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Matrix Biology 18 Ž1999.

211᎐223

Mini-review

Role of fibronectin-binding MSCRAMMs in bacterial


adherence and entry into mammalian cells

Danny Joha,1, Elisabeth R. Wanna , Bernd Kreikemeyer a,2 , Pietro Spezialeb,


Magnus Hook¨¨ a,U
a
Center for Extracellular Matrix Biology, Albert B. Alkek Institute of Biosciences and Technology, Texas A & M Uni¨ ersity System
Health Science Center, 2121 West Holcombe Boule¨ ard, Houston, TX 77030, USA
b
Department of Biochemistry, Uni¨ ersity of Pa¨ ia, 27100 Pa¨ ia, Italy

Received 11 February 1999; accepted 16 February 1999

Abstract

Most bacterial infections are initiated by the adherence of microorganisms to host tissues. This process involves the
interaction of specific bacterial surface structures, called adhesins, with host components. In this review, we discuss a group of
microbial adhesins known as Microbial Surface Components Recognizing Adhesive Matrix Molecules ŽMSCRAMMs. which
recognize and bind FN. The interaction of bacteria with FN is believed to contribute significantly to the virulence of a number
of microorganisms, including staphylococci and streptococci. Several FN-binding MSCRAMMs of staphylococci and strepto-
cocci exhibit a similar structural organization and mechanism of ligand recognition. The ligand-binding domain consists of
tandem repeats of a ; 45 amino acid long unit which bind to the 29-kDa N-terminal region of FN. The binding mechanism is
unusual in that the repeat units are unstructured and appear to undergo a conformational change upon ligand binding. Apart
from supporting bacterial adherence, FN is also involved in bacterial entry into non-phagocytic mammalian cells. A sandwich
model has been proposed in which FN forms a molecular bridge between MSCRAMMs on the bacterial surface and integrins
on the host cell. However, the precise mechanism of bacterial invasion and the roles of FN and integrins in this process have
yet to be fully elucidated. 䊚 1999 Elsevier Science B.V.rInternational Society of Matrix Biology. All rights reserved.

Keywords: Extracellular matrix; FN; MSCRAMM; Bacterial adherence; Bacterial invasion

Abbre¨ iations: ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; BHK, baby hamster kidney; FI, type I module in
FN; FN-N29, the N-terminal 29-kDa fragment of FN; GST, glutathione-S-transferase; MSCRAMM, microbial surface component recognizing
adhesive matrix molecules
U
Corresponding author. Tel.: q1-713-677-7551; fax: q1-713-677-7576.
E-mail address: mhook@ibt.tamu.edu ŽM. Hook ¨¨ .
1
Current address: Xenogen Corporation, 860 Atlantic Avenue, Alameda, CA 94501, USA
2
Current address: Department of Medical Microbiology and Immunology, University of Ulm, Robert-Koch-Strabe 8, D-89081, Ulm,
Germany

0945-053Xr99r$ - see front matter 䊚 1999 Elsevier Science B.V.rInternational Society of Matrix Biology. All rights reserved.
PII: S 0 9 4 5 - 0 5 3 X Ž 9 9 . 0 0 0 2 5 - 6
212 D. Joh et al. r Matrix Biology 18 (1999) 211᎐223

