Download The surface–mosaic model in host– parasite relationships

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TRENDS in Parasitology
Vol.20 No.11 November 2004
The surface–mosaic model in host–
parasite relationships
J. Santiago Mejia1, Fernando Moreno2, Carlos Muskus3, Iván D. Vélez3 and
Richard G. Titus1
1
Department of Microbiology, Immunology and Pathology, Colorado State University,
Central receiving 200 W. Lake St. Campus Delivery 1619, CO 80523, USA
2
Instituto de Ciencias de la Salud (CES), Calle 10a No. 22–04, Medellı́n, Colombia
3
Programa de Estudio y Control de Enfermedades Tropicales (PECET), Universidad de Antioquia,
Calle 62 No. 52–25, Medellı́n, Colombia
The dynamics of protein adsorption to a microbial
surface could be of significance in host–parasite relationships because non-defense proteins might interfere with
the binding of defense proteins. A surface mosaic of
defense and non-defense proteins formed on the
microbial surface could activate one of the tissue
reactivity programs via a binary code (help or silence)
generated by the adsorbed proteins. Understanding the
mechanisms of the mosaic formation and its evolution
might help to identify evasion mechanisms used by
virulent microorganisms. This also provides a conceptual framework to design new strategies to control the
infectious diseases they cause.
The nonspecific interaction between proteins and the
surface of materials used in the manufacture of various
medical devices (including implants, prosthesis, dialysis
membranes and drug delivery systems) has been the focus
of intense research in the field of biomedical engineering
[1–4]. The analysis of plasma proteins adsorbed to the
surface materials indicates that minor differences in
charge density, hydrophobicity or surface-exposed functional groups account for significant changes in the profile
of adsorbed proteins [3,4]. This is of great significance
because it is clear that the nature of the adsorbed proteins
have an effect on subsequent events around the coated
surface [1,5]. The information generated about how the
body isolates, rejects or integrates an artificial material
could provide clues into similar events that occur when the
body is exposed to the surface of a microorganism. This
review describes a model that addresses the potential
significance of protein adsorption to the surface of
microorganisms in the early phase of host–parasite
relationships.
The adsorption process
The adsorption of proteins to a surface is a complex
process driven by the free energy generated at the liquid–
solid interface and is characterized by a fast initial phase
of adsorption (seconds) followed by a slower one that tends
to saturate the surface until an equilibrium is reached [6].
Corresponding author: J. Santiago Mejia ([email protected]).
Available online 26 August 2004
Different forces are at play during this process, including:
(i) the affinity of the proteins for the surface; (ii) the
intermolecular attractions and repulsion forces of proteins; (iii) the lateral diffusion of the adsorbed proteins;
and (iv) the conformational modification that the proteins
could undergo upon adsorption [7–10]. Several physicochemical characteristics of a surface (i.e. hydrophobicity,
electrical charge, chemical reactivity and topology) have
an effect on the adsorption process. Of these, the degree of
hydrophobicity seems to be the major determinant of both
the amount and type of proteins that are adsorbed [3,4,10]
due in part to the higher degree of free energy generated at
the interface. Accordingly, covering surfaces with amphiphilic molecules has been shown to reduce significantly
the amount of proteins adsorbed to the surface [11].
When the surface is in contact with body fluids, a
complex protein layer or mosaic forms at the interface.
Considering the diversity of proteins present in a tissue,
that each one of them might adsorb to a surface via
different domains and that there could be different degrees
of conformational modification of the protein structure
upon adsorption, the mosaic must be a structure of
extraordinary complexity. Furthermore, the mosaic could
evolve as a result of protein exchange (Vroman effect), a
phenomenon whereby initially adsorbed proteins can
desorb to be replaced by other proteins with stronger
attractive interaction for the surface [12].
Defense and non-defense proteins
Any host protein can be part of a mosaic as long as it has
access to the exposed surface and is able to compete with
other proteins, especially those present at the highest
concentrations in tissues. This has been extensively studied
with plasma proteins, where the dominant role played by
the most abundant proteins (albumin, fibrinogen, immunoglobulins and lipoproteins) has been demonstrated [3,4].
Some of the plasma proteins are members of defense
systems (e.g. complement, coagulation and immune),
whereas others are members of non-defense systems in
charge of transporting, for example, lipids, hormones,
vitamins and metals (albumin, lipoproteins and transferrin). This functional separation is crucial because nondefense proteins could interfere with the binding of defense
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Opinion
TRENDS in Parasitology
proteins, making the ratio of defense to non-defense proteins
(DND ratio) an important element in the outcome of the
interaction between a surface and a particular tissue
compartment (intracellular, extracellular or mucosal).
