1. Microreview
How can microbial interactions with the blood–brain
barrier modulate astroglial and neuronal function?
Dennis J. Grab,1
Srabasti J. Chakravorty,2
Henri van der Heyde3
and Monique F. Stins4
*
1
Johns Hopkins SOM, Department Pathology, Division
Medical Microbiology, 720 Rutland Ave, Ross 624,
Baltimore, MD 21205, USA.
2
Institute for Science and Technology in Medicine, Keele
University, Keele, Staffordshire, UK.
3
La Jolla Infectious Disease Institute, Bunker Hill Rd, La
Jolla, CA, USA.
4
Johns Hopkins SOM, Department Neurology,
NeuroSurgery and Psychiatry, Division
NeuroImmunology, 600 N Wolfe street, Meyer 5-134
(mail 6-113), Baltimore, MD 21281, USA.
Summary
The vascular endothelium of the blood–brain
barrier (BBB) is regarded as a part of the neurovas-
cular unit (NVU). This emerging NVU concept
emphasizes the need for homeostatic signalling
among the neuronal, glial and vascular endothelial
cellular compartments in maintaining normal brain
function. Conversely, dysfunction in any compo-
nent of the NVU affects another, thus contributing
to disease. Brain endothelial activation and dys-
function is observed in various neurological dis-
eases, such as (ischemic) stroke, seizure, brain
inflammation and infectious diseases and likely
contributes to or exacerbates neurological condi-
tions. The role and impact of brain endothelial
factors on astroglial and neuronal activation is
unclear. Similarly, it is not clear which stages of
BBB endothelial activation can be considered
beneficial versus detrimental. Although the BBB
plays an important role in context of encephalopa-
thies caused by neurotropic microbes that must
first penetrate into the brain, a crucial role of the
BBB in contributing to neurological dysfunction
may be seen in cerebral malaria (CM), where the
Plasmodium parasite remains sequestered in the
brain vasculature, does not enter the brain paren-
chyma, and yet causes coma and seizures. In this
minireview some of the scenarios and factors that
may play a role in BBB as a relay station to modu-
late astroneuronal functioning are discussed.cmi_1661 1470..1478
The blood–brain barrier endothelium and the
neurovascular unit
The blood–brain barrier (BBB) endothelium forms a highly
selective barrier between the blood and the central
nervous system (CNS). Once regarded as ‘just’ a lining for
vessels to allow blood to flow and nutrients to pass into
the underlying tissues, it is now clear that endothelium in
different tissues is very heterogeneous in its expression of
surface receptors and responses to stimuli (Langenkamp
and Molema, 2009). Contrary to liver endothelium that
displays fenestrae to facilitate plasma exchange, brain
endothelium possesses tight junctions characteristic of its
barrier function. The unique tissue-specific endothelial
characteristics are induced through interactions with the
underlying tissues and in the CNS this includes the under-
lying extracellular matrix, astrocytes and pericytes (Abbott
et al., 2006; Kroll et al., 2009; Bonkowski et al., 2011;
Kamouchi et al., 2011). In addition, brain-trophic BBB-
derived factors can promote differentiation of neuropre-
cursor cells (Guo et al., 2008; Chintawar et al., 2009).
Indeed, the BBB endothelium (BBB-EC) is now regarded
an integral component of the neurovascular unit (NVU),
an emerging concept that underlines the importance of
the homeostatic interactions between the brain’s cellular
components – astroglia, neurons and BBB-EC – for
optimal CNS functioning (Abbott et al., 2006; Persidsky
et al., 2006; Lok et al., 2007; Bonkowski et al., 2011).
Conversely, deregulation in any of the NVU components,
will alter the brains homeostasis leading to a multitude of
neurodysfunctions and BBB activation as has been
observed in multiple sclerosis, Alzheimers disease,
stroke, certain depression disorders and in microbial
infections, among others (Zlokovic, 2008; Reale et al.,
2009; Chung et al., 2010; Holman et al., 2011). The
Received 21 June, 2011; revised 2 August, 2011; accepted 3 August,
2011. *For correspondence. E-mail mstins@jhmi.edu; Tel. (+1)
443 287 8027
Cellular Microbiology (2011) 13(10), 1470–1478 doi:10.1111/j.1462-5822.2011.01661.x
First published online 6 September 2011
© 2011 Blackwell Publishing Ltd
cellular microbiology

2. contribution of several endothelial-activating components,
including microbial involvement, has been suggested to
initiate certain brain diseases (Miklossy, 2008; Zhang
et al., 2009; Humpel, 2011; Ochoa-Reparaz et al., 2011).