1. Introduction molecules, including fibrin, heparin and collagen, as


well as for a number of integrins, including ␣4b1,
␣ 5b1, ␣ IIbb3 and ␣ vb3.
The process of microbial infection involves a com-
plex series of events that can result in host tissue
malfunction or destruction. The adherence of the
microorganisms to host tissues represents a critical 2. FN-binding MSCRAMMs from staphylococci and
first step in this process. Non-adherent bacteria can streptococci
be readily eliminated from the body by such cleansing
mechanisms as peristalsis and excretion. Bacteria that
Staphylococci and streptococci are clinically impor-
adhere to host tissues may remain extracellular or
tant gram-positive bacteria that are capable of caus-
may be internalized into an intracellular compart-
ing a wide variety of diseases in humans and animals.
ment. Cellular invasion enables the bacteria to escape
The specific binding of FN to Staphylococcus aureus
host defense mechanisms, persist in the host and
was first reported by Kuusela Ž1978.. Subsequently,
invade tissues surrounding the initial site of coloniza-
two FN-binding proteins ŽFnbpA and B. and the
tion. As a result of its critical role in the infection
corresponding genes were isolated and characterized
process, bacterial adherence to host tissues represents
a potential target for the development of new antimi-
¨
ŽFlock et al., 1987; Froman ¨ et al.,
et al., 1987; Signas
crobial agents. Agents that can block adherence, such
¨
1989; Jonsson et al., 1991.. Many staphylococci and
streptococci have since been shown to bind FN. At
as specific antibodies, may prove to be effective in
least a dozen FN-binding MSCRAMMs have been
combating infectious disease. For example, active im-
identified and their corresponding genes have been
munization of mice with a recombinant fragment of
sequenced ŽTable 1.. These MSCRAMMs exhibit
the collagen-binding protein from Staphylococcus au- structural features typical of other cell wall-anchored
reus, or passive immunization with antibodies against proteins of gram-positive bacteria. At the N-terminus
this protein, protect against sepsis-induced death is a putative signal sequence involved in transport of
ŽNilsson et al., 1998.. Also, mice actively immunized
the proteins through the cytoplasmic membrane. The
with a recombinant decorin-binding protein from C-terminus is composed of: Ži. a conserved LPXTG
Borrelia burgdorferi are immune to challenge in a motif which is required for accurate sorting and an-
model of lyme borreliosis ŽHanson et al., 1998.. choring of the proteins to the cell wall; Žii. a hy-
The adherence of bacteria involves bacterial sur- drophobic membrane-spanning region; and Žiii. a tail
face components, called adhesins, that recognize and of positively-charged residues which remain in the
bind to host extracellular matrix ŽECM. and cell cytoplasm. Once the protein has been transported to
surface molecules. Host ECM components that are the cell surface, the LPXTG motif is cleaved between
known to support bacterial adherence include fi- the Thr and Gly residues. The carboxyl group of the
bronectin ŽFN., collagen, fibrinogenrfibrin, elastin, Thr residue is then linked to a free amino group of a
vitronectin, laminin, as well as decorin and heparan branch peptide within the peptidoglycan cell wall
sulfate-containing proteoglycans. The subfamily of ŽSchneewind et al., 1995; Ton-Hat et al., 1997.. The
bacterial adhesins that bind to ECM molecules are enzyme responsible for catalyzing these reactions has
collectively known as Microbial Surface Compo- not been identified but has been named ‘sortase’. A
nents Recognizing Adhesive Matrix Molecules proline-rich stretch of residues, thought to span the
ŽMSCRAMMs. ŽPatti and Hook, ¨¨ 1994; Patti et al., peptidoglycan layer of the cell wall, is commonly
1994.. Although a number of microbes have been found on the N-terminal side of the LPXTG motif in
shown to bind host ECM components, the these proteins.
MSCRAMMs responsible for these interactions have, The prototype FN-binding MSCRAMM, FnbpA
in most cases, not been identified or characterized. Žalso called FnbA. from S. aureus, has a molecular
However, a group of related FN-binding MSCRAMMs mass of approximately 100 kDa. FN binds primarily to
from gram-positive bacteria has been analyzed in some a region adjacent to the proline-rich wall-spanning
detail. region of the MSCRAMM ŽFig. 1A.. This binding
In this review, we will discuss the bacterial region is composed of a ; 45 amino acid long unit
MSCRAMMs that interact with FN. FN is a 440-kDa which is tandemly repeated three times ŽD1, D2, D3
mosaic glycoprotein which is present in soluble and units., followed by a single incomplete repeat unit
matrix forms in various body fluids and tissues. It is ŽD4 unit.. A fifth unit ŽDu. is located approximately
composed of three types of modules, presented in two 100 amino acid residues N-terminal of D1. FN can
similar disulfide-linked subunits, and contains discrete bind to each of the D units, as demonstrated using
binding sites for a variety of other extracellular synthetic peptide mimics of the sequences. Amino
D. Joh et al. r Matrix Biology 18 (1999) 211᎐223 213

Table 1
FN-binding MSCRAMMs from staphylococci and streptococci.

Species Protein References

Staphylococcus spp.
S. aureus FnbpA & FnbpB ¨ et al. Ž1989., Jonsson
Signas ¨ et al. Ž1991.

Streptococcus spp.
S. saprophyticus Hemaglutinin Hell et al. Ž1998.

S. pyogenes SfbIrProtein F1 Hanski Caparon Ž1992., Talay et al. Ž1993.


SfbII Kreikemeyer et al. Ž1995.
Protein F2 Jaffe et al. Ž1996.
Opacity factor ŽSof 22. Rakonjac et al. Ž1995.
Glyderaldehyde-3- Pancholi and Fischetti Ž1992.
phosphate dehydrogenase
FBP54 Courtney et al. Ž1994.
M1 Cue et al. Ž1998.

S. dysgalactiae FnbA &FnbB Lindgren et al. Ž1992.

S. equi FNZ Lindmark et al. Ž1996.

S. equisimilis FnB Lindgren et al. Ž1994.

S. mitis Sugano et al. Ž1997.

S. gordonii McNab et al. Ž1994, 1996.

S. pneumoniae van der Flier et al. Ž1995.

S. agalactiae Zabel et al. Ž1996.

S. milleri Willcox et al. Ž1995.

S. anginosus Willcox et al. Ž1995.

Group G streptococci GfbA Kline et al. Ž1996.

acid sequence comparison of the different D units ferent MSCRAMMs may operate by a similar mecha-
shows that the D1᎐D4 units are highly conserved nism and may bind to similar or overlapping regions
whereas the Du unit is more divergent ŽFig. 1A.. in FN. A kinetic analysis of the interaction between
The overall arrangement of the ligand-binding re- the recombinant binding domains and intact FN, us-
gion in FnbpA is also found in the staphylococcal ing BIAcore analysis, indicated that the K d ranged
protein FnbpB and the streptococcal proteins from 3 to 16 nM ŽHouse-Pompeo et al., 1996.. In
SfbIrprotein F1, SfbII, Sof22, protein F2, FnbA, addition, extensive analysis of the residues involved in
FnbB, and FNZ, albeit with slight variations ŽFig. 1A.. ligand binding suggested that a conserved core se-
Furthermore, the sequences of the tandemly repeated quence, EDŽTrS.Ž9 or 10 Xs.GGŽ3 or 4 Xs.ŽIrV.DF,
FN-binding units are quite highly conserved among is important for the ligand-binding activity of these
these proteins ŽFig. 1B. ŽHanski and Caparon, 1992; units ŽMcGavin et al., 1991, 1993.. In FNZ, the FN-
McGavin et al., 1993; Lindgren et al., 1994; Talay et binding MSCRAMM of Streptococcus equi subspp.
al., 1994; Kreikemeyer et al., 1995; Jaffe et al., 1996; zooepidemicus, a strong ligand-binding activity was
Ozeri et al., 1996.. In a comparative study, we ana- found associated with the sequence LAGESGET
lyzed the inhibitory activities of recombinant proteins which is located between the first ŽR1. and second
derived from the ligand-binding sites of FnbpA of S. ŽR2. repeat units of the MSCRAMM ŽLindmark et
aureus, FnbA and FnbB of Streptococcus dysgalactiae, al., 1996.. This sequence is also present in the FN-
and SfbI of Streptococcus pyogenes ŽJoh et al., 1994.. binding sequence ŽUR or UFBD. located upstream of
Each of the polyhistidine-tagged proteins inhibited the tandem repeats in protein F1 of S. pyogenes Žsee
the interaction of FN with S. aureus, S. pyogenes and below. ŽOzeri et al., 1996..
S. dysgalactiae. The cross-inhibitory activities of these The primary binding site in FN for FnbpA of S.
recombinant FN-binding units suggest that the dif- aureus is located in the 29-kDa N-terminal proteolytic
214 D. Joh et al. r Matrix Biology 18 (1999) 211᎐223