The code
The competitive nature of protein adsorption to a surface
provides a scenario in which non-defense proteins generate a
silence code on the surface, isolating it from the defense
systems and minimizing the tissue reactivity against it.
However, by providing a help code, the defense proteins can
focus the activation of the defense systems (contact, coagulation, complement, immune and vascular) on the surface.
The surface–mosaic model
There has been a great deal of discussion as to whether the
initial events in host–parasite relationships involve
danger signals generated by the tissues, or recognition of
molecular patterns present on the microorganism [13–15].
One problem with these models is that they have
neglected the participation of the non-defense proteins
that are abundantly expressed in every tissue compartment. We postulate that defense and non-defense proteins
compete for binding to the injury-associated surface. The
spatial and temporal character of the binary code (help or
silence) generated by the defense and non-defense
proteins, respectively, defines the main tissue reactivity
programs (isolation, containment, rejection or integration)
that are triggered around the surface (Figure 1). The
significance of this feature in a host–parasite relationship
is that non-defense proteins might interfere with the
recognition of the microorganism by the innate or adaptive
defense mechanisms of the body, in effect generating a
period during which isolation and not recognition could be
the initial outcome of the interaction.
Implications of the surface–mosaic model
The DND ratio as a modulator of the mosaic composition
In a healthy non-injured organism, the DND ratio of the
main tissue compartments (mucosal, intracellular and
extracellular) can be anticipated to be set in a silence mode
(low DND ratio) and that a shift towards a proinflammatory mode (high DND ratio) occurs as a response to an
injury. This shift occurs because several events take
place: (i) an increase in vascular permeability allows
high molecular weight proteins of the proinflammatory
systems to leak into the extracellular fluid [16]; (ii) the
activation of cells at the injury site induces the production
of cytokines that in turn promote the expression of
various defense genes [17]; and (iii) during the systemic
acute phase reaction concurrent with the increase in
synthesis of defense proteins, there is a decrease in some
of the most abundant non-defense plasma proteins
(albumin and transferrin) [18].
The mosaic as a danger-sensing structure
Defining the degree of danger associated with a suddenly
exposed surface during an injury is central to tissue homeostasis because an excessive response is as detrimental in
evolutionary fitness as the lack of a response. When an
injury-associated surface is exposed to an environment
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Vol.20 No.11 November 2004
509
with a low DND ratio, the main tissue reactivity program
is isolation. However, if the mostly non-defense mosaic is
modified by proteases associated with the underlying
surface, danger signals (peptides) might diffuse into the
surrounding tissues, thus changing the character of the
tissue reactivity program. In this regard, the surface
mosaic could behave as a proteolysis sensor and thus
represent an additional system for pathogen sensing [19].
The orientation paradox
Because the code generated by a defense protein upon
adsorption to a surface might depend on the appropriate
orientation towards the triggering surface, the defense
protein might behave as a non-defense protein if it adsorbs
to a surface with the inappropriate orientation. This
possibility seems to operate with immunoglobulins in that
they are able to adsorb to a variety of artificial materials in
a process that is not dependent on the specificity of the
antigen-binding site [3,4]. This non-specific interaction of
immunoglobulins with surfaces could provide an alternative explanation to the anti-inflammatory effect that
preparations of human immunoglobulins have in a variety
DND ratio
Low
High
Intermediate
Mosaicforming
proteins
Mosaic
Parasite
surface
Tissue
reactivity
programs
Isolation,
containment,
rejection and
integration
Help
Silence
Code
TRENDS in Parasitology
Figure 1. Elements of the surface-mosaic model. (i) The ratio of defense to nondefense proteins (DND ratio); (ii) pool of mosaic-forming proteins; (iii) mosaic;
(iv) parasite surface; (v) code and (vi) tissue reactivity programs. The
adsorption of defense proteins (red) or non-defense proteins (blue) to the
surface of a parasite might generate a protein mosaic that conveys the code
(help or silence) required to implement one of the tissue reactivity programs.
Each tissue compartment: mucosal (squares), extracellular (spheres) or
intracellular (cylinders) have a particular DND ratio. In those compartments
with low DND ratio, the abundant non-defense proteins generate a silence
code that isolates the surface. When the limits between compartments is
ruptured, as frequently occurs in an injury, a code conflict might ensue
because of two events: (i) elements of the mosaic generated in one
compartment might remain in a different compartment providing an
inadequate code; and (ii) the sudden influx of proteins from one compartment
into another shifts the DND ratio modifying its coding potential. The ability of
some microorganisms to recruit mosaics rich in non-defense proteins or modify the
local DND ratio might represent a general mechanism of evasion of the host
defense mechanisms.
