 
and C, of which influenza A causes the most 
serious disease symptoms [5]. Most infections 
that occur worldwide during the influenza season 
(autumn and winter) are caused by a single type 
of the influenza A virus. Over time, protective 
immunity arises in the population, which mainly 
consists of antibodies and cytotoxic T-

lymphocytes directed against the viral 
hemagglutinin protein [6]. The hemagglutinin is 
involved in attachment to target cells and 
antibodies against hemagglutinin can (thereby) 
prevent the spread of the virus in the body [7,8]. 
Due to changes in the hemagglutinin protein 
(see below), a virus type is created against 
which the accumulated immunity in the 
population does not work or does not function 
properly [9]. Such a changed virus can, therefore, 
cause a new infection. The influenza virus can 
alter the antigenic makeup of the hemagglutinin 
in two ways: antigenic drift and antigenic shift 
(Fig. 3) [10]. Mutations in the gene coding for the 
hemagglutinin (and for the second important 
virus surface protein neuraminidase) produce a 
new variant of the influenza virus (antigenic drift) 
every two or three years [11]. This variant is less 
well recognized by the antibodies and cytotoxic 
T lymphocytes present. This allows the 
influenza virus to cause a - generally mild - flu 
epidemic [12]. Such an epidemic is mild because 
although some epitopes of the hemagglutinin 
and/or neuraminidase have changed, not all of 
them have. So there is still a certain amount of 
residual immunity in the population. Antigenic 
shift is a much rarer event, but with far greater 
consequences [13]. An antigenic shift can occur 
when a (human) influenza A virus ends up in a 
secondary host (e.g. a bird). The influenza RNA 
genome is segmented into eight genes, one of 
which is coding for hemagglutinin and one for 
neuraminidase [14]. In a secondary host, in a cell 
that is infected with two different influenza 
viruses, exchange of a complete RNA segment 
can take place [15]. Thus, in a host cell infected 
with both the human and avian influenza virus, 
exchanges between both viruses can occur.

 

 
 

Fig. 2. Streptococcus pneumoniae, a Gram-positive facultative anaerobic bacterium is 
encapsulated by a thick layer of polysaccharides (arrow in left panel). The capsule is made up 

of one of 93 different types of polysaccharides; the structural composition of four common 
occurring serotypes is shown in the right-hand panel 



 
 
 
 

Nguyen et al.; AJI, 1(1): 1-13, 2018; Article no.AJI.41198 
 
 

 
4 
 

 
 

Fig. 3. Antigenic shift and antigenic drift of influenza A virus. The major surface antigens of the 
influenza A virus are hemagglutinin and neuraminidase. By point mutations in the RNA 

encoding hemagglutinin, the antigenic make-up of the molecule can change somewhat. This is 
called antigenic drift. This allows original antibodies to bind less well or not at all and the 

mutated virus has a better chance of survival. In an antigenic shift, two different influenza A 
virus particles exchange a complete RNA segment, allowing a completely different 

hemagglutinin molecule to be expressed. Accumulated immunological memory from previous 
influenza contacts is then no longer effective because antibodies (and memory T lymphocytes) 

no longer recognize the altered hemagglutinin molecule. Such an altered influenza virus is, 
therefore, more easily able to cause an epidemic 

 
From this, a (human) virus variant can emerge 
with an avian hemagglutinin (Fig. 3). At least 18 
subtypes of the hemagglutinin occur (H1 to H18), 
of neuraminidase 11 (N1 to N11) [16]. The most 
common influenza A types in humans are H1N1, 
H2N2 and H3N2 [17]. H5, H6, H7 and H8 are 
especially common in birds [18]. Due to antigenic 
shift, the H5N1 variant originated in which the 
avian 76 H5 ended up in a human influenza A 
virus [19,20]. The differences between the 
human and avian influenza hemagglutinin are so 
great that antibodies and cytotoxic T 
lymphocytes formed during previous infections 
do not give any cross protection. Influenza 
strains in which such an antigenic shift has 
occurred occur once every 15 to 20 years [10]. 
The so-called Hong Kong influenza pandemic in 
1968, with world-wide one million deaths, was 
caused by a virus variant due to antigenic shift 
[19,21]. 
 
