The Organism Prearranged Recognition Theory

By: Luz P. Blanco Ph.D.

Light White Innovation Technology, Ann Arbor, MI.

E-mail: lwinntech@gmail.com.

Phone: (734) 485-4907

Summary

Presented herein is a theory to explain how organisms' interactions are

prearranged. This theory provides the molecular basis for the initial event in the
establishment of these interactions and should aid in the development of better
vaccine strategies and new, efficient therapies against infectious diseases and
cancer. The theory is as follows: “The recognition and interaction that occur
between organisms is prearranged. There are soluble components derived
from one organism that recognize and allow interaction only with those
unique organisms that have the specific receptors for those soluble
components”. The organisms’ prearranged recognition theory (OPRT) can be
specifically applied to host-microbe interactions where most microbes are coated
(opsonised) by soluble components (opsonins) from the host, but there are also
some microbes that can bypass the host opsonization by directly expressing
receptors for the host cells, thus directly mimicking the host opsonins. The
receptors involved in an organism's interactions, their specificity and repertoire
are based mainly, but not exclusively, on the epitopes of the saccharides located
in the glycoproteins, glycolipids and polysaccharides (glycans) that are highly
abundant on the surfaces and extracellular components of living organisms. This
prearrangement may provide an explanation of species-specific interactions and
several other important and previously unresolved phenomena, such as
hyperinfectivity, tissue tropism, higher sensitivity of people with type O-blood to
certain diseases in comparison with other blood groups, and tumoral cell
promiscuity. The lipid raft domain in the cellular membrane is the main location
where interactions will trigger cellular responses. I herein propose some
alternative routes to modify an organism's interactions as well as the possible
consequences of these manipulations. It is a novel theory regarding the degree
to which an organism’s interactions are prearranged and the importance of
saccharide epitopes in the molecular mechanism of this prearrangement.

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Organisms’ prearranged recognition theory (OPRT):

“The recognition and interaction that occur between organisms is

prearranged. There are soluble components (opsonins) derived from one
organism that recognize and allow interaction only with those unique
organisms that have the specific receptors for those opsonins”.

Based on this theory, there are two types of organisms or microbes for a
specific opsonising host-organism: those for which interactions could not be
established (type I) and those for which interactions could be productively
established (type II). Type I organism which is unable to establish interaction,
will thus go unnoticed because it is without host-specific opsonin receptors and is
unable to directly express receptors specific for the host. Type I organisms for a
human host-organism are those multiple microbes that fail to establish interaction
with us but they will interact (invade, infect, colonize, adhere, etc.) with other
species. Type II organisms, which will productively establish interactions with a
given host-organism are either opsonized by the host opsonins or are able to
directly express receptors for the specific host cells (Figure 1). Depending on
their ability to disseminate and overgrow inside the host, type II organisms can
either be beneficial or deleterious. The latter affect the energy homeostasis of
the host cells and tissues and produce damage and eventually disease. Factors
such as the nutritional or the immune state of the host will determine if a
beneficial organism can be transformed into a deleterious organism. The
damage-response framework theory explains the possible outcomes, once the
initial interactions are established (Casadevall and Pirofski 2003). Antibodies—
and in particular, natural antibodies—play an instrumental role as the main
opsonins in the organisms’ interactions, but so also do other abundant and
ubiquitous glycoproteins and glycolipids. The interactions that happen between
organisms and the immune system follow this theory; however, the type of
receptors and antigens involved in these types of interactions are mainly—but
not exclusively—proteins and peptides. In cell membranes, the lipid raft
platforms are the location where the first events involved in recognition and
interactions are inititated including the vigilance that triggers signalling cascades.

Molecular basis for the repertoire and diversity of receptors:

The diversity and repertoire specificity of opsonin substances, as well as the
organisms’ receptors, are based mainly on the saccharide epitopes present in
the glycans, glycoproteins, glycolipids, sugar coats, capsules, cell walls, etc. The
importance of saccharides in the interaction between different organisms and
elements can be deduced from the mortality rates and high severity of diseases

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related to genetic disorders in the saccharides' biosynthetic pathways (De
Praeter, Gerwig et al. 2000; Freeze 2001; Freeze 2002; Freeze 2006). In the
mucosal system, glycoproteins, such as antibodies and mucins, are the main
prearranged recognition opsonins. In serum, lymphatic fluid, and tissues, the
opsonins can be antibodies, as well other glycoproteins and glycolipids. The
envelope antigens containing saccharide epitopes that are the receptor targets
for opsonization in organisms such as bacteria, fungi, parasites, and viruses are
commonly used in serology to classify their serotype group. The serology of
organisms is related to the surface antigens (usually saccharides) expressed,
such as the lipopolyssacharide’s (LPS) O antigen in Gram-negative bacteria and
this characteristic also determines their ability to productively interact with a
specific host. These receptors are what host opsonins can detect or recognize to
allow interactions with a foreign organism. In fact, applying the OPRT, we can
understand why serotypes are useful in classifying the host's susceptibility range
or the organism's species-specificity. Antibodies (which are glycoproteins) could
basically be considered as the main tools for an organism's interaction because
they allow the interaction of foreign antigens and microorganisms with cells.
Supporting the central role of glycoconjugates in human gut interactions,
saccharides resemble microbial receptors, bacterial LPS, and the structure of
tumoral antigens (Henry 2001), thus ensuring that these structures are familiar to
the host. Human gut mucins, which are components of the mucus, and
glycoproteins are highly diverse and provide a broad repertoire of host receptors
(Robbe, Capon et al. 2004). The mucus layer also has been characterized as
instrumental to the structure and stability of the normal gut flora (Sonnenburg,
Angenent et al. 2004).

