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

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