Circulating gut-derived lipopolysaccharides (LPS), which
are increased in, e.g. HIV-1 infection, alcohol abuse and
depression disorders, can activate brain endothelium to
trigger astroglial activation signals and/or modulate neu-
rological functioning that lead to sickness-related behav-
ioural changes (Schafer et al., 2002; Maes et al., 2008).
Modulation of microglial function by peripheral inflamma-
tion also depends on the prior history and immune status
(Cunningham et al., 2009). Unfortunately, the role of
BBB-EC activation in the development of neurological
diseases is still an understudied area of research.
In vitro BBB endothelial models to study its
involvement in neurological disease
Single- or multi-cell in vitro models of the BBB have
proven useful tools to study BBB-EC and its functionality
in neurological diseases. For elucidation of specific BBB
human endothelium responses, cultures comprising of
only primary or immortalized human brain EC are pre-
ferred (Stins et al., 2001a; Weksler et al., 2005). However,
other models include non-human- and non-brain-
endothelial cell types such as human umbilical vein endot-
helial cells (Weiss et al., 1999; Eugenin et al., 2006),
ECV304/T4 cells (Tan et al., 2001; Neuhaus et al., 2011),
primary porcine brain endothelial cultures (Kroll et al.,
2009), immortalized rat cultures (Roux and Couraud,
2005) and bovine brain endothelial cells (Stins et al.,
1997). Today, a wide availability of diverse immortalized
cell lines have become attractive workhorses and have
greatly facilitated BBB research. However, because
immortalized lines may have changed their physiology
and do not always reflect the heterogeneity of endothelial
populations and responses, it is imperative to verify
results with primary brain endothelial cells that are now
commercially available. With these tools, research to
better understand the intimate interactions between
BBB-EC and other cellular components within NVU and
its contributions to neurological disease is now universally
possible.
To elicit more BBB-like characteristics, BBB-EC can be
cultured on brain-specific extracellular matrix, in combina-
tion multi-cell co-cultures, either with pericytes, astro-
cytes, C-6 glioma cells or in the presence of conditioned
media from these cells (Nakagawa et al., 2009; Hatherell
et al., 2011). The ‘modular’ system approach allows
studies on direct interactions between the different cell
types of the NVU, which may not be possible in vivo.
However, astrocytes are heterogeneous and can be ‘acti-
vated’ upon isolation (Zhang and Barres, 2010), either
positively or negatively impacting on the BBB-EC charac-
teristics when used in co-culture models. Physical factors,
such as vascular sheer stress and red blood cell (RBC)
interactions, can affect BBB characteristics such as
higher trans endothelial electrical resistance (TEER),
decreased permeability and altered expression of multi-
drug transporters (Tripathi et al., 2007; Cucullo et al.,
2011a,b). Complex hollow tube dynamic flow models
and two-dimensional flow models allow for studies on
interactions of (microbial infected-) immune cells and/or
RBCs under flow (Barth et al., 2009; Phiri et al., 2009)
with BBB-EC.
Microbes, BBB and neurological dysfunction; to
cross or not to cross?
Generally, high plasma concentrations of neurotropic
microbes (e.g. sepsis) are a prerequisite for CNS entry.
BBB crossing can occur via transcellular or paracellular
mechanisms, or when immune cells are ‘hijacked’ by
microbes in the periphery, by Trojan Horse mechanisms
(Toborek et al., 2005; Pulzova et al., 2009; Elsheikha and
Khan, 2010; Kaushik et al., 2011). Once inside the CNS,
the neurons, microglia or astrocytes can be infected or
activated by microbial toxins, such as LPS. Innate immu-
nity plays an important role here, as the microbial ligands
are sensed by toll-like receptors (TLRs) leading to signal
transduction via NFkB. The subsequent release of
(inflammatory) mediators by the activated astroglia might
then alter neurological function and affect BBB function
and integrity (Kang and McGavern, 2010).