Carbohydrates provide the molecular basis for specific cell-cell

recognition:
In the model of species-specific cell-cell recognition of the marine sponge, the
role of carbohydrate interaction (glycan-glycan) has been clearly established
(Bucior and Burger 2004; Bucior and Burger 2004; Bucior, Scheuring et al.
2004). The glycans allow species-specific reconstitution of the sponge structure
from individual disaggregated cells. Importantly, the strength of the carbohydrate-
carbohydrate interaction is as strong as a protein-protein interaction, as was
determined using atomic force microscopy (Popescu, Checiu et al. 2003; Bucior,
Scheuring et al. 2004). Carbohydrates have a self-recognition capability, and the
specificity of these interactions has been demonstrated using glycans derived
from marine sponges, a surface plasmon resonance detection system, and
atomic force microscopy (Gradimir 1999; Haseley, Vermeer et al. 2001; Misevic,
Guerardel et al. 2004). In a multicellular organism and a membrane bilayer
environment, protein-glycolipid interactions require a lipid bilayer environment for
proper presentation of the saccharide epitopes with higher affinity and specificity
to proteins (Evans and MacKenzie 1999).

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 Carbohydrates located in the surface of cells, such as glycoproteins,
gycolipids, gangliosides and others, are already known to participate in cell-cell
adhesion and cell response in highly diverse events (Brewer, Miceli et al. 2002;
Hakomori 2004; Hakomori 2004b; Eklund and Freeze 2005). A number of
glycoproteins participate in interactions required for a proper immune system
response (Tsuboi and Fukuda 1998; Tsuboi and Fukuda 2001; Rudd, Wormald
et al. 2004; Arnold, Wormald et al. 2007). Moreover, glycosylation in diverse
viruses plays a role in processes such as attachment, infectivity, entry, and
replication, which also require host glycoproteins (Vigerust and Shepherd 2007).
Some representative examples of microbe- or toxin-host interactions where
saccharides play a role in attachment or infection are depicted in Table 1.
In humans and mice, muscle integrity depends on glycosylation because
mutations in glycosyltransferases have been associated with some muscular
dystrophy cases (Martin and Freeze 2003). Also, endocrine system alterations
are due to congenital glycosylation defects (Miller and Freeze 2003). Overall,
there is strong support for the role of saccharides as the host’s receptors for the
interactions to proceed and for the specificity of interactions even within the
tissues and organs of the host itself. The molecular mechanism involved in
particular in the host-pathogen interactions described here probably has long
been hindered because 2-3% of the total genome is involved in saccharide
biosynthesis pathways that are not yet well characterized (Freeze 2001). Also,
the genetic manifestations of saccharide disorders that affect specific host-
pathogen interactions probably require multiple simultaneous gene changes that
are not necessarily linked.

Molecular basis for species-specificity, tropism, and hyperinfectivity

phenomenon:
The organism prearranged recognition theory gives the molecular basis for
species-specificity of colonization, infection phenomenon, and also for in vivo cell
tropism of some infectious or deleterious organisms. Species-specificity is given
by an organism’s ability to express appropriate receptors for the host's opsonins,
and this allows the host to interact specifically with only those organisms. Also,
the cell tropism of certain organisms is determined by recognition of the
opsonins, for which there are host tissues or cell-specific receptor(s) that allow
an interaction to proceed only with those particular tissues. Applying the OPRT
to understand the hyperinfection phenomenon is straightforward, where
pathogens that have been inside a host acquire a more virulent phenotype and
already carry the host’s opsonins that optimizes them for interaction with any
subsequently appropriate hosts. The enteropathogens Vibrio cholerae (Merrell,
Butler et al. 2002) and Citrobacter rodentium (Wiles, Dougan et al. 2005; Bishop,
Wiles et al. 2007) display hyperinfection, or host-adapted phenotypes. The
hyperinfectious phenotype is acquired after host passage and is temporarily
acquired because it is gradually lost once the pathogen is outside the host. The
host’s shield of opsonins probably aids the organism in resisting stressing

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conditions inside and outside the host, such as the acid pH, the temperature, the
osmolarity, and the proteases. Opsonins also may help organisms to build
biofilms, where they are in a more protected state, compared with their
planktonic, free-living state. In support of this hypothesis, it has been recently
shown that aggregates or biofilm arrangements of Vibrio cholerae contribute both
to increased infectious capability and greater environmental persistence, when
compared to free-swimming planktonic cells (Faruque, Biswas et al. 2006).
The OPRT explains why it is usually difficult to reproduce the species-
specificity property of interactions in vitro, probably because species-specific
opsonins are not present (the fetal serum used in culture is from a different
species), changing the organism's coat of opsonins and rendering them unable to
interact optimally or—the opposite—making them artificially able to interact with a
non-host organism. For example, the in vitro ability of different Salmonella
serotypes to resist macrophages does not correlate with their in vivo virulence
(Watson, Paulin et al. 2000). However, there are several non-invading bacteria
in vivo that are invasive to some cells like tumor cells in vitro.