Fig. 1. ŽA. Domain organization of FnbpA from Staphylococcus aureus, the prototype of the FN-binding MSCRAMMs from staphylococci and
streptococci. S, signal peptide; A, non-repetitive region; ␦, two almost identical repeats of 30 amino acid residues with unknown function;
Du-D4, FN-binding units; W, cell wall-spanning region; M, cytoplasmic membrane-spanning region; C, positively-charged intracellular
residues. The cell wall-anchoring LPXTG motif is indicated between regions W and M. ŽB. Alignment of the amino acid sequences of the
ligand-binding units from FnbpA of S. aureus, and FnbA and FnbB of Streptococcus dysgalactiae. Conserved residues that have been
implicated as being important for FN binding are shown in bold face.

fragment of FN ŽFN-N29. ŽMosher and Proctor, 1980.. proteins, recognized the 4FI᎐5FI pair. Additional
This fragment is composed of five type I modules, binding to 2FI᎐3FI was observed for recombinant D1,
designated 1FI, 2FI, 3FI, 4FI and 5FI, each of which whereas recombinant D4 only bound to 2FI᎐3FI.
is folded tightly through hydrophobic packing and two Analysis of the FN-binding units from other
disulfide bonds ŽPotts and Campbell, 1994.. The MSCRAMMs revealed different binding patterns ŽJoh
repetitive nature of the binding sites in both FN and et al., 1998.. The B3 unit of S. dysgalactiae FnbB, for
the MSCRAMM represents a two-dimensional com- example, bound to 1FI᎐2FI and 2FI᎐3FI, whereas the
plexity in the interaction of these proteins. This raises A2 unit of S. dysgalactiae FnbA bound only to 4FI᎐5FI
several intriguing questions concerning the binding ŽJoh et al., 1998.. According to Huff et al. Ž1994., the
mechanism that investigators have attempted to an- stoichiometry of the interaction of FN-N29 with a
swer. Experiments with recombinant FN fragments, recombinant protein containing the D1᎐D3 units of
expressed in baculovirus-infected insect cells, sug- FnbpA was 1.9:1. However, the data regarding the
gested that deletion of any of the five FI modules specificity of the individual FI modules and the lig-
abolished the binding of the recombinant proteins to and-binding units should be interpreted with caution.
S. aureus ŽSottile et al., 1991.. Analysis of the interac- These experiments were performed using short re-
tion of FI modules with FnbpA fragments, using combinant proteins or synthetic peptides correspond-
fluorescence polarization and affinity chromatogra- ing to the MSCRAMM ligand-binding units or the FI
phy, revealed that the 4FI᎐5FI pair was the dominant module pairs. How the units and modules interact in
binding site for the D3 unit of this protein ŽHuff et the context of the full-length proteins may not be
al., 1994.. We recently confirmed these findings and directly inferred from experiments with truncated re-
further analyzed the binding patterns of the other D combinant proteins.
units ŽJoh et al., 1998.. Each of the full-length D units Other regions of FN may also interact with
ŽDu, D1, D2, and D3., expressed as GST fusion MSCRAMMs ŽKuusela et al., 1984, 1985; Bozzini et
D. Joh et al. r Matrix Biology 18 (1999) 211᎐223 215

