Bartonella henselae by b2oGBV


									Bartonella henselae

       Sarah J. Bow
     February 7, 2012
1.0 Introduction

          Bartonella henselae is an aerobic, oxidase negative, gram-negative rod. This facultative
intracellular pathogen is the etiological agent of Cat Scratch Disease (CSD). B. henselae is an -
proteobacterium a that causes a long-lasting intraerythrocytic bacteraemia in its natural reservoir host, the
cat (Felis catus). This bacterium has a worldwide distribution with an estimated 20,000 cases per year in
the United States. Nearly one third of all domestic cats being carriers of the pathogen. Fifty-five to eighty
percent of cases occur in patients under that age of 20 and prevalence of infections are seen in warm and
humid climates, where cat fleas (Ctenocephalides felis), the vector for transmission of this bacterium
between cats, are abundant. There are nineteen distinct Bartonella species, nine of which are known to
infect humans. B. henselae is one of the nine Bartonella species that infects humans by incidental
transmission through cat scratches or bites. Human to human transmission has never been documented.

          During human infections, vascular endothelial cells are the primary cellular targets but the bacteria
are also capable of infecting monocytes and macrophages. In the natural feline reservoir, erythrocytes are
the primary cells infected. Infection of erythrocytes involves firm bacterial adhesion, followed by bacterial
internalization into membrane-bound compartments in which the bacteria replicate. Bacterial growth ceases
after few divisions, and intraerythrocytic bacteria circulate in the bloodstream for the remaining lifespan of
the infected erythrocyte, which can be several weeks to months. The resulting long-lasting intraerythrocytic
infection represents a specific adaption to the modes of transmission by blood-sucking arthropods. In
immunocompetent patients infected with B. henselae, CSD is self-limiting and causes swelling of the
lymph nodes and fever. Immunocompromised patients infected with B. henselae, will however develop
bacillary angiomatosis-peliosis (BAP) and present with tumour-like vasoproliferative lesions on the skin
and the internal organs. The pathogen is detectable within these BAP lesions by a special stain called
Warthin-Starry stain (Figure 1). CSD is diagnosed by histology of biopsied lymph node tissues, Polymerase
chain reaction (PCR), Immunofluorescence Assays (IFA), and serology. B. henselae infections can be
treated with antibiotics, such as trimethoprim-sulfamethoxazole, gentamicin, ciprofloxacin, and rifampin.
B. henselae is generally resistant to beta-lactam antibacterial agents (ie, penecillins). Antibiotic treatment
results in regression of the angiomatosis tumors and clearance of the bacteria.

2.0 Endothelial Cell Invasion and Colonization

          Colonization of vascular endothelial cells is considered the initial step in the formation of the
vasoproliferative BAP lesions associated with B. henselae infection. Bacterial adhesion and invasion of
endothelial cells are primarily studied in cultured human umbilical vein endothelial cells (HUVECs). Such
processes are actin-dependant and result in clusters of bacteria residing in membrane-bound compartments
that are typically localized in the perinuclear region.

          Infection of endothelial cells, monocytes, and macrophages results in inhibition of host cell
apoptosis and the secretion of vascular proliferative compounds (ie, VEGF and IL-8) that induce
endothelial proliferation. Little is known of the exact compartment in which B. henselae resides once inside
its host cell and the bacterial genes implicated in intracellular survival. B. henselae has been shown to enter
endothelial cells by two independent mechanisms. The first is by conventional phagocytosis and the second
is by the formation of a unique invasome structure.

          Individual B. henselae bacteria can enter its target endothelial cells by conventional endocytosis
and reside in membrane-bound intracellular compartments rather than the cytoplasm. These compartments
are called Bartonella-containing vesicles (BCVs) (Figure 2). Twenty-four hours after infection we see that
all internalized bacteria are within membrane-bound compartments. Phagosomal maturation is fundamental
to the control of intracellular pathogens yet it is known that BCV do not mature into phagosomes or into
another type of acidified vacuole, nor do they arrest early endosomal compartments (Kyme, 2005). This
allows the bacteria to survive and continue to replicate at a neutral pH and while avoiding innate immune
effectors or degrading enzymes. It has been shown in HUVECs that viable B. henselae delay the fusion of
BCVs with lysosomes (Kyme, 2005). This was done by monitoring the acquisition of commonly used
endocytic marker proteins, such as LAMP1 (late endosomes and lysosomes) and EEA1 (early endosomes).
The majority of BCVs do not contain the typical endocytic markers 2hrs after infection with viable B.
henselae, and complete avoidance of lysosomal fusion is observed in HUVECs (Figure 3) (Kyme, 2005).
Thus active modulation of the host cell is more likely to be involved in controlling phagosome maturation
than preformed bacterial surface proteins, such as BadA. BadA, a surface adhesin has been shown to be a
key pathogenicity factor for B. henselae also prevents phagocytosis of the bacterium. Thus B. henselae has
an alternative mechanism for entering the host cells.