Molecular basis for promiscuity of tumoral cells:

The more promiscuous an organism is (in other words, the more interactions it is
able to establish), the more chances it has to develop a deleterious interaction or
to acquire pathogenic organisms. The promiscuity is a function of the repertoire
or the diversity of the opsonins and receptors each organism expresses and
carries. Diversity can probably be induced, and it is different between even
individuals of the same species. Tumoral cells are one of the most promiscuous
of cell types because they change their "coat" or outer shell, unlike normal, non-
transformed cells; thus, tumoral cells express a variety of saccharides on their
surfaces, presenting a broader repertoire of receptors and opsonins, such as
novel membrane-associated mucins (Walsh, Young et al. 2007). These novel
envelope glycoproteins allow tumoral cells to be colonized by different types of
bacteria and viruses, and to interact with each other and with other normal cells
both in vivo and in vitro with high avidity and efficiency (Figure 1). Tumoral cells
express organisms’ interaction molecules in their membranes, so they are
prompted to adhere and to interact, and they express mucin and mucin-like
glycoproteins containing N- and O-glycans that play a role in cell transformation,
cell adhesion, invasion, immune escape, and metastasis (Brockhausen 2003;
Hollingsworth and Swanson 2004). Understanding the chemistry of carbohydrate
biosynthesis in cancer cells should help in defining innovative therapies against
them (Paulsen and Brockhausen 2001). Other glycoproteins, particularly, those
with a high sialic acid content, are also associated with the inherent properties of
cancerous cells (Dall'Olio and Chiricolo 2001; Ono and Hakomori 2003; Suzuki,
Suzuki et al. 2005), and these properties have recently been used to target
cationic polymers against certain mucosal tumoral cells (Azab, Kleinstern et al.
2008).

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Vigilance toward and detection of type II organisms:
The vigilance toward and detection of type II organisms by the host are mediated
through receptors able to recognize saccharide epitopes—for example,
gangliosides and cell differentiation molecules or lectin-like molecules in the
cellular membrane of innate immune cells. Also, toll-like receptors that recognize
microbe-derived molecules play a role in host vigilance, as is discussed below. I
have deduced from my study with Vibrio cholerae, which is a human species-
specific pathogen (Blanco and DiRita 2006; Blanco and DiRita 2006a), that
gangliosides are host receptors playing a role in the organism's interaction. The
main virulence factor of this pathogen is the cholera toxin, the host receptor of
which is the ubiquitous glycosphingolipid ganglioside GM1. The ganglioside
GM1 has the same structure in different species, but only humans are sensitive
to V. cholerae infection—and especially subjects having blood type O (Barua and
Paguio 1977). Therefore, I propose that a cholera toxin-GM1 link exists in the
human intestine that is missing in other species but is present especially in the
more sensitive blood type O individuals, allowing V. cholerae to colonize and to
produce the cholera disease. Previously it has been demonstrated that the type
O blood group antigen in host cells is unable to directly interact with cholera toxin
better than A or B blood group antigens (Sugii 1990) can. However, nonimmune
human antibodies (sIgA or IgG), which are glycoproteins (Arnold, Wormald et al.
2007) from healthy non-immunized people, recognize V. cholerae and also
interact with GM1 (Blanco and DiRita 2006a). It is possible therefore to envision
these antibodies as host opsonins which bridge the microbe with the host cells.
Most humans at 6 months of age have cross-reactive anti-GM1 antibodies in
their serum. The generation of these antibodies coincides with the appearance
of anti-blood group antigen and anti-Forssman antibodies; this has been related
to immune response development against microbes or, applying the OPRT,
probably the development of the organism's interactions (Alaniz, Lardone et al.
2004). Recently, analyses of antibodies against tumoral antigens (mostly
saccharide epitopes) demonstrate that they are only natural antibodies or germ-
line coded IgM (Vollmers and Brandlein 2006; Vollmers and Brandlein 2007);
strikingly, no affinity-maturated, anti-tumor-specific IgG antibodies were found.
Also, there are anti-saccharide antibodies (opsonins) present in the gut
environment about which “a protective role against pathogens” has been
proposed (Hansen, Pedersen et al. 2005), but they are likely allowing the
colonization or interaction with the highly abundant, normal mucosal flora. In a
different context, antibodies against gangliosides have been associated with
some neurological diseases, but there is no direct correlation between the
presence of the antibodies and the manifestation of disease (Garcia Guijo,
Garcia-Merino et al. 1995); however, the antibodies' affinity, amount, or other
inherent characteristics could be involved in neurological pathology triggering.
The glycosynapse concept developed by Hakomori supports the proposal
that gangliosides play a functional role in organisms’ interactions (Hakomori
2002). In the review cited, Hakomori shows how gangliosides in clusters or

