BACTERIAL MENINGITIS
Basic Science review of Host-Pathogen interactions
Nemani V. PrasadaraoDivision of Infectious Diseases, Children’s Hospital Los Angeles
Molecular Microbiology and Immunology, University of Southern California School of Medicine
Los Angeles, CA 90027
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A brief introduction to bacterial meningitis1. Bacterial meningitis is a serious health threat worldwide with a case fatality rates
ranging from 10% to 50% and reaching 100% if left untreated.2. Neisseria meningitidis, Streptococcus pneumoniae, Hemophilus influenzae,
Group B. streptococcus and Listeria monocytogenes account for 85% of meningitis cases in infants and adults.
3. Other bacteria that cause meningitis include Escherichia coli K1, Salmonella, Klebsiella spp., Staphylococcus aureus, and a zoonotic pathogenStreptococcus suis.
4. Mycobacterium tuberculosis (Mtb) also cause meningitis in 1% of all TB cases. Mtb-meningitis affects all age groups, but very common in young children and in people with untreated HIV-infection.
5. Despite treatment with effective antibiotics and required supportive care, 50%of survivors suffer neurological complications such as mental retardation, hearing loss, and learning deficits.
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Major steps and mechanisms involved in the pathogenesis of meningitis …….
Colonization
Survival inblood
CNS entry
NM SP GBS EC MtbNasopharynx Nasopharynx Hematogenous Hematogenous Lung
Nasopharynx Nasopharynx/GIT Hematogenous?Common inhabitant
Colonizer of femalegenital tract
Common inhabitant
Capsule, Pili, Outer membraneproteins
Capsule, cell-wall proteins,cytolysin
Nosocomial infections/environm-ental
Inhalation
OmpA, Capsule, CNF-1,Fimbriae,
IbeAHABA
Cell-wall anchored proteins, capsule, LTA, pili, cytolysin.
Complement inhibition
ComplementInhibition,
intracellular survival
Compl. inhibition, PMN & MΦintracellular survival
Compl. Inhibition?, PMN & MΦintracellular survival
B-CSFB
Pili, Opa proteins
B-CSFBP-choline
pneumolysin
BBBSeveral genes are required for
entry
BBBBBB
Fimbriae, Omps, CNF-1
BBBPili, LTA,
other adhesins
Complementinhibition, PMN-killing
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NM interaction with epithelial cells of nasopharynx
Ref: Hill et al., Clinical Science (2010), 118, 540-564.
Receptor mediated endocytosis
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E. coli K1 interaction with epithelial cells
Figure B, reused from Burns et al., Pediatrics Research, 49, 30-37, 2001, (Copy Right permission obtained) 5
B
C D
E
EC: Mittal et al., J. Biol. Chem. 286, 2183-93, 2011 and unpublished results
Syndecans are involved in Mtb attachment to lung epithelial cells
Figures reused from Zimmerman et al., Cellular Microbiology, 18, 1846-1856, 2016 (copyright permission obtained from Nature publications).
Mouse naïve lung 15 days p.i. with Mtb Ab control
10X 40X 10X 40X 40X*
2.5X 20X 40X 2.5X 2.5X*
Lung biopsies from a patient with active TB Ab control
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Sdc4
A549 cells9
Complement evasion strategies of meningitis-causing bacteria
Hill et al. Clinical Science 118, 540-564, 2010; Malito E. et al., Biochem. J. 15: 4699-4713, 2016. 7
C3 convertaseC4b2a
C3 C3b
C3 convertaseC3bBb
C5 convertaseC4b2a3b
PorBOpa
LOS
MBL
Lectin pathway
C4bp
Factor HPorA
fHBP
NspA
C5 C5b C6, 7, 8, 9 MAC
Classical pathway
Alternative pathway
C6a
C4bp OmpA of E. coli K1
Nei
sser
ia
Mycobacterium tubercusosis
?
NM survival in monocytes and macrophages
Ref: Cecchini et al., PloS One (2011), 9, e25089; Quattroni et al., Cell. Microbiol. (2012) 14, 1657–1675. 8
Neisseria meningitidis
LOS
TLR4
MyD88-dependent
TNF, IL-1,MCP-1,MIP-3
IFN-β, NOIFN-indu. protein 10
MyD88-independent
?
NhhA
G-CSF, M-CSFIL-6
TLR4
MyD88-dependent
FL-LPS Galactin-3
Increased adhesionto immune cells
Survival to establishbacteremia
(immune cells)
NO & TNF-αHMGB-1 (organ damage in sepsis)
Apoptosis
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E. coli K1 entry and survival mechanisms in macrophages
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Ref: Doran KS, Fulde M, Gratz N, Kim BJ, Nau R, Prasadarao NV, Schubert-Unkmeir A, Tuomanen EI, Valentin-Weigand P.Acta Neuropathol. (2016) 131:185-209.
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Mechanisms of Mtb entry and survival in macrophages
Ref: Awuh and Flo, Cell. Mol. Life Sci. (2017) 74:1625–1648.
TLR2: LAM, LM, 38- and 19-kDa (LpqH) mycobacterial glycoproteins, PIM, triacylated (TLR2/TLR1), or di-acylated (TLR2/TLR6) lipoproteins, chaperon proteinsTLR4: Tetra-acylated LM, HSP65, 50S ribosomal proteinTLR9: CpG DNA
MR: Mannose (LAM and manLAM)FcgR: Fc-gamma receptorsCR: Complement receptors
Mechanisms of Mtb inhibition of phagosome maturation include:1. Prevention of Rab5 recruitment2. Deactivation of PI3K3. Ndk (Mtb nucleoside diphosphate kinase)
interact with Rac1 and blocks NOX2 assembly(mechanism is not clear).
4. Ndk also blocks the fusion of Rab7.
Autophagy is another mechanisms by which macrophagesrecognize Mtb antigens on cell surface.
Coureuil et al., Virulence, 3, 164-172, 2012; Trends in Mol. Medicine, 20, 572-578, 2014; Nature Microbiology Reviews, 15, 149-158, 2017.
NM binding to and invasion of brain endothelial cells
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Type IV pili
β-adrenoreceptorCo
rtic
al p
laqu
e
Cell polarity regulatory complex
CD147
CEACAMs
VN
Opa
Opc
Invasion mechanisms involved in E. coli K1 crossing of the BBB
This figure is generated based on the data from Prasadarao’s, Huang’s and Kim’s labs (partial) 12
EGFR
Src
Cytoskeletal rearrangements
RhoGTPases
TSRG
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Mtb invasion of brain endothelial cells
Be et al., Curr Mol Med. 2009, 9: 94–99; Michiel van der Flier et al., The Ped. Infect. Dis. J. (2004), 23:608-613;Tucker et al., Disease Models & Mechanisms (2016) 9, 1497-1506.
Summary of overview of bacterial meningitis
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1.
Infection stage Bacterial pathogens Mycobacterium tuberculosis
Entry into the host Asymptomatic colonizers of nasopharynx, Inhalation of droplets containingfemale genital tract or GIT Mtb
2. Colonization Mucosal epithelial cells Lung epithelial cells
3. Complement evasion Binding to C4bp or FH Mechanism unclear (C4bp?)
4. Immune cell interaction Binding to receptors to avoid Prevents phagosome maturationkilling by different immune cells by altering their function.
5. Interaction with the BBB Several bacterial ligand-interactions Bacterial ligands and their cognitivewith BMEC receptors. receptors are not known.Cytoskeletal rearrangements required Cytoskeletal rearrangements required