The most recent influenza pandemic started in 
Mexico in 2009 and was initially called swine flu. 
Later, under pressure from Mexico, this name 
was changed to new influenza A (N1H1) (Fig. 4). 
What was special was that this variant 
particularly affected young children, while 
normally older people are particularly 
susceptible to influenza [22,23]. In retrospect, 

many people aged about 50 years and older 
were already found to have (cross-reactive and 
protective) antibodies against this virus, due to 
exposure to a similar influenza in their youth [24]. 
The N1H1 spread rapidly around the world, and 
initially, there was fear that millions of people 
would be killed. 
 
A vaccine against H1N1 has been accelerated 
and offered to major risk groups i.e. children 
between 6 months and 4 years, household 
members of younger children, and adults with 
chronic disease [25]. In retrospect, the H1N1 
pandemic was mild, probably mainly because 
the elderly - in which the mortality is 
concentrated during the annual flu season - 
were barely susceptible to the new influenza A 
(N1H1) [24]. An estimated 300,000 people 
worldwide have died directly or indirectly from the 
virus [26]. A total of 65,600 deaths was 
confirmed in Africa, 29,700 in the Americas, 
31,000 in Europe, and 78,600 in Asia [26]. At the 
moment the H1N1 vaccine became available, the 
peak of the pandemic might already have 
passed. 
 
The third way in which antigenic variation can 
occur is due to programmed changes in the DNA 
of the micro-organism or parasite [27]. In its most



 
 
 
 

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5 
 

 
 

Fig. 4. A worldwide outbreak of new N1H1 influenza virus in 2009, as reported in the press and 
communicated to travelers 

 

extreme form, this mechanism is used by 
trypanosomes. Trypanosomes are protozoans 
that are transmitted by insects and cause 
sleeping sickness [28,29]. The trypanosome is 
surrounded by a single protein, the variant-
specific glycoprotein (VSG) [30]. After infection, 
this VSG generates a powerful antibody 
response that neutralizes the parasite. However, 
trypanosomes have a thousand different VSG 
genes of which only one is expressed each time. 
The le trypanosome that has been altered from 
VSG expression thus escapes the immune 
system and leads to renewed growth and flare-
up of the disease [30]. This will result in a chronic 
cycle of trypanosome degradation with immune 
complex formation and inflammation, followed by 
renewed disease activity. Ultimately, this leads to 
severe neurological age and coma. 
 
The malaria parasite also uses this mechanism of 
antigenic variation to protect itself against the 
immune system [31]. In the erythrocyte stage of 
malaria, there is an expression of parasite 
proteins on the membrane of the red blood cell, 
especially of the PfEMP1 protein [32,33]. The 
PfEMP1 protein suppresses the production of 
IFN- and thus a cellular immune response [34]. 
Via PfEMP1 an infected erythrocyte adheres to 
vascular wall tissue and can thus prevent 
phagocytosis by spleen macrophages. PfEMP1 
does elicit an antibody response and these 
antibodies can bind to infected erythrocytes. 
Antibody-loaded erythrocytes are captured in the 
spleen and phagocytosed. The malaria parasite 

has sixty variants of PfEMP1, of which only one 
is expressed each time [35]. Switching to 
another variant of PfEMP1 means that the 
already produced antibodies can no longer bind 
and that infected erythrocytes are no longer 
trapped. 
 

2.2 Micro-organisms Produce Proteins 
that can Degrade or Inactivate 
Antibody Molecules 

 

Micro-organisms can protect against antibody-
mediated complement lysis or phagocytosis by 
enzymatic degradation of the antibodies. A 
number of bacteria, including Neisseria species, 
Haemophilus influenzae and Streptococcus 
pneumoniae form proteolytic enzymes that can 
split secretory IgA (SIgA) antibodies into two 
monomeric Fab fragments and an Fc fragment 
[36,37]. This IgA protease is capable of cleaving 
both free SIgA and bound SIgA antibodies. The 
Fab fragments remain on the surface of the 
micro-organism but are unable to activate 
effector mechanisms (complement, 
phagocytosis) [38]. Infections with the above 
bacteria occur on mucous membranes and IgA is 
the most important isotype of the antibodies 
present [39]. The bacterial IgA proteases are 
especially capable of splitting SIgA1 while SIgA2 
is relatively resistant to IgA proteases [36,37]. 
But because the IgA1 Fab fragments remain 
bound on the surface of the micro-organism, 
binding of IgA2 antibodies can be inhibited 
thereby [40,41]. 