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microdomains, together with functional membrane proteins, play a significant role
in processes such as cell-adhesion, development, and differentiation and in
tumor progression (Hakomori 2002). The role of gangliosides in pathogen
detection and host-pathogen interactions is suggested by the long list of
pathogens that are able to recognize the carbohydrate portion of the
glycosphingolipids (Schengrund 2003). Importantly, some viruses, toxins, and
bacteria use gangliosides as receptors (Blanco 2008) to infect cells. Also, in
order to adhere, several pulmonary pathogenic bacteria recognize and bind to
glycosphingolipids, and common saccharide moieties in vitro abrogate their
adherence (Krivan, Roberts et al. 1988; Thomas and Brooks 2004; Thomas and
Brooks 2004). Moreover, ganglioside GM1 is able to present antigens (Nashar,
Betteridge et al. 2002) to activate secretion of neurotrophins (Rabin, Bachis et al.
2002) together with other gangliosides to insert into membranes (Schwarzmann
2001; Lauc and Heffer-Lauc 2006), and they also stabilize lipid domains in
cellular membranes (Sonnino, Mauri et al. 2007). Remarkable, some tumoral
cells secrete gangliosides; this ability probably allows them to modify and to
improve their interactions with other cells as well as to regulate the immune
responses (Shen, Falahati et al. 2005).
If there is the ability to sense or to be recognized, then there is the
ability to interact and to produce cellular responses. This property of the
interactions facilitates vigilance against any organism that can trespass,
overgrow, or invade deeper portions of the body that might remain sterile. The
sensing is accomplished through detection of the microbe's derived molecules by
toll-like receptors, gangliosides, or CD receptors, and cellular responses or
signaling events are originated in lipid raft platforms in the membranes. These
kinds of receptors are expressed by innate immune cells that, when they sense
any potential deleterious organism, trigger an alarm response, especially when
the detection or interaction is happening in tissues that must remain sterile and is
disrupting the energy homeostasis balance. For example, in dendritic cells the
CD209 (DC-SIGN) receptor recognizes the N-acetylglucosamine sugar residues
within the core LPS of diverse bacteria (Zhang, Snyder et al. 2006). The alarm
response is based on the type, location, amount of cytokines, and heat shock
proteins (HSP) produced or expressed by the cells and will trigger a specific
defensive immune response—for example, a cellular- and humoral-specific
immune response. Strikingly, the specific immune responses also require
prearrangement to take place. Accordingly, antigens interact with MHC molecule
receptors in order to be presented to lymphocytes that might have the precise
prearranged receptor, and antibodies that are already present recognize specific
antigens. Clearly, prearrangement in a broad variety of interactions is constantly
present.
The interaction of immune-specific cells and antibodies with the triggering
target antigens or the recognized microbe produces a defensive response
towards elimination of the organism because it allows interaction of the invading
organism or antigen with specific immune effector cells; however, low-affinity and

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high-multiplicity interactions through saccharide moieties in antibodies
(erroneously considered “non-specific” types of interactions) allow the
prearranged interaction to proceed without an aggressive component. This
proposition is clearer to visualize by analyzing sIgA interaction with normal
colonizing flora in the gut. High-affinity specific sIgA is probably involved in the
immune exclusion phenomena of pathogens, but normal flora microbes—which
exist as a highly stable ecosystem—are coated with sIgA. They are not excluded
from the intestinal lumen and neither do they induce a specific immune effector
response (Kroese, de Waard et al. 1996; Mestecky, Russell et al. 1999), despite
the fact that they are processed by mucosal dendritic cells (Macpherson and Uhr
2004). As an example, gut antigen-specific sIgA against Reovirus type 1 Lang is
able to block and to neutralize viral infections (Hutchings, Helander et al. 2004).
However, in a murine model of Streptococcus pneumoniae colonization where
the bacteria interact with the host, antibodies do not participate in bacterial
clearance (McCool and Weiser 2004).

Glycoproteins that play a role in organisms’ interactions:

The role of glycans in mucins for colonization, biofilm formation, and cell-cell
interaction phenomena is well-documented. Mucins are important for interaction
phenomena such as colonization and adhesion of a variety of microorganisms,
not only in the gut but also in the airway apparatus, in the oral micro-biota and
even between tumoral cells (Alice and Molakala 1996). A septic shock in mice
infected with the human species-specific pathogen Salmonella typhi can be
induced only when the bacteria are pre-opsonized with mucin (Sein, Cachicas et
al. 1993). The S. typhi-mucin inoculums are able to survive inside murine
peritoneal macrophages, contrary to nude S. typhi that go unnoticed in mice and
are eradicated without causing disease, even in immune-deficient SCID mice
(Sein, Cachicas et al. 1993). Mucin gives a new coating to the bacterium that
bridges the interaction of S. typhi with murine cells. Importantly, the expression
of certain envelope-mucin molecules has been associated with the malignancy of
tumoral cells and metastasis. In fact, inhibition of MUC-4 (a surface associated
mucin) expression in a highly aggressive pancreatic tumor cell line suppresses
metastasis in mice (Singh, Moniaux et al. 2004), and MUC1 expression
suppressed by RNA interference reduces the growth rate and metastasis ability
of human pancreatic cancer cells (Tsutsumida, Swanson et al. 2006).
Applying the OPRT, it is possible to understand why there are several
pathogens—not only V. cholerae, but Norwalk virus (Hutson, Atmar et al. 2002),
Escherichia coli O157 (Blackwell, Dundas et al. 2002), and Helicobacter pylori
(Mentis, Blackwell et al. 1991) infections—found more frequently in type O blood
group subjects. People of the type O blood group have antibodies against the A
and B saccharide antigens that cross-react with microbial and viral envelope
saccharide epitopes (Springer 1970), giving type O blood group antigen
individuals more opportunities to interact with different organisms or to enhance
interactions with those that are prearranged or express the right receptors. Other