Remarkably, not all pathogens that cause neurological
disease breach the vascular barrier and enter the CNS. In
low numbers, circulating microbes and their toxins might
not penetrate into the CNS but can still activate the
BBB-EC to release signals that affect the underlying
neuropil (i.e. brain cells) (Fig. 2). Mild stimulation of the
brain endothelium with low amounts of microbes/toxins
increases expression of cell adhesion molecules and
release of cytokines/chemokines, whereas stronger
stimulation also includes opening of the intercellular junc-
tions and increased barrier permeability (Tripathi et al.,
2006; 2009), thus exposing the brain to neurotoxic plasma
substances, including serum albumin that can induce
seizures (Friedman et al., 2009; Hooper et al., 2009) or
antibodies to ion channels, thus affecting neurological
function (Lang et al., 2005). Little is known how brain EC
activation by itself can contribute to neuropathogenesis.
Here, we examine microbial CNS infections in the context
of the BBB as a relay station and modulator of astroglial–
neuronal function.
A fascinating example of peripheral influences that
affect neurological functioning can be appreciated in cere-
bral malaria (CM) where the Plasmodium falciparum para-
How can the blood–brain barrier endothelium influence the brain? 1471
© 2011 Blackwell Publishing Ltd, Cellular Microbiology, 13, 1470–1478

3. site that lives inside an infected RBC (PRBC) ‘remodels’
the PRBC surface with parasite-encoded proteins (Pf-
EMP-1) that then bind to endothelial receptors such as
ICAM-1, resulting in a sequestration of PRBCs in the
vascular lumen. PRBC sequestration is considered
central to CM pathology and concomitant with other brain-
endothelial activating factors likely contributes to the neu-
rological symptoms (Turner et al., 1994; Adams et al.,
2002; van der Heyde et al., 2006; Combes et al., 2010).
Non-immune adults (e.g. travellers) and mostly young
children are especially susceptible to CM, manifested by
impaired consciousness, seizures and coma (Idro et al.,
2005). Unfortunately, even after successful treatment and
recovery, neurological sequelae can remain (Idro et al.,
2010). Understanding CM pathogenesis is therefore
of utmost importance and may clarify the BBB role in
other neurological diseases. In our laboratories we are
currently studying the mechanisms whereby PRBC
induce neurological dysfunction. Using Transwelltm
-based
in vitro human BBB models validated for CM research
(Tripathi et al., 2006; 2007; 2009), we found that PRBC-
mediated activation of the host BBB-EC leads to increase
expression of luminal ICAM-1 and polarized release of
cytokines/chemokine to both luminal (blood-facing) side
and basal (brain-facing) side of the monolayers. A signifi-
cant loss of barrier integrity was only observed upon addi-
tion of high numbers of PRBC. Traditionally cytokines/
chemokines are thought to be released to the luminal side
of the BBB in order to alarm the immune system.
However, circulating cytokines can also shuttle across the
BBB into the CNS (Banks et al., 1995) and both luminal
and basal release of cytokines from BBB-ECs in response
to LPS has also been described (Verma et al., 2006). To
test if the BBB secretions towards the brain side would
affect astrocytes and/or neurons, we collected this con-
ditioned BBB medium from our CM experiments and
added it to astrocyte and neuronal cultures (Fig. 1). Here,
we found a concentration-dependent activation of astro-
cytes (by GFAP immunocytochemistry) and in neurons
disruption of axonal transport and retraction of neuronal
extensions (Stins laboratory, unpubl. obs.). This is in
agreement with axonal damage as found in human
CM autopsies (Medana et al., 2007). These cytokines/
chemokines present in the basal BBB-EC secretions may
play a role in glial cell migration, angiogenesis, tumorigen-
esis, and wound healing, but also modulate astrocyte–
neuronal interactions and thus be involved in neurological
dysfunction.