al., 1992; Sakata et al., 1994.. Protein F1 from included in the assay. This antibody was shown to
S.pyogenes and GfbA from group G streptococci, for recognize an epitope that was formed in the
example, possess a FN-binding unit designated UR in MSCRAMM upon binding to FN. Subsequent epitope
addition to the repeat unit region ŽOzeri et al., 1996.. mapping experiments, using truncates of FnbA, re-
The binding site in FN for UR is located in the vealed that the epitope for 3A10 resided within Au,
40-kDa collagen-binding domain, which is adjacent to one of the FN-binding units of the MSCRAMM ŽFig.
the N-terminal 29-kDa region. The C-terminal hep- 1.. Furthermore, 3A10 enhanced, rather than inhib-
arin-binding domain of FN may also bind to the ited, the interaction between FN and the Au unit.
streptococcal and staphylococcal MSCRAMMs, al- The unexpected behavior of these antibodies has
though comparatively weakly ŽKuusela et al., 1984; provided invaluable clues as to how the MSCRAMMs
Bozzini et al., 1992.. The binding site for this domain interact with FN. It appears that the FN-binding
appears to lie outside the repeat units in these pro- repeat units of the MSCRAMMs have a largely unor-
teins ŽBozzini et al., 1992.. It is interesting to note ganized structure and only assume an ordered struc-
that the collagen- and heparin-binding domains of FN ture upon binding to FN. This hypothesis is supported
also contain FI module pairs. However, the by the results of biophysical studies of the
MSCRAMM binding sites in these domains have not MSCRAMM᎐FN interaction ŽHouse-Pompeo et al.,
yet been localized. 1996; Penkett et al., 1998.. For example, circular
dichroism spectroscopy of recombinant proteins cor-
responding to the ligand-binding domains of FnbpA,
3. Mechanism of FN-MSCRAMM interaction: insights FnbA, FnbB and SfbI has demonstrated that these
from immunological studies proteins lack a secondary structure and undergo a
structural change upon binding FN ŽHouse-Pompeo
Analysis of the interactions of polyclonal and et al., 1996.. Furthermore, gel permeation chromatog-
monoclonal antibodies with the FN-binding raphy indicated that the complex of recombinant
MSCRAMMs of staphylococci and streptococci has D1᎐D3 and FN-N29 was more compact than free
provided important insights into the mechanism of D1᎐D3 Žunpublished observations.. MAbs that react
ligand-MSCRAMM binding. Interestingly, it has been with ligand-induced binding sites ŽLIBS., such as
noted by several investigators that antibodies raised 3A10, appear to recognize a conformation of the
against the FN-binding units of FnbpA of S. aureus MSCRAMM induced upon binding to FN. The ability
do not effectively inhibit the binding of FN to the of 3A10 to enhance the MSCRAMM᎐ligand interac-
MSCRAMM ŽSchennings et al., 1993; Mamo et al., tion may be the consequence of the mAb stabilizing
1994, 1995.. In a recent study, sera were collected the MSCRAMM᎐FN complex. The binding mecha-
from more than 30 individuals who had a history of S. nism of 3A10 is reminiscent of some anti-␣ II b ␤ 3
aureus infection. The IgG fractions were isolated and integrin mAbs which have been reported to bind the
analyzed for reactivity with FnbpA ŽCasolini et al., integrin only when it is bound to fibrinogen and which
1998.. Essentially all of the IgG preparations reacted also enhance fibrinogen binding ŽFrelinger et al., 1990,
with the MSCRAMM, consistent with the presence of 1991.. Thus, these anti-MSCRAMM and anti-integrin
the gene encoding FnbpA in ) 90% of S. aureus antibodies both appear to bind to cell surface ‘recep-
clinical isolates ŽMinhas et al., 1995.. Epitope map- tors’ which undergo conformational changes upon
ping, using recombinant truncates of FnbpA, revealed ligand binding.
that the different IgG preparations reacted preferen- The presence of anti-LIBS antibodies in immunized
tially with the ligand-binding site ŽDu-D4., suggesting animals or infected humans is, perhaps, not surpris-
that this is the immunodominant region of the ing. When a FN-binding MSCRAMM is used as an
MSCRAMM. However, the IgG preparations did not immunogen, it is likely that the protein quickly inter-
effectively inhibit the binding of FN to the acts with plasma FN before the immune system has
MSCRAMM ŽCasolini et al., 1998.. Similarly, we have time to recognize the unoccupied form of the binding
found that antibodies raised against recombinant or site in the MSCRAMM. However, Sun et al. Ž1997. by
synthetic peptide forms of the FN-binding units failed immunizing with short subsegments of the FN-binding
to display any significant inhibitory activity. In fact, we units of FnbpA, were able to generate antibodies that
observed several monoclonal antibodies ŽmAbs., blocked the binding of the individual binding units to
raised against FnbpA of S. aureus and FnbA of S.dys- FN . The rationale behind this approach was that, as
galactiae, which actually enhanced the ligand-binding the FnbpA-derived peptides were too short to bind
activities of the MSCRAMMs ŽSpeziale et al., 1996, FN, antibodies raised against them should recognize
manuscript in preparation.. For example, one mAb, the binding units in their unoccupied form in the
3A10, was incapable of binding FnbA by itself and native protein and thus block the MSCRAMM᎐FN
only bound to the MSCRAMM if soluble FN was interaction. The success of this approach is consistent
216 D. Joh et al. r Matrix Biology 18 (1999) 211᎐223

