BACTERIAL MENINGITIS

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1 BACTERIAL MENINGITIS Basic Science review of Host-Pathogen interactions Nemani V. Prasadarao Division of Infectious Diseases, Children s Hospital Los Angeles Molecular Microbiology and Immunology, University of Southern California School of Medicine Los Angeles, CA

2 A brief introduction to bacterial meningitis 1. 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 pathogen Streptococcus 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. 2

3 Colonization Survival in blood Major steps and mechanisms involved in the pathogenesis of meningitis. NM SP GBS EC Mtb Nasopharynx Nasopharynx Hematogenous Hematogenous Lung Nasopharynx Nasopharynx/GIT Hematogenous? Common inhabitant Capsule, Pili, Outer membrane proteins Complement inhibition, PMN-killing Common inhabitant Capsule, cellwall proteins, cytolysin Complement inhibition Colonizer of female genital tract Cell-wall anchored proteins, capsule, LTA, pili, cytolysin. Complement Inhibition, intracellular survival Nosocomial infections/environmental OmpA, Capsule, CNF-1,Fimbriae, IbeA Compl. inhibition, PMN & MΦ intracellular survival Inhalation HABA Compl. Inhibition?, PMN & MΦ intracellular survival CNS entry B-CSFB Pili, Opa proteins BBB B-CSFB P-choline pneumolysin BBB Pili, LTA, other adhesins BBB Fimbriae, Omps, CNF-1 BBB Several genes are required for entry 3

4 NM interaction with epithelial cells of nasopharynx Receptor mediated endocytosis Ref: Hill et al., Clinical Science (2010), 118,

5 E. coli K1 interaction with epithelial cells B E C D EC: Mittal et al., J. Biol. Chem. 286, , 2011 and unpublished results Figure B, reused from Burns et al., Pediatrics Research, 49, 30-37, 2001, (Copy Right permission obtained) 5

6 Syndecans are involved in Mtb attachment to lung epithelial cells Mouse naïve lung 15 days p.i. with Mtb Ab control Sdc4 * 10X 40X 10X 40X 40X * 2.5X 20X 40X 2.5X 2.5X A549 cells9 Lung biopsies from a patient with active TB Ab control Figures reused from Zimmerman et al., Cellular Microbiology, 18, , 2016 (copyright permission obtained from Nature publications). 6

7 Complement evasion strategies of meningitis-causing bacteria Neisseria PorB Opa LOS PorA Lectin pathway MBL C4bp Factor H C3 C3 convertase C4b2a C3 convertase C3bBb Classical pathway C4bp C3b OmpA of E. coli K1 Alternative pathway fhbp NspA? Mycobacterium tubercusosis C6a C5 convertase C4b2a3b C5 C5b C6, 7, 8, 9 MAC Hill et al. Clinical Science 118, , 2010; Malito E. et al., Biochem. J. 15: ,

8 NM survival in monocytes and macrophages Neisseria meningitidis LOS? NhhA FL-LPS Galactin-3 NO & TNF-α HMGB-1 (organ damage in sepsis) TLR4 TLR4 (immune cells) Apoptosis MyD88- dependent MyD88- independent MyD88- dependent Increased adhesion to immune cells TNF, IL-1, MCP-1,MIP-3 IFN-β, NO IFN-indu. protein 10 G-CSF, M-CSF IL-6 Survival to establish bacteremia Ref: Cecchini et al., PloS One (2011), 9, e25089; Quattroni et al., Cell. Microbiol. (2012) 14,

9 E. coli K1 entry and survival mechanisms in macrophages 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:

10 Mechanisms of Mtb entry and survival in macrophages TLR2: LAM, LM, 38- and 19-kDa (LpqH) mycobacterial glycoproteins, PIM, triacylated (TLR2/TLR1), or di-acylated (TLR2/TLR6) lipoproteins, chaperon proteins TLR4: Tetra-acylated LM, HSP65, 50S ribosomal protein TLR9: CpG DNA MR: Mannose (LAM and manlam) FcgR: Fc-gamma receptors CR: Complement receptors Autophagy is another mechanisms by which macrophages recognize Mtb antigens on cell surface. Ref: Awuh and Flo, Cell. Mol. Life Sci. (2017) 74: Mechanisms of Mtb inhibition of phagosome maturation include: 1. Prevention of Rab5 recruitment 2. Deactivation of PI3K 3. Ndk (Mtb nucleoside diphosphate kinase) interact with Rac1 and blocks NOX2 assembly (mechanism is not clear). 4. Ndk also blocks the fusion of Rab7. 10

11 NM binding to and invasion of brain endothelial cells Opa Type IV pili β-adrenoreceptor CEACAMs Opc VN CD147 Cortical plaque Cell polarity regulatory complex Coureuil et al., Virulence, 3, , 2012; Trends in Mol. Medicine, 20, , 2014; Nature Microbiology Reviews, 15, ,

12 Invasion mechanisms involved in E. coli K1 crossing of the BBB EGFR RG TS Rho GTPases Src Cytoskeletal rearrangements This figure is generated based on the data from Prasadarao s, Huang s and Kim s labs (partial) 12

13 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: ; Tucker et al., Disease Models & Mechanisms (2016) 9,

14 Summary of overview of bacterial meningitis Infection stage Bacterial pathogens Mycobacterium tuberculosis 1. Entry into the host Asymptomatic colonizers of nasopharynx, Inhalation of droplets containing female 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 maturation killing by different immune cells by altering their function. 5. Interaction with the BBB Several bacterial ligand-interactions Bacterial ligands and their cognitive with BMEC receptors. receptors are not known. Cytoskeletal rearrangements required Cytoskeletal rearrangements required 14

15 THANK YOU FOR YOUR ATTENTION 15