BBB activation by other pathogens
In advanced stages of Toxoplasma gondii encephalitis
(TE), BALB/c and more sensitive C57BL/6 murine models
show BBB activation and damage as reflected by (i) a
prominent induction of major histocompatibility complex
(MHC) class I and II antigens, (ii) cell adhesion molecules
VCAM-1 and ICAM-1 expression (Deckert-Schluter et al.,
1999; Wang et al., 2007), (iii) a higher ALCAM expression
and (iv) increased BBB permeability (Silva et al., 2010).
T. gondii binds and infects retinal-brain endothelial cells,
bovine umbilical vein endothelial cells (BUVEC) and
human endothelium in vitro, leading to BBB activation. In
retinal EC and BUVEC, T. gondii induces increases in
transcripts for E-, P-selectin, VCAM-1 and ICAM-1 within
1–4 h and inflammatory mediators including GRO1,
MCP-1, Fractalkine, RANTES, IL8, IP10, MCP-1,
GM-CSF, COX2 and iNOS persist at least up to 72 h post
infection (Daubener et al., 2001; Stumbo et al., 2002;
Fig. 1. In vitro set-up to study effects of brain endothelium on underlying brain cells. Shown here is a Transwelltm
tissue culture insert that can
be seeded with brain endothelial cells and inserted in a tissue culture wells, thus creating a two-chamber model where the upper compartment
represents the blood side and the bottom compartment the brain side. Dependent on the experimental set-up astrocytes, pericytes can be
incorporated on the abluminal side on the membrane (in contact with the brain endothelial cells) (B), in the bottom compartment or in a
separate tissue culture well (A). Upon confluence and when sufficient barrier function is obtained, microbes can be added to the upper
compartment. Activation of the BBB endothelium, release of factors to either side and their effects on the underlying brain cells can then be
studied.
1472 D. J. Grab, S. J. Chakravorty, H. van der Heyde and M. F. Stins
© 2011 Blackwell Publishing Ltd, Cellular Microbiology, 13, 1470–1478

4. Smith et al., 2004; Knight et al., 2005; Taubert et al.,
2006a,b). Once T. gondii crosses the BBB, subsequent
microglial infection and astrocyte activation can then have
a negative effect on the BBB leading to activation and loss
of integrity (Silva et al., 2010; Dellacasa-Lindberg et al.,
2011).
African trypanosomes (Trypanosoma brucei spp.)
upregulate brain endothelial expression of ICAM-1,
VCAM-1 and E-selectin and release of IL-6, CXCL8,
CCL2 and TNF-a (Mulenga et al., 2001; Girard et al.,
2005; Grab and Kennedy, 2008). Matrix metalloprotease
MMP2 was increased in CSF (Hainard et al., 2011) and in
vitro studies showed that brain endothelium can poten-
tially contribute to this (D. Grab, unpublished). In vitro and
gene-profiling studies showed that Trypanosome transmi-
gration requires cysteine proteases Gaq-mediated
calcium and protease-activated receptor-2 (PAR-2) sig-
nalling (Nikolskaia et al., 2006; Grab et al., 2009a), initial
events that are precursory to CNS neuroinflammatory
disease (Grab et al., 2009a).
Activation of BBB-EC by Borreliia burgdorferi alone
or in co-infection with Anaplasma phygocytophilum-
infected neutrophils has also been observed. Increased
expression of host cell adhesion molecules, plasmino-
gen activators, plasminogen activator receptors and
increases release of cytokines, chemokines and metal-
loproteases might contribute to neuropathogenesis
(Sellati et al., 1995; Burns et al., 1997; Grab et al., 2005;
2007; 2009b).