with the idea that rapid binding of the MSCRAMM both within a particular species and between different
to plasma FN hampers the formation of inhibitory species. Recently, two separate FN-binding sites have
antibodies specific for the unoccupied binding site of been identified on the M. kansasii Ag85B homologue
the MSCRAMM. Inhibitory antibodies have also been which appear to be conserved in the Ag85 proteins
successfully raised in rabbits against SfbI of S. pyo- from this and other mycobacterial species ŽNaito et
genes ŽMolinari et al., 1997.. In this study, recombi- al., 1998.. Studies with synthetic peptides defined 11
nant SfbI fragments, containing the FN-binding re- residues as a minimum binding unit on Ag85B. This
peat units and also the upstream ‘FN-binding spacer peptide could inhibit the binding of FN to Ag85B and
2’ region, were used as immunogens. The latter region to other Ag85 proteins from different species ŽNaito
is equivalent to the UR unit Župstream FN-binding et al., 1998.. A sequence composed of six residues
sequence. of protein F1 of S. pyogenes, which appears ŽFEWYYQ., which has no homology to other known
to be the dominant FN-binding unit in this bacterial FN-binding proteins, was shown to be criti-
MSCRAMM ŽOzeri et al., 1996.. As the UR unit cal for FN binding. The binding site in FN for the
binds to the 40-kDa collagen-binding domain of FN, Ag85 complex has not been defined. The interaction
the ligand-induced-conformation mechanism de- of recombinant Ag85B with FN could be specifically
scribed above may not apply to either the SfbI-FN or inhibited by gelatin but not by heparin, tentatively
protein F1᎐FN interactions. Thus, it is possible that localizing a binding site to the 40-kDa collagen-bind-
the inhibitory activities of the antibodies described by ing domain of FN ŽPeake et al., 1993..
Molinari et al. may be due to antibodies specific for Several other mycobacterial FN-binding proteins,
the upstream FN-binding spacer 2 region of SfbI. distinct from the Ag85 complex, have been identified.
A 50-kDa FN-binding protein, FAP, has been purified
from M. ¨ accae culture supernatant ŽRatliff et al.,
4. FN-binding MSCRAMMs from other bacteria 1993.. Polyclonal and monoclonal antibodies to this
protein recognized a cell wall component in M. ¨ ac-
A variety of other important pathogenic bacteria, cae and several other mycobacterial species, including
including Mycobacterium spp., Escherichia coli, and M. bo¨ is BCG, M. tuberculosis, M. kansasii and M.
Borrelia burgdorferi, are also capable of binding speci- a¨ ium ŽRatliff et al., 1993.. Antibodies to FAP inhib-
fically to FN. The MSCRAMMs involved in these ited the binding of several mycobacteria to FN and to
interactions have been characterized to varying de- mammalian cells ŽKuroda et al., 1993.. Thus, FAP is a
grees ŽTable 2.. As a detailed account of all these putative FN-binding MSCRAMM on mycobacteria.
FN-binding organisms is beyond the scope of this FAP homologues have also been identified in M.
article, we have chosen to discuss only the interac- tuberculosis ŽFAP-TB. ŽAbou-Zeid et al., 1991., M.
tions that have been analyzed in some detail. leprae ŽFAP-L. ŽSchorey et al., 1995. and M. a¨ ium
Mycobacterium bo¨ is BCG and Mycobacterium ŽFAP-A. ŽSchorey et al., 1996.. Purified recombinant
paratuberculosis bind soluble FN in a saturable, dose- FAP-L bound to plasma FN and the C-terminal hep-
and time-dependent fashion ŽAslanzadeh et al., 1989; arin-binding chymotryptic fragment of FN. A study
Valentin-Weigand and Moriarty, 1992.. The number with overlapping synthetic peptides revealed two dis-
of FN binding sites was determined to be 8000᎐15 000 tinct FN-binding sites conserved among FAPs from
and 1600 per bacterium for M. bo¨ is BCG and M. different mycobacterial species ŽSchorey et al., 1996..
paratuberculosis, respectively. In addition, Scatchard These units possess little sequence similarity with
analysis indicated the presence of a homogeneous FN-binding MSCRAMMs from other bacteria.
population of FN-binding components, which bound A large number of Escherichia coli strains from
the ligand with a K d of 1.25= 10y9 M in the case of animal and human sources have been reported to
M. paratuberculosis. Several mycobacterial species se- adhere to FN in solid phase assays and to attach to
crete a set of FN-binding proteins Ž30᎐31 kDa. into ¨
fibroblasts via FN ŽFroman et al., 1984; Faris et al.,
the culture medium in ¨ itro. These proteins are known 1988; Ljungh et al., 1990; Yu et al., 1995.. The binding
as the Antigen ŽAg. 85 complex Žrelated to MPB or of this gram-negative bacterium to FN appears to be
MPT51. ŽAbou-Zeid et al., 1988, 1991; Pessolani and mediated by several types of fimbriae Žpili. on the
Brennan, 1992; Thole et al., 1992; Ohara et al., 1995; bacterial cell surface. Fimbriae are hair-like struc-
Naito et al., 1998.. However, as these proteins are tures that are composed of repeating major subunit
primarily extracellular, it is unclear whether they me- proteins, often arranged in an alpha helical array
diate the adherence of mycobacteria to FN. The Ag85 ŽSmyth et al., 1996.. Minor subunit proteins are pre-
complex is composed of three proteins, Ag85A sent at the tip and sometimes along the length of
ŽMPT44., B ŽMPT59. and C ŽMPT45., which are these organelles and often mediate the binding activi-
genetically distinct but show extensive immunological ties of these structures. Two distinct sites in FN are
cross-reactivity and amino acid sequence similarity, targeted by the E. coli receptors, FN-N29 and the
D. Joh et al. r Matrix Biology 18 (1999) 211᎐223 217

Table 2
FN-binding MSCRAMMs from other bacterial species

Bacterial Species Protein References

Mycobacterium spp. Ag85A ŽMPT44. Borremans et al. Ž1989., DeWit et al. Ž1990.

Ag85B ŽMPT59. Matsuo et al. Ž1988., Thole et al. Ž1992.

Ag85C ŽMPT45. Abou-Zeid et al. Ž1991., Peake et al. Ž1993.

MPT51 ŽMPB. Ohara et al. Ž1995, 1997.

FAP ŽFAP-TB, FAP-L, FAP-A. Abou-Zeid et al. Ž1991., Kuroda et al. Ž1993., Schorey et al. Ž1995, 1996.

Escherichia coli P fimbriae ŽFsoE, FsoF. Westerlund et al. Ž1989, 1991.


Type I fimbriae Sokurenko et al. Ž1992.
Curli Olsen et al. Ž1989.

Campylobacter jejuni CadF Konkel et al. Ž1997.


Flagellin Moser et al. Ž1997.

Salmonella enteritidis Fimbriae Collinson et al. Ž1993.

Yersinia spp. YadA Tertti et al. Ž1992., Schulze-Koops et al. Ž1993.

Porphyromonas gingi¨ alis 150-kDa protein Lantz et al. Ž1991.


Fimbrillin Murakami et al. Ž1996.

Aeromonas salmonicida A-protein Doig et al. Ž1992.

Aeromonas hydrophila Ascencio et al. Ž1991.

