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Noah Riccelli

Bacterial Meningitis and The Blood-Brain-Barrier

Noah Riccelli
Seton Hill University
SPA 220-02
October 28, 2020
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Meningitis is a serious and potentially life-threatening infection characterized by an
inflammation of the arachnoid and pia mater in the brain and spinal cord. 1,2 This illness can be
viral, fungal, or bacterial. On a worldwide scale, bacterial meningitis is on the top ten list of
deaths related to infectious disease. All individuals are susceptible to this infection, but infants,
college students, and the elderly are the most at-risk. Even though an effective vaccine exists
and there are proven antibiotics readily available, approximately 1.2 million individuals contract
the illness in a given year and 170,000 of these cases are fatal. 1,2 Additionally, 50% of those who
survive deal with permanent neurological impairment. 1-3 The limitations to treating this
infection based on the blood-brain-barrier (BBB) are partially explained by the BBB itself as both
a physical and functional unit. Bacterial meningitis is treated through the use of steroids and
antibiotics, but there are many potential complications involved due to the physical and
chemical selectivity of the BBB.
Diagnosis of bacterial meningitis is difficult because symptoms are varied. A severe
headache, fever, and neck tightness are most common. In more advanced cases, though, a
patient presents with neurological impairment, epileptic seizures, or even a coma. 3 The onset
and progression of the symptoms occur so rapidly that by the time a patient seeks medical
treatment the prognosis is often bleak. Though most individuals recover from bacterial
meningitis, a lack of prompt-treatment can result in death within days or hours. Although blood
tests or imaging techniques like a CT scan or MRI are common methods to suggest an infection
is present, the collection of cerebrospinal fluid (CSF) through a lumbar puncture can give a
definite answer on bacterial meningitis. Additionally, it provides physicians information on the
specific types of bacteria present so they can prescribe the correct antibiotic. Antibiotic
resistance can be the difference between life and death, so having the information to prescribe
an appropriate antibiotic is necessary. 1,3 Unlike a case of viral or fungal meningitis where the
patient is often sent home and prescribed bedrest, bacterial meningitis requires treatment with
antibiotics.3 This intervention is complicated for two reasons: one is quickly finding an antibiotic
for the specific bacteria and the second is finding an antibiotic able to cross the BBB.
The composition of the BBB provides understanding about the pathophysiology of
bacterial meningitis. Ultimately, the ability to cross the BBB depends on the size of the
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molecule, the positive or negative charge, how lipophilic it is, binding of certain proteins, and
flow of CSF.3 Small molecules with little to no plasma protein binding and many lipophilic
substances are ideal candidates to cross the barrier, but many other substances face a
restriction.1,3 Lipid solubility determines how fast and effective a drug can diffuse into the brain.
Some drugs with polar components are likely to experience a delayed entry while other drugs
with a high lipid solubility will leave the bloodstream and enter the CNS extremely quickly and
efficiently.3-5 Adherens junctions and tight junctions are located in endothelial cells. These
junctions control BBB permeability as well as monitor the polarity of cells, signaling proteins,
and transcription.1 These specific characteristics explain the mechanisms in which blood-borne
bacteria are able to cross the BBB.
Bacteria involved with bacterial meningitis undergo several mechanisms in order to
reach the BBB. Besides entering the BBB, the bacteria must first survive within the bloodstream
then colonize to the circulatory system of the brain. 4 There is not a complete scientific
consensus on how exactly the bacterial components are able to cross the barrier, but the
specific component involved as well as how it interacts with receptors on endothelial cells can
help scientists to make predictions.1,4 Common microbes that can cause bacterial meningitis
include N. meningitidis, S. pneumoniae, and H. influenzae. E. coli and group B Streptococcus
(GBS) are two examples that occur mainly in infants. 1,3,4 The microbiological and chemical
makeup of these microbes provide information on the characteristics and properties that
permit them to cross the BBB. There are multiple ways of gaining entry, but the two most
common are through a transcellular pathway that invades the endothelial cellular layer and a
paracellular pathway that inflicts trauma on the tight and adherens junctions. 4 For example,
GBS, N. meningitidis, and E. coli have been shown to bind to brain microvascular endothelial
cells (BMECs). Many of these bacteria contain a polysaccharide in the form of a capsule that
regulates their invasion.1 As the pathogens attach to the host receptors, regulation becomes a
factor. The laminin receptor and the platelet activating factor receptor are the two main points
at which N. meningitidis, H. influenzae, and S. pneumoniae enter the CNS.1-3 The attachment of
bacteria to the endothelium as well as the interactions between bacteria and receptors both
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explain the invasion aspect, but the defensive response and breakdown of BBB integrity provide
clarity on the physiology of bacterial meningitis.
There is more to the physiological process than bacteria crossing the BBB and producing
the effects on the brain and meninges. The pathophysiology of bacterial meningitis starts and
ends with the chemical and physical disruption of the BBB. The way the BBB responds to defend
itself can pose additional risks for the patient. The pathogens affect the integrity of the
endothelial cells that serve as the barrier between the brain and the outside environment. 1,4,5
This mechanism can occur through toxic effects and also by disrupting both the structure and
formation of the adherens junctions and tight junctions. In some instances, there are pore-
forming toxins given off by bacteria such as GBS and S. pneumoniae. Consequently, the risk for
developing meningitis is proportional to the secretion of these toxins. 1,3 Furthermore, the
response from the BBB to these toxins includes the formation of cytokines and chemokines,
which disrupt the integrity of the BBB.1 As this integrity becomes disrupted, the permeability of
the barrier increases.1-4 When the barrier is weakened, bacteria and other molecules can cross