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examples of antibody- enhancing interactions involve IgG and IgE, which can
have a role in antigen-sampling through the epithelial barriers; particularly critical
is the role of lumenal IgE in people with food hypersensitivity (Berin, Li et al.
2006; Li, Nowak-Wegrzyn et al. 2006) and in pregnancies where non-immune
IgG enhances infection of the placental erythrocytes with Plasmodium
falciparium (Flick, Scholander et al. 2001).
The sIgA is important for the microorganism’s colonization of oral, airway
and gut environments together with mucus. The amount of sIgA in the gut’s
lumen is determined by the type and presence of bacteria (Macpherson,
Hunziker et al. 2001; Jiang, Thurnheer et al. 2004; Haghighi, Gong et al. 2006;
Ohashi, Hiraguchi et al. 2006). Secretory IgA and mucins form high-molecular-
weight aggregates or networks that allow microorganism colonization in the form
of biofilms. Another example: sIgA and mucins promote interaction of
Salmonella typhimurium with rat intestines (Magnusson and Stjernström 1982).
The presence of sIgA in gut biofilms has been characterized in different species
(Palestrant, Holzknecht et al. 2004), but the repertoire of sIgA is limited (Stoel,
Jiang et al. 2005; Stoel, Evenhuis et al. 2008); however, glycans in the sIgA
structure allow the innate recognition of microbe surface saccharides, broadening
the range of interactions sIgA is able to establish (Wold, Mestecky et al. 1990;
Royle, Roos et al. 2003; Perrier, Sprenger et al. 2006). Also, gut sIgA has two
different origins; one is dependent on (75%) and the other is independent (25%)
of T lymphocytes (Kerr 2000). This dichotomy may help in understanding
conflicting data about the protective role of sIgA. But supporting a role of sIgA in
establishment of organism interactions, sIgA has been proposed as an
endogenous adjuvant (a promoter of element interactions) because antigenic
epitopes expressed in the secretory component of the IgA can induce antigen-
specific systemic and mucosal immune responses (Corthesy, Kaufmann et al.
1996), sIgA has immune modulatory effects similar to a common adjuvant
(Favre, Spertini et al. 2005), and because it can enhance Vibrio cholerae
transcytosis through mucosal antigen-sampling, M-like cells (Blanco and DiRita
2006a).
There are so many examples of host glycoproteins that are important for
the adhesion or attachment processes of viruses, bacteria, fungi, and parasites
that they are difficult to fully enumerate. For example, fibronectin (glycoprotein)
and other extracellular matrix components have been described as important
host elements in pathogen-host interactions, and fibronectin is also able to
interact with ganglioside GM1 (Spiegel, Schlessinger et al. 1984), so fibronectin
is a perfect host opsonin or adjuvant molecule because it bridges the organism’s
interactions. Some gut bacteria are able to interact with mucins and even
express mucin-like proteins in their surface. Also, epithelial cells express
receptors for mucin-like proteins which are important for the promotion of
interactions (Karjalainen, Barc et al. 1994). More examples of host glycoproteins
involved in host-pathogen interactions are depicted in Table 2.

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Manipulating organisms’ interactions:
The prediction is that most of the species-specificity interactions are probably
ruled by the OPRT. One important application of the OPRT is that interactions
between organisms can be modulated, changing the saccharides exposed on
surfaces or expressed by opsonin molecules in the host. This could be exploited
to develop more efficient antibiotics and anti-tumoral drugs with a broader
spectrum by creating saccharide synthesis inhibitors and using enzymes involved
in polysaccharide synthesis, or free saccharides as competitors. Conditions that
affect saccharide interactions, such as changing the pH or the ionic strength
environment, should also block the attachment between tumoral cells or
pathogens and the host cells.
Most organism-host interactions are developed in a lipid raft environment
where clusters of receptors and sugar epitopes are produced. This is why, for
the development of preventive or therapeutic saccharide therapies, the "multi-
valent saccharides" approach should be applied (Schengrund 2003). Non-toxic
carriers of multivalent saccharides, such as dendrimers, can be used; however,
they should be designed specifically to each pathogen and their pathogen-neut-
ralizing ability needs to be tested (Schengrund 2003; Anne Imberty 2008). For
example, mouse influenza pneumonitis can be prevented by polyvalent sialic
acid dendrimers against certain virus subtypes (Landers, Cao et al. 2002). A re-
cently described lectin microarray technique may be useful in characterizing the
organisms’ glycomes (Hsu, Pilobello et al. 2006). Lipid raft domains are impor-
tant not only for cell activation but also for cell-cell interaction and the organisms’
interactions. In this GM1 ganglioside-enriched environment, signaling proteins
are organized, and many microbes use lipid rafts as gateways for invasion or in-
teraction with eukaryotic cells (Manes, del Real et al. 2003; Stuart, Webley et al.
2003; Zaas, Duncan et al. 2005; Blanco 2008). Even immune cell interaction
happens through the immunological synapses that are located in lipid raft do-
mains (Monks, Freiberg et al. 1998; Saito and Yokosuka 2006).
An interesting and encouraging finding is that the adherence in vitro of
enteropathogenic bacteria to epithelial cells is abrogated by prebiotic
galactooligosaccharides (Shoaf, Mulvey et al. 2006), and peptides that recognize
hyaluronic acid prevent wound infections by staphylococcal bacteria in a mouse
model of infection (Zaleski, Kolodka et al. 2006). Using a sialyltransferase
inhibitor in a mouse model, the pulmonary metastasis of a mouse colon
adenocarcinoma was blocked, probably through inhibition of the tumor cells-
platelets interaction because of a reduction in tumor sialic acid residues (Kijima-
Suda, Miyamoto et al. 1986; Kijima-Suda, Miyazawa et al. 1988). Another sialic
acid incorporation inhibitor also was able to inhibit hepatic metastases in a
mouse model (Wagner, Thomas et al. 1990). And recently heptyl α-D-mannose
–high affinity ligand of the FimH type 1 pili from uropathogenic Escherichia coli-
has been shown to inhibit biofilm formation, bacterial adhesion and invasion of
host cells (Wellens, Garofalo et al. 2008). These data encourage the field of