 
 
 
 

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6 
 

IgG antibodies can also be broken down by 
bacterial enzymes. Pseudomonas aeruginosa 
and other bacteria produce cysteine proteases 
that can cleave IgG molecules at the hinge 
region. 
 

Besides proteolytic cleavage of the molecule, IgG 
can also be functionally inactivated by certain 
bacterial proteins [42-44]. Staphylococcus 
aureus expresses a protein on its surface called 
protein A, which can bind to the Fc portion of IgG. 
Binding of protein A to IgG blocks Fc receptor-
mediated phagocytosis [45,46]. Moreover, it 
inhibits the binding of C1q to IgG and thus 
complement activation [47]. In other bacteria, 
proteins with similar functions are found: Group-
G streptococci produce protein G and 
Peptostreptococcus produces protein-L. These 
proteins can also bind to IgG [48-50]. 
 

2.3 Some Bacteria and Viruses Produce 
Proteins that Inhibit Complement 
Activation 

 

Many bacteria produce N-formyl peptides such 
as fMLP [51]. These peptides are very potent 
chemoattractants for phagocytes [52]. fMLP is 
bound to phagocytes via specific receptors: 
formyl peptide receptor (FPR) and the related 
FPR-like-1 receptor (FPRL1) [53]. The fMLP is 
not only an chemoattractant but also stimulates 
phagocytosis [54,55]. Staphylococcus aureus 
has developed a strategy to prevent the 
attraction of phagocytes to the site of the 
infection by producing the protein CHIPS 
(chemotaxis inhibiting protein of S. aureus) [56]. 
CHIPS binds to FPRL1 and thus blocks the 
functioning of this receptor [57]. CHIPS also 
binds to the C5a receptor on phagocytes and 
thereby blocks the function of another 
chemotactic peptide, the complement fragment 
C5a [58]. Another staphylococcal protein that 
interferes with the complement system is SCIN 
(staphylococcal complement inhibitor) [59]. SCIN 
blocks the C3 converter activity of C4b2a and 
C3bBb [60-62]. In total, S. aureus possesses 
about ten different proteins that can all inhibit 
complement activation. Together, this will disrupt 
all functions mediated by the complement 
system (chemotaxis and lysis and opsonization) 
[62-64]. These and other proteins that are used 
to escape the immune system of the host lie 
encoded on the bacterial genome together in a 
so-called immune vascular cluster (IEC), of which 
S. aureus possesses two [65,66]. 
 

Not only S. aureus and other bacteria use 
proteins to prevent activation of the complement 

system (Fig. 5) but also certain viruses. Vaccinia 
virus encodes a strong complement inhibitor, 
vaccinia complement control protein (VCP). VCP 
strengthens the split of C3b and C4b by factor I 
and thus inhibits both the classic and alternative 
complement activation path [67-70]. 
 

2.4 Interference with Antigen 
Presentation Makes Viruses Invisible 
for Recognition by T-lymphocytes 

 
Viruses have developed different ways to escape 
the immune system. It is, of course, important 
that virus replication occurs only in host cells, 
where the virus is not immediately accessible to 
the immune system. During viral replication, 
components of viral proteins are presented to the 
immune system by MHC class I and class II 
proteins. In that way, the virus would betray its 
presence in an infected cell. However, if the virus 
does not replicate, but remains latent, it is 
invisible. 
 

Herpes simplex virus type I infects epithelial cells 
and sensory neurons [71]. After a cellular 
immune response, the infection is under control, 
but the virus can still remain latent in the nerve 
cells [72]. Reactivation of the virus can if the 
antiviral immunity is reduced or temporarily 
disturbed, lead to a re-infection of the skin [73]. 
Another herpes virus, the previously discussed 
Epstein-Barr virus, can remain latent in B 
lymphocytes [74]. For this, it must express a 
certain viral protein, EBNA-1, since this is 
necessary to maintain the viral genome. EBNA-1 
cannot be presented in the context of MHC class 
I, because it cannot be broken down by the 
proteasome. This keeps the virus invisible to the 
immune system [75-77]. 
 