over more easily. Substances previously unable to cross the barrier will be able to.
When the BBB senses the presence of harmful bacteria, there is a rush to recruit and
activate neutrophils as an initial response. How fast and effectively the neutrophils are
recruited determines both the response by the BBB and the overall outcome of the disease.
When the pathogens overtake the barrier, the common response is inflammation due to the
endothelial cells being overactivated.1,3-5 In fact, a main cause of the change in permeability is
inflammation of the BBB.1 This inflammation points to the barrier as not only a physical layer of
protection, but also a functional one. Research to help demonstrate this is ongoing. A study
done on a mouse with meningitis showed that when the neutrophils did not experience
apoptosis quick enough, the inflammation in the BBB increased and the outcome of the disease
worsened.1 In further studies, scientists want to figure out the mechanisms behind the
neutrophils acting normally in some instances and their delayed response in other cases. When
the barrier becomes inflamed, the main danger is that it will now be susceptible to foreign
bacterial elements and certain drugs.
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A common first line of treatment for bacterial meningitis is a corticosteroid. Often,
steroid hormones can cross the BBB by transmembrane diffusion. 6 With an extracellular
pathway, extremely large hormones cross by residual leakiness.7 The properties of these steroid
hormones explain why they can penetrate the barrier. For example, steroid hormones are
typically small and lipid soluble, which allows them to cross bidirectionally. 6,7 In addition,
binding proteins help the molecules cross the BBB. The rate and the degree of penetration are
altered by circulating half-life.6 A commonly prescribed steroid is a glucocorticoid called
dexamethasone. Patients with inflammatory issues dealing related to the immune system,
allergic reactions, and infection are given this drug. Other commonly used steroids include
prednisone, hydrocortisone, and betamethasone. 5,6,7 These steroids are not meant to be a cure
for bacterial meningitis but are meant to decrease inflammation in and outside of the CNS.
With bacterial meningitis and other diseases, the typical defensive response of the BBB is to
become inflamed. This response is similar to the body becoming inflamed as a result of certain
diseases and infection. The endothelial permeability and the diameter of vessels both increase,
so there is less regulation of substances leaking through. 1,6 An inflamed barrier will be less
effective at inhibiting the entry of unwanted molecules, so the body is susceptible to many new
hazards. Furthermore, certain antibiotics that could normally cross the BBB may not be able to
as quickly or effectively as before. Since the increase in inflammation associated with bacterial
meningitis negatively affects the integrity and permeability of the BBB, a decrease in
inflammation restores this integrity.6 Antibiotics used to treat the infection can now penetrate
the barrier without difficulty.5,7
The treatment of bacterial meningitis with antibiotics involves many factors. First, the
infection can overtake the body in days or hours, so physicians must make the proper diagnosis
and treatment decisions quickly. With diagnosing, there must be tests ordered and a lumbar
puncture performed very early on to determine the type of bacteria present in the CSF. 7 With
this knowledge, an effective antibiotic can be paired to treat the infection. Physicians must also
take into consideration the properties of each antibiotic to determine whether it will be able to
cross the BBB. One property that can determine the outcome of using the drug is whether it is
lipid or water soluble. Drugs of both solubilities are commonly used, but fat-soluble once are
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always preferred. Some common antibiotics used to treat bacterial meningitis include
cephalosporins like ceftriaxone and cefotaxime. Other examples include vancomycin,
meropenem, and medications in the penicillin family.4,6,7 Since antibiotics in the penicillin family
are highly water-soluble, they have difficulty crossing the BBB. 7 Additionally, meropenem and
vancomycin are also water-soluble. Since the BBB favors lipid-soluble drugs, many of these
water-soluble drugs experience more difficulty and take longer to cross the barrier than fat-
soluble drugs. To overcome this limitation, physicians give patients a combination of antibiotics
(usually two or three). Using this strategy helps combat potential antibiotic resistance,
increases the probability of the drug successfully treating the disease, and speeding up the
penetration into the BBB.6,7 More research is being conducted to discover a better option for
treatment. A lot of this research involves individual case studies and is considered anecdotal
evidence. There was a case study involving a patient with bacterial meningitis caused by
Acinetobacter baumannii. The patient was given three different antibiotics intravenously:
vancomycin, meropenem, and tigecycline. After several days, the vancomycin and meropenem
were stopped while the tigecycline doses continued. A number of tests on CSF showed the
meningeal bacteria still present, but a slight increase in the dosage resulted in negative tests for
meningitis only three days later.7 While a number of drugs are effective at treating bacterial
meningitis, scientists are searching for more effective drugs.
Due to the complexity of symptoms and how fast a patient’s condition can worsen
without proper intervention, diagnosis and treatment of bacterial meningitis can be
complicated. The BBB is used to develop understanding of the pathophysiology of bacterial
meningitis. The defensive response and loss of integrity along with the increase in permeability
and inflammation explains how the BBB acts as both a physical and functional unit.1,2,6 Steroids
are used to decrease this inflammation and prevent other unwanted molecules from
penetrating. The limitations to treating this infection stem from the specific properties of the
drugs and how they interact with the BBB. Lipophilic and smaller size molecules are best-suited
to penetrate the barrier.1,6 Besides using corticosteroids to decrease inflammation, there are a
number of antibiotic interventions to treat the symptoms. While most of these drugs are water-
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soluble and cannot cross the barrier very fast, physicians use combination therapy to combat
this limitation.
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References