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prophylactic and therapeutic drug development based on saccharide moieties
modification or recognition.
However, a warning: we must be very careful manipulating saccharide
interactions and always keep in mind that they will determine the ability of
organisms and cells to interact, so, in changing saccharides, we can create new
repertoires of possible interactions and also change species-specificities, create
organisms that can be highly deleterious for different hosts, or interfere with host
immune cell-cell interactions. In fact, the glycosylation levels in the organism,
per se, are critical for interactions to proceed. For example, in elderly humans
augmented glycosylation of critical proteins may cause poor activation of their
immune cells. T cells from aging mice also show defects in activation correlated
with hyperglycosylation patterns; once the modified glycoproteins are
enzymatically corrected, T cell activation is restored (Sadighi Akha and Miller
2005; Sadighi Akha, Berger et al. 2006). Also, the humoral immune response is
impaired in transgenic mice that overexpress O-linked glycans on T cell
membranes because the T-B cell interaction is affected (Tsuboi and Fukuda
1998). Even at the level of transcription regulation in the T and B lymphocyte
activation, the O-glycosylation of NFAT and NFκB is required for transcription
factor translocation into the nuclei and for the induction of IL-2 cytokine
production, as was recently described (Golks, Tran et al. 2007). On the other
hand, excessive deglycosylation can also be deleterious—in fact, deglycosylation
of serum IgA seems to be related to IgA nephropathy, the enhanced attachment
of IgA to mesangial cells, and the induction of apoptosis and proliferation
reduction in these cells (Amore, Cirina et al. 2001; Gao, Xu et al. 2007).
Moreover, in autoimmunity process development, saccharide epitope recognition
may have an important role (Buzás, György et al. 2006). So it is clear that the
state of glycosylation is delicately balanced in nature, and is not straightforward
to manipulate.
Therapies with saccharides also may have a detrimental effect, interfering
with required immune system interactions of innate or adaptive mechanisms,
such as the undesired effect that is produced by glucuronoxylomannan-derived
saccharide from the capsule of the Cryptococcus neoformans fungus. This
saccharide is produced during C. neoformans infections and interferes with
surfactant protein D recognition and agglutination of acapsular opportunistic
pathogens, enhancing the virulence potential of the fungus and probably of other
pathogens in vivo (van de Wetering, Coenjaerts et al. 2004). In fact,
Pseudomonas aeruginosa is opsonized by the surfactant protein D, and this
enhances its phagocytosis and destruction by alveolar macrophages (Restrepo,
Dong et al. 1999). Another example: in vitro studies have demonstrated that
saccharide residues in the C1 inhibitor that recognize LPS can prevent septic
shock. This interaction inhibits up-regulation of TNFα production (Liu, Cramer et
al. 2005), so exogenously added saccharides in this particular case can interfere
with an inherent protective pathway, and that could lead to septic shock.
Nonetheless, certain polysaccharides have robust immune-modulator properties

Luz P. Blanco Ph.D. (March, 2009)

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and can be used as therapeutic agents (Cisneros, Gibson et al. 1996; Tzianabos
2000; Balachandran, Pugh et al. 2006). The overall conclusion is that
glycosylation is a clue to interactions between organisms, and great caution is
advisable in its manipulation.
Overall in this work, a novel hypothesis is presented regarding both the
degree to which organisms’ interactions are prearranged and the importance of
saccharide epitopes in the molecular mechanism of this prearrangement.

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 Acknowledgments
I would like to emphasize that this theory is the result of my experiences as a
scientist and that I have created it thanks to the constant support and help of my
husband. Thus, I would like to dedicate this theory to my husband, Victor A.
Aguero. I would also like to thank all the people who have touched my life: thank
you for being there for me because each of you has inspired me in some way
and my special thanks to Pat Gold and Shraddha Nigavekar for their insightful
editorial contributions and support.