          B. henselae can also enter endothelial cells via an invasome-mediated mechanism and has been
show in HUVECs in vitro. Invasome-mediated entry is dependant on the VirB/VirD4 type IV secretion
system and involves the formation of cell surface-associated bacterial aggregates (Rhomberg, 2009 and
Dehio, 1997). VirB/VirD4 effector proteins, such as BepG aid in the initiation of invasome-medaited
internalization of B. henselae aggregates by inhibiting the endocytic uptake of bacteria into BCVs (Figur 7)
(Rhomberg, 2009). The membranes engulfing the bacterial aggregates do not acquire any detectable
LAMP-1 protein markers, indicating that they constitute a unique membrane compartment that is strictly
separated from the endosomal-lysosomal network (Rhomberg, 2009).

          This mechanism begins with the leading lamella of the endothelial cells (ECs) establishing contact
with sedimented bacteria and bacterial aggregates on the cell surface. Bacteria accumulating on the host
cell surface will induce an F-actin rearrangement event that is characteristic of the invasome mechanism.
Studies have shown that cortical F-actin and phosphotyrosine are highly enriched in the membrane
protrusions that are involved in entrapping the bacterial aggregate (Rhomberg, 2009). The bacterial
aggregate is then engulfed by host cell membrane protrusions and eventually internalized in a unique
structure called an invasome (Figure 4 and 5). This process takes approximately 24 hours to complete and
is mainly a host cell driven process (Figure 6). Invasome-mediated internalization is considered to represent
a specific mechanism for endothelial cell colonization in vivo. This reflects the characteristic bacterial
aggregates found in bacillary angiomatosis lesions in association with proliferating endothelial cells.

3.0 Pathogenicity Factors

          The genus Bartonellae has defined two primary pathogenicity factors: Adhesins and Type IV
secretion systems. Bartonella adhesion A (BadA) is an important and extensively characterized
pathogenicity factor of B. henselae which mediates adhesion to the extracellular matrix and mammalian
host cells. BadA belongs to the class of trimeric autotransporter adhesins (TAAs) which represent
important virulence factors of many gram-negative pathogens. It is modularly constructed and consists of a
head domain, a long, repetitive neck-stalk module and a membrane anchor (Figure 8) (Kaiser, 2011). The
BadA head domain is crucial for bacterial adherence to endothelial cells through its recognition of host cell
β1- integrins as well as mediating binding to several extracellular matrix proteins, such as collagen, laminin
or fibronectin. The head domain is also crucial for the induction of VEGF secretion and is the most
biologically active domain (Kaiser, 2011). All TAAs share this similar modular organization, displaying a
‘lollipop-like’ surface structure. The C-terminal membrane anchor is highly conserved in all TAAs and
contains the autotransporter activity. The long and highly repetitive neck-stalk region that links the head
and anchor domains can vary significantly in length in different B. henselae isolates (Kaiser, 2011). The
modular structure of BadA leads to the hypothesis of a domain-function relationship in which certain
domains are responsible for different biological functions.

4.0 Type IV Secretion Systems (T4SSs)

          Type IV Secretion Systems (T4SSs) are macromolecular protein assemblies that mediate the
intercellular transfer of effector protein substrates from a bacterial donor cell into eukaryotic host cells.
T4SS effectors, in turn, subvert the recipient cell to accommodate the pathogen’s specific growth
requirements and conditions (Figure 9). T4SSs consist of a substrate translocation channel spanning the two
membranes of gram-negative bacteria, and a surface filament extending from the bacterial envelope. The
translocation channel is believed to extend to the target cell membrane to facilitate substrate translocation.

         Common infection strategies of Bartonella species evolved initially without the contribution of
T4SSs. Colonization of endothelial cells and erythrocytes occurred by direct mechanisms and resulted in a
long-lasting intraerythrocytic infection. Subversion of vascular endothelial cell functions were mediated by
bacterial effector proteins translocated by VirB-like T4SSs and interactions with erythrocytes was mediated
by pilus-associated variant surface proteins expressed by the Trw T4SS. The molecular mechanisms
facilitating T4SS-dependent host adaptability remain elusive; however, gene duplication and diversification
by combinational sequence shuffling and point mutations seem to have contributed to the accelerated
evolution of the translocated effector proteins of the VirB-like T4SSs and the surface-expressed pilus
components of the Trw T4SS (Figure 10).