Blood–brain barrier breakdown as a loss of junctional
molecules has been shown during advanced neuro-HIV
infection based on biopsy and post-mortem samples and
in vivo disease models (Persidsky et al., 2006; van
Horssen et al., 2007). During initial infection, high viral
titres and secreted viral proteins activate the BBB-EC
resulting in increases in expression of cell adhesion mol-
ecules and release of cytokines and chemokines (Stins
et al., 2001b; 2004; Persidsky et al., 2006; Shiu et al.,
2007; Chaudhuri et al., 2008), which directed towards the
brain side can affect neurological functioning and contrib-
utes to sickness behaviour. The dysregulation of the BBB
during and after neuroinvasion is a critical component of
the neuropathogenic process (Strazza et al., 2011). An
indirect pathogen-induced peripheral stimulus can also
alter neurological function and behaviour. Circulating
LPS, which is present in low concentrations in conditions
including HIV infection, alcohol abuse and some major
depression disorders (Frank et al., 2004; Maes et al.,
2008; Nowroozalizadeh et al., 2010), does not readily
enter the CNS, but accumulates in the BBB-EC, but still
astroglial activation is observed (Singh and Jiang, 2004;
Banks and Robinson, 2009).
Mechanisms for BBB-related neurological
modulation
In neurotropic infections, generally similar host responses
are observed at the BBB, but a role of the BBB in confer-
ring neurological dysfunction is most clearly observed in
CM. However, the mechanisms that are responsible are
unclear, as is their exact function and how they will affect
neuronal function. Reduced release of neuroprotective
Fig. 2. Transmission of astroglial and
neuronal modulating signals from the BBB
endothelium. Neurotropic microbes, like
PRBC, HIV-1 or Trypanosomes, can stimulate
the release of soluble factors (represented by
the arrows), such as astroglial-activating
matrix metalloproteases, cytokines and
chemokines such as IL-1b, IL-6, CCL20,
GRO’s and TNFa from the basal side of brain
endothelial cells. Targets for these mediators
are present in the brain on either astroglial
cells and/or neurons and can result in
modulation of astroglial activation and both
directly and indirectly of neuronal function.
Vessel lumen
Microbial ac!va!on
= Cell adhesion
molecules
= signaling
BBB-
endothelium
Brain parenchyma
endothelium
NO
+ ?
MMP’s
Cytokines
Chemokines
Astrocytes/
microglia
+ -? + -?
Neuron
+ -?
Neurological Modula!on > BeneÞts versus Complica!ons
How can the blood–brain barrier endothelium influence the brain? 1473
© 2011 Blackwell Publishing Ltd, Cellular Microbiology, 13, 1470–1478

5. secretions like brain-derived neurotrophic factor (BDNF)
versus increases in release of nitric oxide (NO), glycine,
cytokines, chemokines and/or MMPs could contribute to
these effects (Fig. 2). Dependent on the individual,
release of BBB-EC-derived cytokines/chemokines could
be very robust in CM (Tripathi et al., 2009; Wassmer et al.,
2011). Inside the CNS, the BBB-derived cytokines/
chemokines may play a role in glial cell migration, angio-
genesis, tumorigenesis and wound healing, but may
also modulate astrocyte–neuronal interactions and thus
be involved in neurological dysfunction. At this moment, it
is unclear as to which particular cytokines/chemokines
are involved, their exact function, how they will affect
neuronal functioning and whether their targets are on
brain cells.
Using in vitro BBB-CM models we observed large
increases in CCL20 transcripts and release (Tripathi
et al., 2009). The non-promiscuous receptor for CCL20,
CCR6 is generally non-detectable in control brains,
but upregulated in brain inflammation, such as in the
murine model for CM that replicates certain features of
human pathology (Hunt et al., 2010), and we see
increased CCR6 immunostaining in cells resembling
neuroglia, possible oligodendrocytes. Oligodendrocytes
are believed to be involved in neuronal signal modula-
tion, and as such, BBB-released CCL20 could affect
neuronal transmission. Astrocytes also secrete CXCL1,
2, 3 and their receptor (CXCR2) is present on neuron
(Dorf et al., 2000). CXCR2 can regulate APMA type
glutamate receptor function by increasing receptor coop-
erativety and postsynaptic transmission amplitude (Lax
et al., 2002). Furthermore, IL8 and CXCL1 can modulate
Purkinje neuron activity (Giovannelli et al., 1998).
CXCL1 increases ERK phosphorylation in cortical
neurons (Xia and Hyman, 2002). Thus, these may be
potential mechanisms whereby release of CXCL1, 2 or 3
from the basolateral side of the BBB, may modulate
astroglial and/or neuronal function. Taken together, alter-
ation of the chemokine/receptor ratio in the brain may be
a mechanism to modulate neuronal function, but when
the BBB is over activated, this may lead to neuronal
dysfunction.