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 14

Figure 1: Diagram depicting the organisms’ prearranged recognition

theory (OPRT) in a simplified view. Type I organisms are not opsonized nor
are they able to express a host-specific receptor; thus, type I organisms are not
able to interact with that specific host-organism and they will go unnoticed.
Examples of type I organisms for the human host-organism are the microbes
that affect species other than humans. Host-specific opsonins recognize type II
organisms or type II organisms directly express host-specific receptors. These
type II organisms’ characteristics allow interaction with that specific host.
Tumoral host cells express additional envelope receptors mimicking the host
opsonins and host-specific receptors, which molecularly explains their higher
promiscuity or higher ability to interact with each other and normal cells better
than normal cells.

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 15

Table 1: Saccharides involved in microbe- or toxin-host interactions.

Microbe or toxin/tissue Process or molecules involved Reference

cell interaction
Acanthamoeba keratitis/
corneal epithelial cells
Actinomyces naeslundii/
colonizing oral epithelium
Arcanobacterium
pyogenes/ adhesion to
host cells
Bacteria (Yersinia and
Mycobacterium)/ infection
of nematodes
Burkholderia cepacia/
human airway explants
Candida albicans/ model
of haematogenously
disseminated candidiasis
in mice
Candida albicans/ host
epithelial and innate
immune cells
Candida glabrata/ human
epithelial cells
Cry toxin from Bacillus
thuringiensis/ intoxication
of target nematode cells
Filovirus/ entry into
human macrophages
Helicobacter pylori/
colonization of transgenic
A mannose-binding lectin from (Yang, Cao et al.
the parasite is involved in
interaction with host cells
Saccharides in gangliosides
are recognized by the
pathogen
Bacterial neuraminidase
involved in host cell adhesion 2002)
SFR-3 expressed in
nematodes' secretory cells
plays a role in surface
glycoconjugates composition
Dextran and xylitol inhibit
adherence to human airway
transplant
Fungal glucanase adhesin
has a role in hyphal
morphogenesis, adherence to
plastic, and pathogenesis
Fungal O- and N-glycosylation
required for interactions with
mannose-binding receptor
and TLR
Fungal lectin involved in
adherence
Saccharide biosynthesis of
pathways related with
gangliosides in nematodes
are required for toxin
sensitivity
Entry into human
macrophages is promoted by
C-type lectin specific for
galactose and N-
acetylgalactosamine
Saccharides expressed in
porcine milk proteins inhibit
1997; Cao,
Jefferson et al.
1998; Garate,
Marchant et al.
2006)
(Brennan, Cisar et
al. 1984; Brennan,
Joralmon et al.
1987)
(Jost, Songer et al.
(Cipollo, Awad et al.
2004; Höflich,
Berninsone et al.
2004)
(Sajjan, Moreira et
al. 2004)
(Sandini, La Valle et
al. 2007)
(Munro, Bates et al.
2005; Bates,
Hughes et al. 2006;
Netea, Gow et al.
2006)
(Cormack, Ghori et
al. 1999)
(Griffitts, Huffman et
al. 2003; Griffitts,
Haslam et al. 2005;
Barrows, Griffitts et
al. 2006)
(Takada, Fujioka et
al. 2004)
(Gustafsson,
Hultberg et al.

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mice
Helminth parasites and
tumor antigens/ human
dendritic cells
Pseudomonas
aeruginosa/ model
epithelial cells
Pseudomonas
aeruginosa/ colonization
of the respiratory tract
Streptococcus
pneumoniae/ colonization
of nasopharyngeal and
lung tissues
Streptococcus
pneumoniae/human
airway epithelial cells
Streptococcus
pneumoniae/ chinchilla
tracheal epithelium
Type I reovirus/ M cells
interaction
Yersinia pestis/ human
respiratory epithelial cell
lines
Luz P. Blanco Ph.D. (March, 2009)
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16
mice colonization 2006)
C-type lectin MGL recognizes (van Vliet, van
parasite and tumor antigen Liempt et al. 2005)
carbohydrates
MDCK mutants in saccharide (Apodaca, Bomsel
biosynthesis are protected et al. 1995)
from bacteria toxicity
Neuraminidase has a role in (Soong, Muir et al.
mucosal infection enhancing 2006)
biofilm formation
Bacteria express a surface (Blau, Portnoi et al.
lectin to recognize flamingo 2007)
cadherin receptor
Host species specificity (King, Hippe et al.
probably related with 2006)
deglycosylation of
glycoconjugates by bacterial
exoglycosidases
Lacto-N-neotetraose, (Tong, McIver et al.
asialoganglioside-GM1 inhibit 1999)
adherence but neuraminidase
enhances adherence
Virus recognizes (Helander, Silvey et
glycoconjugates containing al. 2003)
sialic acid in the apical
membrane of M cells
Modified disaccharides affect (Thomas, Hacking
bacterial adhesion et al. 2007)
 17

Table 2: Host glycoproteins involved in organisms’ interactions.