         Among the members of the Bartonellae genus are three distinct Type 4 Secretion Systems
(T4SSs) which have all been implicated as pathogenicity factors for each bacterial species and will be
discussed below.

4.1 VirB/VirD4 Type IV Secretion System

         The VirB/VirD4 T4SS was the first to be identified by exploration of the genetic locus encoding a
17kDa protein that was previously recognized as an immunodominant antigen of B. henselae. This T4SS
represents the most significant system in the pathogenicity of B. henselae and thus will be discussed in
length in this work.

          Endothelial cells are the primary target cells for the activity of the VirB/VirD4 T4SS and the
virB/virD4 locus is highly conserved in the genome sequence of modern Bartonellae, including B.
henselae. Deletion mutants in either VirB4 or VirD4 fail to cause bacteraemia, demonstrating the essential
role of the VirB/VirD4 T4SS in establishing intraerythrocytic infection. The VirB/VirD4 T4SS is a
macromolecular assembly of at least 10 essential protein components, VirB2-VirB11, and an associated
substrate recognition receptor known as the type IV secretion coupling protein (T4CP), VirD4 (Figure 11).

         The VirB/VirD4 system mediates most of the cellular phenotypes associated with B. henselae
infection of HUVECs but has three main roles. First, this T4SS mediates rearrangement of the actin
cytoskeleton resulting in the formation and internalization of large bacterial aggregates by invasome-
mediated entry. Secondly, the VirB/BirD4 system triggers a proinflammatory phenotype via NFκB-
dependent activation that leads to cell adhesion molecule expression and chemokine secretion. Thirdly, the
VirB/VirD4 T4SS is also crucial for the inhibition of apoptotic cell death that results in enhanced
endothelial cell survival. So just from these three roles alone, we can see that the VirB/VirD4 T4SS is an
important pathogenicity factor for these bacteria and it is critically involved in establishing a chronic and
bacteraemic infection in its host.

          The VirB/VirD4 type IV secretion system modulates mammalian host cell functions through
translocation of Bartonella effector proteins (Beps) into host cells. Seven VirB/VirD4 translocated
Bartonella-effector proteins (Beps) have been identified, BepA-BepG which are translocated by T4SS
machinery. Beps are the major effector proteins that mediate VirB/VirD4-dependent cellular processes and
display a modular structure. At the C-terminus, each effector protein contains a bipartite translocation
signal, a 140 amino acid Bartonella intracellular delivery (BID) domain that mediates Bep intracellular
delivery and a positively charged but unconserved tail sequence.

          VirB/VirD4-dependent inhibition of apoptosis protects the cellular habitat of Bartonella which
contributes indirectly to vasoproliferative growth due to an increase in cellular survival. The capacity of B.
henselae to inhibit apoptosis of HUVECs is dependent upon the effector protein BepA. Upon translocation,
BepA localizes to the plasma membrane, where it triggers the production of the second messenger cyclic
AMP (cAMP) by an unknown mechanism. This results in an increase in the steady-state concentration of
cAMP which blocks apoptotic cell death. The BID domain of BepA is also sufficient to mediate membrane
localization, elevation of cAMP levels and the resulting protection from apoptosis. BepG inhibits BepA-
dependent sprouting and thus both effector proteins control angiogenesis. BepG as well as BepC and BepF
together are able to induce invasome-mediated internalization by inhibiting bacterial endocytosis and
promoting actin rearrangement of the cell cytoskeleton. The mechanism of how BepG inhibits endocytosis
remains unclear, but it is suspected to relate to the colocalization of BepG with F-actin (Figure ).
4.2 Trw Type IV Secretion System

          Trw is another T4SS utilized by several Bartonella species but was first recognized in B. henselae
in a search for promoters that are differentially regulated during infection. The Trw system is required for
erythrocyte infection but appears to not be required for infection of endothelial cells. B. henselae strains
with mutations in the trw locus fail to cause bacteraemia in vivo and fail to colonize HUVECs in vitro.

         The Trw system lacks the T4CP-encoding gene trwB, which is homologous to VirD4. It has been
reported that the T4CP TraG of plasmid RP4 can functionally substitute for TrwB for Trw-dependent
plasmid mobilization in E. coli but there is no data to support a functional interaction of the T4CP VirD4
and Trw in Bartonella.