510
Opinion
TRENDS in Parasitology
of human inflammatory diseases [20]. The abundance of
receptors for a variety of host proteins (defense and nondefense) in virulent microorganisms [21,22] emphasizes
the significance of this evasion mechanism in host–
parasite relationships.
The dilemma of isolation versus recognition
The ability of mucins to isolate surfaces (microbial and
otherwise) is one of the main defense mechanisms at
mucosal surfaces [23,24], and is very effective as long as
the covered surface remains in the luminal side of the
mucosa. The silence code conveyed by the mucins when a
mucin-covered microorganism reaches the underlying
tissues could represent an important evasion mechanism
in the immunobiology of microorganisms that first
colonize mucosal surfaces before invading and disseminating [25,26]. In order to invade the tissues, the virulent
microorganism implements one of a variety of mechanisms
to breach the structural elements (plasma membranes and
cytoskeletons) which define the compartments. A code
conflict might be generated by such disruption because
each compartment has different DND ratios. When cells
with a very high concentration of non-defense proteins,
such as hemoglobin-rich erythrocytes, are ruptured, the
extracellular DND ratio is suddenly shifted toward a
silence code, a phenomena that might explain why the
expression of hemolysins is associated with virulence [27].
Role of the surface mosaic in defense evasion
mechanisms of virulent microorganisms
The expression of receptors for non-defense proteins such
as albumin [28,29], Hb [30] or lipoproteins [31] by virulent
microorganisms could represent an evasion mechanism
because they tend to recruit a mosaic enriched in nondefense proteins. The expression of hydrophobic surfaces,
as has been shown in virulent bacteria [32], fungi [33]
and helminths [34], might represent a similar evasion
mechanism because some of the most abundant nondefense proteins (albumin, lipoproteins) have affinity for
hydrophobic compounds. For all of these microorganisms,
the stability of the surface mosaic is anticipated to be
crucial because the surface mosaic tends to perpetuate
isolation from host defenses. However, a stable surfacemosaic might interfere with molecular interactions that
are essential for the survival of some microorganisms with
complex life cycles such as Leishmania, Plasmodium or
Schistosoma. Perhaps the expression of amphiphilic
compounds [35–37] or proteases [38,39] on the surface of
some of these parasites represent mechanisms to minimize the potential isolating effect of the surface mosaic. In
some of the most complex parasites, such as Plasmodium
sporozoites [40] or adult stages of Schistosoma japonicum
[41], the same effect might be accomplished with a
complex mechanism of surface renewal.
The mosaic as a potential target of protective immunity
The pathogens transmitted by hematophagous arthropods
represent a special group of diseases because proteins
from the invertebrate host might form a mosaic on the
surface of the infective stages of the microorganism, thus
raising two important considerations for the
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Vol.20 No.11 November 2004
immunobiology of these diseases: (i) the invertebrate
mosaic might initially interfere with recognition of the
parasite by the vertebrate host immune system; and (ii)
the invertebrate mosaic itself might be a target of
protective immunity against these microorganisms.
The saliva of hematophagous arthropods has been shown
to interfere with the functionality of many defense systems
of the vertebrate hosts [42–44], and to increase the
infectivity of several microorganisms [45–48]. Accordingly,
neutralization of the disease-promoting molecules present
in arthropod saliva is now being used as an approach to
develop vaccines against arthropod-borne diseases [49,50].
It remains to be studied which salivary components tend to
adsorb to the surface of these microorganisms because they
could represent yet another target for the development of
vaccines against diseases such as malaria, leishmaniasis,
Lyme borreliosis or dengue fever.
Concluding remarks
The role that non-defense proteins play in the biology of
artificial surface rejection or integration has been studied
extensively. It is necessary to examine whether they play a
similar biological role in host–parasite relationships
because it might help our understanding of the evasion
mechanisms used by virulent microorganisms in their
interaction with vertebrate and invertebrate hosts. This
might also provide a conceptual framework to design new
strategies to control the infectious diseases they cause.
Acknowledgements
We are grateful to Carolina Barillas-Mury, Sara Robledo and Juan F.
Alzate for helpful suggestions, and to Barry J. Beaty, Stephen M.
Beverley, Salvatore J. Turco, Jose M. Ribeiro, Clotilde K. Carlow, William
C. Black IV, Francisco J. Diaz, Jeannette V. Bishop, Keith Nelson,
Gustavo G. Carrio and Juan F. Granada for critical review of the
manuscript. In addition, J.S.M. acknowledges Claudia Bernal. This work
was supported by funds from: Instituto de Ciencias de la Salud; Programa
de Estudio y Control de Enfermedaded Tropicales; Universidad de
Antioquia; and by National Institutes of Health grant no. AI27511.
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