Glycoprotein and Microbe Process or molecules involved Reference

Collagen
Haemophilus ducreyi Collagen-binding NcaA outer (Fulcher, Cole et
membrane protein has a role in al. 2006)
infections that lead to chancroid
(genital ulcer disease)
Staphylococcus Adhesin with a role in (Arrecubieta, Lee
epidermidis establishment of biofilms in et al. 2007)
implant devices infections
Complement C3 factor
HIV Virus opsonization enhances (Bouhlal,
infection of dendritic cells and T Chomont et al.
cells via CR3 and DC-SIGN 2007)
receptors
Klebsiella pneumoniae Adherence and internalization of (de Astorza,
bacteria into airway epithelial Cortes et al.
cells is enhanced by 2004)
opsonization
Defensin
Haemophilus influenzae Interaction with epithelial cells is (Gorter, Oostrik
and Neisseria enhanced by opsonization et al. 2003)
meningitides
Extracellular matrix
Paracoccidioides Interaction with cells through a (Barbosa, Bao et
brasiliensis surface-associated al. 2006)
glyceraldehyde-3-phosphate
dehydrogenase
Factor H
Streptococcus Invasion of mouse lungs in vivo (Quin, Onwubiko
pneumoniae is promoted by host factor H that et al. 2007)
recognizes surface bacterium
PspP receptor
Fibronectin
Bartonella henselae and Pathogen recognition of (Dabo, Confer et
Pasteurella multocida fibronectin plays a role for al. 2005; Dabo,
interaction with host Confer et al.
2006)
Clostridium difficile Adherence to epithelial cells (Hennequin,
Janoir et al.
2003)
Salmonella typhimurium Adenosine induces polarized (Walia,
fibronectin secretion by epithelial Castaneda et al.
cells and both adenosine and 2004)
fibronectin enhance bacterial
attachment and invasion

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Staphylococcus aureus
Streptococcus
Streptococcus agalactiae
Streptococcus group A
Vibrio vulnificus
Yersinia
pseudotuberculosis
Glycosaminoglicans
Streptococcus
pneumoniae
Streptococcus uberis
Lactoferrin
HIV-1
Mucin
Clostridium difficile
Group A Streptococci
Helicobacter pylori
Lactobacillus johnsonii
Luz P. Blanco Ph.D. (March, 2009)
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18
Truncation of fibronectin binding (Grundmeier,
protein inhibits bacterium Hussain et al.
interaction with host cells 2004)
A surface collagen-like protein (Caswell,
Scl1 has a role in integrins
recognition in host cells Lukomska et al.
2007)
FbsA (fibronectin receptor) (Schubert,
enhances adherence to human Zakikhany et al.
epithelial cells and to human 2004;
brain microvascular endothelial Tenenbaum,
cells Bloier et al. 2005)
Fibronectin binding gene prtF2 is (Gorton, Norton
associated with enhanced et al. 2005)
bacterial internalization
Outer membrane OmpU has a (Goo, Lee et al.
role in microbe pathogenesis 2006)
YadA recognition of fibronectin is (Heise and
determinant of their ability to Dersch 2006)
infect human cells
Attachment to nasopharyngeal (Tonnaer,
epithelial cells mediated by Hafmans et al.
glycosaminoglycans 2006)
The adherence and (Almeida, Luther
internalization of the bovine et al. 2003)
mastitis-associated bacteria is
enhanced by host
glycosaminoglicans
Together with natural antibodies (Saidi, Eslaphazir
enhances adsorption on et al. 2006)
epithelial cells and dendritic cells
Flagellar proteins FliC and FliD (Tasteyre, Barc
play a role in adherence and gut et al. 2001)
colonization in mice
Mucin and human pharyngeal (Ryan, Pancholi
cells are recognized through et al. 2001)
receptors containing sialic acid
Co-localizes with MUC5AC in (Van den Brink,
human stomach Tytgat et al.
2000)
Bacterial surface-associated (Granato,
elongation factor Tu mediates Bergonzelli et al.
attachment to human intestinal 2004)
 19

cells and mucins

Lactobacillus reuteri A prevalent gut microbe, (Miyoshi, Okada
expresses a surface protein et al. 2006)
MapA with a role in mucus and
human epithelial Caco-2 cells
recognition
Pseudomonas Mucin is recognized by adhesin- (Ramphal, Arora
aeruginosa flagellar system et al. 1996)
Staphylococcus aureus Bacterial surface proteins (Shuter, Hatcher
recognize saccharide moieties in et al. 1996)
mucin, possible role in nasal
colonization
Vibrio cholerae Adherence to mucus and villus (Yamamoto and
surface in human small intestine Yokota 1988)
Salivary CD14
Actinobacillus Invasion of human oral epithelial (Takayama,
actinomycetemcomitans cells and interleukin-8 production Satoh et al.
is enhanced 2003)
Tamm-Horsfall
Pseudomonas Urine glycoprotein enhances in (Harjai, Mittal et
aeruginosa vivo urinary infections produced al. 2005)
in mice
Thrombospondin-1
Gram-positive pathogens Adherence to host cells is (Rennemeier,
promoted through recognition of Hammerschmidt
peptidoglycan et al. 2007)
Vitronectin
Pseudomonas Enhances infection via (Leroy-Dudal,
aeruginosa integrins in airway epithelial Gagniere et al.
cells 2004)
Low-molecular-weight
human salivary mucin
Some oral bacteria Bridges interaction of bacteria (Prakobphol,
and neutrophiles Tangemann et al.
1999)
Streptococcus Surface glycoproteins GspB and (Takamatsu,
Hsa recognize mucin and sIgA Bensing et al.
2006)

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 20

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