          Absence of the TrwB in Bartonella species indicates that the Trw T4SS lacks the capacity to
translocate substrates. So instead, multiple copies of trw genes in the Bartonella trw locus encode variant
forms of surface-exposed pilus components. Other genes in the trw locus encode for pilus elongation and
anchorage components. These variant pili may facilitate the interaction with different erythrocyte receptors
within the feline reservoir. Thus the Trw T4SS may represent a major determinant of host range/host
specificity as well as an important pathogenicity factor for establishing chronic bacteraemia in the feline
reservoir host.

4.3 Vbh Type IV Secretion System

         Vbh is the third T4SSs found in Bartonella species and it is closely related to the VirB/VirD4
system as the virB/virD4 locus arose by duplication of vbh or by lateral gene transfer. Vbh only appears to
be functional in species that do not encode VirB/VirD4. In contrast, Vbh apparently deteriorates in the
presence of the VirB/VirD4 T4SS. The lateral acquisition of the vbh locus by the modern lineage thus
occurred coincidentally with the separation from the ancestral lineage.

          All three T4SSs mentioned here have been acquired by the modern lineage via lateral gene
transfer that gives us some insight into the evolution of this pathogenic genus of bacteria. The T4SSs are
crucial for the evolutionary success of the radically expanding modern lineage of the Bartonella genus and
their capacity to confer host adaptability. The acquisition of Trw thus contributed to the capacity of modern
Bartonellae to adopt novel reservoir hosts within relatively short evolutionary distances. This also
correlates with the loss of flagella in the modern lineage. Flagella are known to be major pathogenicity
factors for the invasion of erythrocytes by B. bacilliformis, which is a member of the ancient lineage. Trw
and subsequently VirB/VirD4 seem to have functionally replaced flagella for mediating host cell invasion
by the modern Bartonella species such as B. henselae.

5.0 Angiogenesis and Vasoproliferative Tumour Growth

          Bartonella-induced vascular proliferations are benign and depend on the continued presence of the
bacteria, which produce angiogenic factors that maintain the angiogenic process (Figure 12). Angiogenesis
is the process of forming new capillaries from pre-existing ones. This involves the migration and
proliferation of endothelial cells as well as their reorganization into capillary-like structures. Bartonella
spp. can provoke angioproliferation by at least two independent mechanisms: directly, by triggering
proliferation and inhibiting apoptosis of endothelial cells and indirectly, by stimulating a paracrine
angiogenic loop of vascular endothelial growth factor (VEGF) production by stimulated macrophages.

5.1 Apoptosis

          Programmed cell death by apoptosis is a common response of mammalian cells to bacterial
infection. The ability of B. henselae to prevent endothelial cell apoptosis is dependent upon bacterial
effector proteins, specifically BepA and can contribute indirectly to vasoproliferative growth by enhancing
host cell survival (Figure 13). As mentioned previously, this is accomplished by BepA binding to the
endothelial membrane receptor that induces a transmembrane signal that increases cytosolic cAMP levels.
The high cAMP levels then upregulate cAMP responsive genes that induce an antiapoptotic state in
endothelial cells (Mosepele, 2012).

5.2 Vascular Endothelial Growth Factor (VEGF)

          VirB/VirD4-dependent pro-inflammatory activation of endothelial cells is thought to mediate the
recruitment of monocytes and macrophages, which are activated upon B. henselae infection. The activated
macrophages are then triggered to release proangiogenic factors, such as VEGF, that promote endothelial
cell proliferation in a paracrine manner (Figure 13). VEGF is one of the most potent inducers of
angiogenesis and treatment with neutralizing anti-VEGF antibody will block most of the angiogenic
activity (Kempf, 2001).

          Polymorphonuclear leukocytes (PMNs) represent a major constituent of the mixed inflammatory
infiltrates of Bartonella-triggered angioproliferative lesions. PMNs are also capable of secreting VEGF in
response to bacterial infection. However, it is unknown to what extent B. henselae can stimulate VEGF-
secretion by PMNs. There is no evidence to suggest that B. henselae can stimulate an autocrine loop of
VEGF-mediated endothelial proliferation (Kempf, 2001).