1. van Sorge NM, Doran KS. Defense at the border: the blood-brain barrier versus bacterial
foreigners. Future Microbiol. 2012;7(3):383-394. doi:10.2217/fmb.12.1
2. Hoffman O, Weber RJ. Pathophysiology and treatment of bacterial meningitis. Ther Adv
Neurol Disord. 2009;2(6):1-7. doi:10.1177/1756285609337975
3. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal
fluid/blood-brain barrier for treatment of central nervous system infections. Clin
Microbiol Rev. 2010;23(4):858-883. doi:10.1128/CMR.00007-10

4. Guennec LL, Coureuil M, Nassif X, Bourdoulous S. Strategies used by bacterial pathogens

to cross the blood–brain barrier. Cellular Microbiology. 2019;22(1).
doi:10.1111/cmi.13132 
5. Yau B, Hunt NH, Mitchell AJ, Too LK. Blood‒brain barrier pathology and CNS outcomes
in streptococcus pneumoniae meningitis. Int J Mol Sci. 2018;19(11):3555. Published 2018
Nov 11. doi:10.3390/ijms19113555
6. Banks WA. Brain meets body: the blood-brain barrier as an endocrine
interface. Endocrinology. 2012;153(9):4111-4119. doi:10.1210/en.2012-1435
7. Nau R, Seele J, Djukic M, Eiffert H. Pharmacokinetics and pharmacodynamics of
antibiotics in central nervous system infections. Curr Opin Infect Dis. 2018;31(1):57-68.
doi:10.1097/QCO.0000000000000418