Haemophilus ducreyi Abeck et al. Ž1992.

Propionibacterium acnes 80-kDa protein Yu et al. Ž1997.

Fusobacterium nucleatum Winkler et al. Ž1987., Babu et al. Ž1995.

Neisseria gonorrhoeae OpaA van Putten et al. Ž1998.

Neisseria meningitidis Eberhard et al. Ž1998.

Mycoplasma penetrans 65-kDa protein Giron et al. Ž1996.

Treponema pallidum P1 and P2 proteins Peterson et al. Ž1987.

Treponema denticola 53- and 72-kDa proteins and Umemoto et al. Ž1993.
38-kDa axial flagellar protein

Borrelia burgdorferi Fn-BA Probert and Johnson Ž1998.


BBK32 Grab et al. Ž1998.

Borrelia garinii 147-kDa protein Kopp et al. Ž1995.

¨
120-kDa C-terminal region ŽFroman et al., 1984; Faris 1991.. Although it has not been demonstrated that
et al., 1988; Westerlund et al., 1989; Visai et al., these subunit proteins bind specifically to FN-N29, it
1991.. The P-fimbriae ŽPap pili. of uropathogenic E. is noteworthy that they do contain sequences similar
coli mediate adherence to immobilized intact FN and to the FN-binding repeat units of the staphylococcal
also to FN-N29 and the 120-kDa fragment of FN, but and streptococcal FN-binding MSCRAMMs ŽWest-
do not bind soluble FN ŽWesterlund et al., 1989.. The erlund and Korhonen, 1993..
FsoE and FsoF Žalso called PapE and PapF, respec- Campylobacter jejuni, another gram-negative
tively. minor subunit proteins of the P-fimbriae have pathogenic bacterium which causes gastrointestinal
been implicated in this interaction ŽWesterlund et al., diseases such as diarrhea, can adhere to ECM pro-
218 D. Joh et al. r Matrix Biology 18 (1999) 211᎐223

teins including FN ŽKuusela et al., 1989; Moser and Szczepanski et al. Ž1990. demonstrated that anti-FN
Schroder, 1995.. Proteinase K treatment of the bacte- antiserum could inhibit the binding of B. burgdorferi
ria abolished FN binding and demonstrated that the to a subendothelial matrix.. Recently, a surface-ex-
binding components on the cell surface are proteina- pressed protein ŽBBK32. with FN-binding activity was
ceous in nature ŽMoser and Schroder, 1995, 1997.. A purified from B. burgdorferi and the corresponding
major outer membrane protein, CadF, has been iden- gene was cloned ŽProbert and Johnson, 1998.. The
tified as a FN-binding protein. The corresponding binding site for BBK32 was localized to the
gene has been cloned, sequenced and identified in all gelatinrcollagen-binding domain in FN. The ability of
isolates tested so far ŽKonkel et al., 1997.. Another recombinant BBK32 to bind FN and inhibit the at-
major outer membrane protein, flagellin, has also tachment of B. burgdorferi to FN was demonstrated
been shown to bind FN and intestinal epithelial cells ŽProbert and Johnson, 1998.. A 52-kDa protein ŽFn-
ŽMoser et al., 1997.. The sites in the FN molecule BA. has also been identified as a FN-binding compo-
targeted by these putative MSCRAMMs have not nent on the surface of B. burgdorferi, however, the
been identified. relationship between this protein and BBK32 is un-
The adherence of Porphyromonas gingi¨ alis to ECM clear ŽGrab et al., 1998.. It has been observed that B.
components, such as FN, appears to play a role in the garinii can bind FN in a specific and saturable fashion
pathogenesis of periodontal disease caused by this and Scatchard analysis revealed the presence of two
organism ŽWinkler et al., 1987.. The binding of solu- types of receptors on the spirochetal surface, one with
ble FN to P. gingi¨ alis was demonstrated to be time- high and one with low affinity for FN ŽKopp et al.,
dependent, specific, reversible, and saturable. The K d 1995.. A 147-kDa protein with high FN-binding activ-
for the interaction was estimated to be in the order of ity was subsequently solubilized from the surface of
10y7 M, with approximately 3500 binding sites per B. garinii. This protein, soluble FN and anti-FN anti-
cell ŽLantz et al., 1991.. Lantz et al. identified a bodies could competitively inhibit the adherence of
FN-binding protein of 150-kDa in SDS-solubilized P. B. garinii to epithelial cells ŽKopp et al., 1995..
gingi¨ alis. Fimbrillin, a major component of the fim-
briae of P. gingi¨ alis, has also been identified to be a
FN-binding MSCRAMM ŽMurakami et al., 1996.. The 5. Role of FN-binding MSCRAMMs in bacterial
fimbriae appeared to interact with the N-terminal invasion of mammalian cells
heparin-binding and C-terminal cell-binding domains
in FN ŽMurakami et al., 1996.. In addition, by using a The ability to invade non-phagocytic mammalian
series of synthetic 20 mer fimbrillin peptides, two cells may provide bacteria with a niche in which they
distant regions in this protein have been implicated in are protected from host defense mechanisms or an-
binding FN ŽSojar et al., 1995.. Interestingly, Kontani timicrobial agents, which often operate in the extra-
et al. Ž1997. recently demonstrated that an arginine- cellular melieu. This may enable the bacteria to per-
specific protease expressed by P. gingi¨ alis enhanced sist in the host and may also provide a route for tissue
the binding of purified fimbriae to immobilized FN invasion from a primary site of colonization. Recent
using BIAcore analysis . It was proposed that the P. observations suggest that FN-binding MSCRAMMs,
gingi¨ alis protease exposes a cryptic binding site host integrins and FN play important roles in cellular
Žcryptitope. in FN, allowing the bacteria to adhere invasion by a variety of bacteria.
more efficiently to FN-coated surfaces. Several gram-positive bacteria, such as Streptococ-
The syphilis-causing spirochete, Treponema pal- cus spp. and S. aureus efficiently multiply in the
lidum, has been reported to bind to cultured mam- extracellular environment but also have the ability to
malian cells via the C-terminal cell-binding domain of invade host cells ŽHamill et al., 1986; Boschwitz and
FN ŽThomas et al., 1985.. The binding of intact FN Timoney, 1994; Lapenta et al., 1994; Almeida et al.,
and its cell-binding domain to the spirochetes was 1996; Calvinho and Oliver, 1998; Winram et al., 1998..
saturable, with an estimated K d of 10y7 M. Intact FN Expression of the FN-binding MSCRAMMs SfbI or
and FN fragments containing the cell-binding peptide, protein F1 promoted the invasion of cultured human
RGDS, also supported the tip-mediated adhesion of epithelial cells by S. pyogenes and soluble forms of
the human oral pathogen T. denticola ŽDawson and these proteins inhibited this process ŽMolinari et al.,
Ellen, 1990.. These spirochetes express surface pro- 1997; Jadoun et al., 1998; Okada et al., 1998..
teins of 53 and 72 kDa as well as a 38-kDa axial Polystyrene beads coated with SfbI or protein F1 were
flagellar protein that have been shown to bind to FN also effectively internalized by these cells ŽMolinari et
ŽUmemoto et al., 1993.. Several reports have indi- al., 1997; Ozeri et al., 1998.. Anti-FN antibodies com-
cated that FN may play a role in the interaction of pletely abolished protein F1-mediated invasion,
Borrelia burgdorferi and Borrelia garinii, both causative whereas increasing FN concentrations resulted in a
agents of lyme disease, with cells and the ECM. significant enhancement of bacterial uptake, suggest-
D. Joh et al. r Matrix Biology 18 (1999) 211᎐223 219