6.0 Immunology and Activation of Endothelial Cells

          Two general strategies are employed by intracellular pathogens to evade the host immune system
and allow them to establish a chronic infection. The first is to dismantle immune system effectors or their
regulation using a variety of mechanisms, and the second, which is utilized by Bartonella species, is to
underwhelm the immune system by utilizing subinflammatory or antagonistic molecules (Minnick, 2009).
Bartonella lipopolysaccharide (LPS) is composed of a unique combination of Lipid A and long-chain fatty
acids and likely contributes to the bacteria’s ability to evade the host immune system (Mosepele, 2012).
Bartonella’s low-potency LPS is not recognized by TLR-4 on dendritic cells or macrophages thus allowing
for the establishment of persistent infections.

          Little is known about the specific humoral and cellular immune mechanisms involved in
establishment and persistence of Bartonella infection in humans. In general, an acute inflammatory
response induces a mediator cascade that activates endothelial cells. This activation of the endothelium then
results in the sequential establishment of receptor-ligand interactions between the activated endothelium
and the circulating leukocytes. This will in turn lead to the attachment, rolling, firm adhesion, and
transmigration of PMNs through the endothelium into the tissue. Transendothelial migration of PMNs into
the tissue occurs in response to chemoattractants such as IL-8 and tissue necrosis factor-α (TNFα) that are
secreted by macrophages that are all controlled by NF-κB-dependant mechanisms. Infection of HUVECs
by B. henselae results in the activation and nuclear localization of NF-κB that is also involved in the
transcription of genes associated with the immune response (Fuhrman, 2001). Infiltrating PMNs and
lymphocytes release pro-inflammatory cytokines, such as TNFα which on its own has the capacity to
stimulate angiogenesis. The release of TNFα is greatly increased upon B. henselae stimulation of
monocytes (Figure 13).

          NF-κB-mediated acute inflammatory reaction of the Bartonella-infected endothelium appears to
be critical for the recruitment of monocytes/macrophages as well as the initiation and maintenance of the
paracrine angiogenic loop (Fuhrman, 2001). Monocytes and macrophages that are recruited to
angioproliferative lesions will propagate chronic inflammation by releasing proinflammatory cytokines
(Figure 13).

         Since the response to B. henselae infection in the competent immune system involves the innate
immunity through macrophages, it would be correct to assume that immunocompromised hosts would be
unable to eliminate the infection and thus would develop a systematic infection which is what is seem in B.
henselae infections in humans.
7.0 Experimental Models

          A three-dimensional in vitro angiogenesis assay of collagen gel-embedded endothelial cell
spheroids has been developed to study the pro- and anti-angiogenic properties of B. henselae quantitatively.
In this assay, the sprouting seen from the spheroid embedded in collagen gel correlates to the process of
angiogenesis in endothelial cells infected with B. henselae. HUVECs are isolated and cultured in EGM
medium at 37°C as described by Dehio, 1997. HUVECS were infected with B. henselae at an MOI of
300 24hrs before a defined number of cells were suspended in culture medium containing methylcellulose
and grown overnight as hanging drops. Spheroids were whole-mount stained with mouse anti-human
CD31-specific monoclonal antibody and detected with an anti-mouse secondary antibody conjugated to
AlexaFluor488. Bright field image and maximum intensity z-projections of stacks acquired by confocal
spinning disc microscopy was performed for visualization of angiogenic properties (Figure 14)
(Scheidegger, 2009).

          Wild type B. henselae activates HUVEC spheroids and triggers radial outgrowth. This process is
modulated by the VirB/VirD4 T4SS and is induced by VEGF. This assay shows that spheroids of
uninfected HUVECs embedded in collagen gel show a very low level of spontaneous sprouting but were
readily responsive to exogenous addition of VEGF (Figure 14B and F) clearly illustrating the inducing
affect of VEGF on angiogenesis. Comparatively, spheroids infected with wild type B. henselae yield high
sprouting activity (Figure 14C) comparable to the control stimulated with VEGF. This shows that wild
type B. henselae has a clear VirB/VirD4- and Bep-dependent angiogenic activity on top of a basal level of
VirB/VirD4 and Bep-dependent sprout formation (Figure 14G) (Scheidegger, 2009).

                   The collagen gel-embedded HUVEC spheroid model represents a valid quantification in
vitro assay of sprouting angiogenesis that will aid further studies to elucidate the molecular basis of the pro-
and anti-angiogenic activities of the Bartonella effector proteins (Beps). A recent report has demonstrated
that HUVEC spheroids can also be used in vivo to study sprout angiogenesis (Alajati, 2008). They propose
a novel murine xenotransplatation model with HUVEC spheroids pre-infected with B. henselae that may
allow future studies to establish a highly desired animal model to study Bartonella-induced angiogenesis in

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