Other viruses also have proteins that interfere 
with antigen presentation and thus try to prevent 
a cellular immune response from getting under 
way. For example, the cytomegalovirus (CMV) 
has at least twelve different proteins that block 
the presentation of CMV peptides in the MHC at 
different sites [78]. These CMV proteins are 
encoded on the unique long (UL), or unique short 
(US) part of the CMV genome [79]. US3 and 
US10 proteins prevent MHC class I molecules 
from leaving the endoplasmic reticulum [80,81]. If 
nonetheless MHC class I molecules are formed, 
US2 and US11 proteins bind to this, after which 
the MHC molecules are degraded by 
proteasomes [82,83]. Disabling MHC class I 
expression prevents recognition by cytotoxic T 
lymphocytes but makes the cell susceptible to 



 
 
 
 

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7 
 

killing by NK cells [84]. The CMV protein UL16, 
however, blocks the activating NK cell receptor 
NKD2D and UL18 stimulates the inhibitory NK 
cell receptors [85,86]. CMV, therefore, has an 
extensive package of viral proteins at its disposal 

to combat killing by CD8+ T lymphocytes or by 
NK cells. 
 

2.5 Viral Homologues of Cytokines and 
Cytokine Receptors and Other 
Proteins Suppress Antiviral Immunity 

 

If a virus, despite its attempts to prevent 
recognition by the immune system, would still 
evoke an immune response, it can try to 
suppress that response. One of the strategies 
employed is that the viral genome encodes 
homologues of suppressive cytokines and/or 
soluble cytokine receptors. [87-90]. EBV encodes 
a viral homolog of IL-10, which is very similar to 
human IL-10 but has only its 
immunosuppressive properties [91,92]. EBV 
also encodes an IL-12p40 related protein [93]. 
Pox viruses use soluble cytokine receptor 

homologous proteins and cytokine binding 
proteins to neutralize proinflammatory cytokines 
[94]. These viruses also code for a soluble 
chemokine antagonist that binds with high affinity 
to CC-chemokines. Fungi also use inhibition of 
cytokines to escape the immune response of the 
host. Virulent cryptococcal strains secrete 
proteins with anti-TNF-α and anti-IL-12 activity 
while stimulating the IL-10 production of the host 
[95]. 
 

In addition to blockade of the cytokine function, 
viruses can also neutralize the action of 
antibodies by synthesis of viral Fc receptors 
(herpes simplex and cytomegalovirus) [96,97]. 
Finally, viruses can also resist apoptosis in order 
to escape cytotoxic T lymphocytes and NK cells. 
The most successful is the adenovirus, which 
possesses a protein that is very similar to the 
anti-apoptotic Bcl-2. EBV also has two proteins 
that resemble Bcl-2 [98]. Inhibition of caspase 
activity and reduction of the expression of 
apoptosis receptors such as FasL are other ways 
in which viruses prevent apoptosis [99-101]. 

 

 
 

Fig. 5. Complement evasion by bacterial proteins. Figures show examples of bacterial proteins 
which can interfere with specific pathways of the complement system. Further explanation is 

given in the text 



 
 
 
 

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8 
 

Despite the extensive immune evasion strategies 
used by viruses, bacteria and other micro-
organisms, the immune system in most cases is 
ultimately able to control an infection. However, 
when components of the immune system do not 
function adequately, such as with congenital or 
acquired immune deficiencies, even seemingly 
innocent micro-organisms can lead to serious 
infections. 
 

3. CONCLUSION 
 

Saint Julia, by changing her antigenic makeup, 
tried to evade from her husband to be. This relief 
was only temporary, because another man, 
notably her own father, had her crucified. The 
analogy with micro-organisms that try to escape 
the immune system partly holds true. Escape from 
complement mediated killing does not prevent 
phagocytosis and subsequent intracellular killing. 
 

CONSENT  
 

It is not applicable. 
 

ETHICAL APPROVAL  
 

It is not applicable. 
 

ACKNOWLEDGEMENTS 
 

No external funding for this study was used. The 
University College Roosevelt covered all costs 
associated with the development and the 
publishing of the present manuscript. The 
corresponding author had full access to the data 
and final responsibility for the submission of the 
publication. 
 

COMPETING INTERESTS 
 

Thuc Anh Nguyen, Angkarina Angkasuwan, 
Claudia Rossi, Dr Frans J. van Overveld, and 
Prof. Dr Ger T. Rijkers declare that they have no 
relevant affiliations or financial involvements with 
any organization or entity with a financial interest 
in or financial conflict with the subject matter or 
materials discussed in the manuscript. This 
includes employment, consultancies, honoraria, 
stock ownership or options, expert testimony, 
grants or patents received or pending, or 
royalties. No writing assistance was utilized in the 
production of this manuscript. 
 

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