ing a role for FN in this process ŽJadoun et al., 1998.. the invasin protein of Yersinia spp. ŽIsberg et al.,
It has recently been demonstrated that the host cell 1987; Isberg and Leong, 1990; Isberg and Van Nhieu,
receptors involved in protein F1-mediated entry of S. 1994.. This suggests that these host receptors may
pyogenes are the FN-binding a v ␤ 3 and ␤ 1 integrins play a central role in the internalization process. The
ŽOzeri et al., 1998.. Antibodies against these integrins binding of an integrin to immobilized FN initiates a
effectively inhibited invasion by this bacterium ŽOzeri complex cascade of cell signaling that leads to reorga-
et al., 1998.. The entry of S. pyogenes into human nization of cytoskeletal components, resulting in cell
epithelial cells also can be mediated by protein M1, a spreading and the formation of adhesion plaques.
multifunctional surface protein, in an FN-dependent Engagement of integrins with FN bound to a bacterial
manner which is inhibited by anti-␣ 5␤ 1 integrin anti- cell surface may trigger a similar process but, due to
bodies ŽCue et al., 1998.. Our preliminary observa- the small size and curvature of the bacterial cells, the
tions indicate that the FN-binding MSCRAMMs are interaction may result in internalization of the bacte-
essential for S. aureus invasion of mammalian cells. ria. Consistent with this notion, FN-coated polystyrene
Simultaneous inactivation of the genes encoding Fn- beads are effectively internalized by BHK cells ŽMc-
bpA and FnbpB resulted in a 100-fold reduction in Abee and Grinnell, 1983.. Furthermore, inhibitors of
the invasion of HeLa cells by the mutant staphylococ- actin polymerization, such as cytochalasin D, inhibit
cal cells. In addition, soluble fragments of FnbpA and the invasion of several bacterial species, suggesting
a RGD-containing peptide inhibited the invasion that the process does involve rearrangement of cy-
Žmanuscript in preparation.. Taken together, these toskeletal components of the host cell ŽYoung et al.,
studies suggest that FN may act as a bridging molecule 1992; Almeida and Oliver, 1995; Greco et al., 1995;
between FN-binding bacterial MSCRAMMs and Menzies and Kourteva, 1998.. How similar are the
mammalian cell integrins. intracellular signaling pathways that induce mam-
Mycobacteria are obligate intracellular pathogens malian cells to spread on FN-coated surfaces or to
which naturally infect macrophages but can also in- internalize FN-coated bacteria? Does the integrin-de-
vade non-phagocytic cells such as HEp-2 cells and pendent internalization of various bacterial species
Schwann cells ŽBermudez et al., 1995; Schorey et al., proceed through similar or different mechanisms?
1995.. The ability to bind FN appears to play an These are some of the intriguing questions that war-
important role in cellular invasion by these bacteria. rant further investigation.
Schorey et al. Ž1995.. observed that the invasion of
Schwann cells was enhanced by pretreatment of the
mycobacteria with FN and that this enhancement was 6. Are FN-binding MSCRAMMs virulence factors?
abolished by anti-FN antibodies or antibodies against
the mycobacterial FN-binding protein FAP. Despite the general belief that FN-binding
FN also mediates efficient entry of the facultative MSCRAMMs are pathogenic determinants of mi-
intracellular bacterium Neisseria gonorrhoeae into croorganisms, the importance of these MSCRAMMs
HEp-2 cells Žvan Putten et al., 1998.. The FN-induced in the infection process remains to be determined in
entry of OpaA-expressing N. gonorrhoeae, which also many cases. For example, it is clear from studies with
appeared to be dependent on glycosaminoglycans, was isogenic mutants lacking FnbpA and FnbpB that these
inhibited by RGD-containing peptides and anti-␣ 5 ␤ 1 proteins are responsible for mediating the attachment
integrin antibodies Žvan Putten et al., 1998.. The of S. aureus to immobilized FN in ¨ itro and contribute
N-terminal region of FN is believed to interact with to the adherence of this bacterium to plasma clots
OpaA, through the bridging action of glycosaminogly- and ex vivo biomaterial ŽVaudaux et al., 1993; Greene
cans, while the type III modules of FN bind ␤ 1 et al., 1995; Vaudaux et al., 1995.. However, data on
integrins on the HEp-2 cell surface Žvan Putten et al., the role of these FN-binding MSCRAMMs in animal
1998.. However, studies have revealed that vitronectin models of staphylococcal endocarditis are conflicting
and ␣ v integrins may be more important for the ŽKuypers and Proctor, 1989; Flock et al., 1996; Greene
internalization of N. gonorrhoeae by other cell lines et al., 1996.. These conflicting results may be due to
ŽDuensing and van Putten, 1997; Gomez-Duarte et the difficulties inherently associated with animal stud-
al., 1997; Dehio et al., 1998; Duensing and van Put- ies, such as variability among the animals used in
ten, 1998.. each case. In addition, the outcomes of experimental
The mechanism by which FN-binding MSCRAMMs infections may be dependent on the animal model
trigger the internalization of bacteria by mammalian employed. For example, if a collagen-binding
cells is unknown. Many bacterial surface proteins that MSCRAMM is responsible for colonization of carti-
mediate invasion interact with integrins via bridging laginous tissues, such as joints, it may be more rele-
molecules such as FN, or directly bind to integrins, as vant to use an animal model of septic arthritis than a
has been demonstrated by Isberg and colleagues for model of endocarditis to assess the role of this
220 D. Joh et al. r Matrix Biology 18 (1999) 211᎐223