Other factors, such as MMPs or NO basally released
from an activated BBB can modulate not only matrix–
BBB-EC interactions and thus barrier integrity but
also synaptic function and long-term potentiation by
cleavage of NR1 subunit of the NMDA receptor and
ICAM-5 (Szklarczyk et al., 2002; Huang et al., 2008;
Conant et al., 2010; Louboutin et al., 2010). In CM, NO
released from the BBB can have a dual effect; luminal
released NO is quenched by free haemoglobin and
reactive oxygen species and therefore results in a low
peripheral NO bioavailability (Gramaglia, 2006). As
serum arginine levels are coupled to eNOS activity, it is
not clear how this affects NO released to the basal side
of the BBB in CM and other neuromicrobial diseases.
NO has various effects on neuronal function, including
anterograde signalling (Fernandez-Alvarez et al., 2011),
cognitive learning (Paul and Ekambaram, 2011), depres-
sion behaviour (Workman et al., 2011), glutamatergic
transmission (Sardo et al., 2011) and altering of sensi-
tivity of dopamine release to presynaptic activation
(Hartung et al., 2011). In astrocytes, NO alters connex-
ins leading to reduction of inter-astrocytic gap-junction
communications (Ball et al., 2011) which could also
affect astrocyte–BBB-EC or astrocyte–neurons com-
munications. Reactive nitrogen species can trigger lipid
peroxidation chain reactions throughout the cerebral
vasculature, and brain parenchyma and thus contribut-
ing neurocognitive sequelae as seen in sepsis survivors
(Berg et al., 2011).
Conclusions
It makes sense that, in the context of the NVU principle,
an alteration in the ‘resting’ status of the BBB-EC by
neurotropic microbes can lead to modulation of
astroglial/neuronal function. Thus, an activated BBB
could function as a communication-relay station between
peripheral signals to the brain and contribute to symp-
toms ranging from mild symptoms such as malaise to
serious neurological dysfunction such as coma in CM.
Brain endothelial-derived modulating factors that play a
role in NVU function include the and increased release
of local and brain-directed cytokines, chemokines, NO
and MMPs versus a decreased release of neurotrophic
and protective factors. It is not clear at what point the
altered release of these factors would tip the balance
from playing a beneficial role in astroneuronal homeo-
stasis and repair to a detrimental one leading to neuro-
logical dysfunction (Fig. 3). Therefore, it is important to
understand BBB-EC factors that are involved in mediat-
ing and regulating the responses to microbial exposure
and ‘decide’ at which point the balance tips from a ben-
eficial neuroprotective response to a detrimental reac-
tion. BBB responses, like in CM or stroke, can be very
local and affecting only small brain areas. Therefore,
changes in these factors can be missed in systemic
measurements of blood or CSF samples. In vitro
systems can aid to identify these factors that subse-
quently can be validated in vivo. Many questions still
remain and further clarification of interactions between
the BBB-EC and underlying CNS components are
needed as this may not only lead to novel therapeutic
targets for treating neurological dysfunction in a wide
variety of disorders but could also be beneficial in the
repair of astroneuronal function in conditions such as
stroke.
1474 D. J. Grab, S. J. Chakravorty, H. van der Heyde and M. F. Stins
© 2011 Blackwell Publishing Ltd, Cellular Microbiology, 13, 1470–1478

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Fig. 3. The balance of factors derived from the activated BBB
endothelium could determine a neuroprotective versus detrimental
response. Under homeostatic conditions, the BBB endothelium
releases substances such as cytokines, chemokines, NO and
MMPs, neurotrophic and neuroprotective factors towards the brain
side. Upon activation, the BBB endothelium releases factors in
order to ‘alert’ brain cells and protect the neurological function.
However, with strong activation the BBB may ‘overreact’ and these
otherwise positive factors may turn into detrimental substances. A
decrease in neuroprotective and neurotrophic secretions may occur
concomitantly. It is not yet clear which BBB-EC factors govern the
release of these substances and at what point the balance tips
from being protective of the brain’s homeostasis to being negative
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