MSCRAMM in virulence. Furthermore, it is likely sis to invade and replicate within HEp-2 epithelial cells. Tuber.
that multiple adhesins are involved in different stages Lung Dis. 76, 240᎐247.
Borremans, J., DeWit, L., Volckaert, G., Ooms, J., DeBruyn, J.,
of a particular infection and that a degree of redun- 1989. Cloning, sequencing determination and expression of a
dancy exists in the activities of these adhesins. All of 32-kilodalton-protein gene of Mycobacterium tuberculosis. Infect.
these issues should be taken into consideration when Immun. 57, 3123᎐3130.
investigating the potential roles of individual Boschwitz, J.S., Timoney, J.F., 1994. Characterization of the an-
MSCRAMMs in the infection process. tiphagocytic activity of equine fibrinogen for Streptococcus equi
subsp. equi. Microb. Pathog. 17, 121᎐129.
In this review, we have tried to describe the multi- Bozzini, S., Visai, L., Pignatti, P., Petersen, T.E., Speziale, P., 1992.
tude of interactions which exist between bacterial Multiple binding sites in fibronectin and the staphylococcal
MSCRAMMs and FN which promote both bacterial fibronectin receptor. Eur. J. Biochem. 207, 327᎐333.
adherence to host tissues and invasion of host cells. Calvinho, L.F., Oliver, S.P., 1998. Invasion and persistence of
During the course of evolution, pathogenic microbes Streptococcus dysgalactiae within bovine mammary epithelial cells.
J. Dairy Sci. 81, 678᎐686.
have developed elaborate ways to effectively colonize Casolini, F., Visai, L., Joh, D. et al., 1998. Antibody response to
their hosts, evade host defense systems, interfere with fibronectin-binding MSCRAMM in patients diagnosed with
normal cellular activities and destroy host tissues, Staphylococcus aureus infection. Infect. Immun. 66, 5433᎐5442.
resulting in the symptoms of disease. The expression Collinson, S.K., Doig, P.C., Doran, J.L., Clouthier, S., Trust, T.J.,
of FN-binding MSCRAMMs is only one example of Kay, W.W., 1993. Thin, aggregative fimbriae mediate binding of
Salmonella enteritidis to fibronectin. J. Bacteriol. 175, 12᎐18.
this adaptation. With the emergence of multiple drug
Courtney, H.S., Li, Y., Dale, J.B., Hasty, D.L., 1994. Cloning,
resistance, it is critical to expand our knowledge of sequencing, and expression of a fibronectinrfibrinogen-binding
the molecular mechanisms of microbial pathogenesis protein from group A streptococci. Infect. Immun. 62, 3937᎐3946.
to target the development of novel preventive and Cue, D., Dombek, P.E., Lam, H., Cleary, P.P., 1998. Streptococcus
therapeutic strategies. pyogenes serotype M1 encodes multiple pathways for entry into
human epithelial cells. Infect. Immun. 66, 4593᎐4601.
Dawson, J.R., Ellen, R.P., 1990. Tip-orientated adherence of Tre-
ponema denticola to fibronectin. Infect. Immun. 58, 3924᎐3928.
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Vitronectin-dependent invasion of epithelial cells by Neisseria
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The studies performed in our laboratories were 84᎐88.
supported by National Institutes of Health grant DeWit, L., DeLaCuvellerie, A., Ooms, J., Content, J., 1990. Nu-
AI20624, by Inhibitex, Inc., and by the Fondo d’Ateneo cleotide sequence of the 32 kDa-protein gene Žantigen 85A. of
per la Ricerca, Italy. Mycobacterium bo¨ is BCG. Nuc. Acids Res. 18, 3995.
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