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Investigating the cervicovaginal mucus barrier properties of women with bacterial vaginosis Thuy Hoang May 18, 2015
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  • Investigating the cervicovaginal mucus barrier properties of women with bacterial vaginosis

    Thuy Hoang

    May 18, 2015

  • Highly adhesive and viscoelastic 3

    Mucus coats entry points1 Nanoporous mesh2

    1. Iwasaki, A., Nat Rev Immunol. 2010 2. Sanders et al., AJRCCM, 2000

    3. Cone, R.A., Mucosal Immunology, 1999

    Mucus is a barrier to pathogens

    2

    Mucus can sterically and adhesively block pathogens THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

  • Cervicovaginal Mucus (CVM)

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

    • Mucus is secreted by endocervix

    • Expelled into vaginal compartment through cervical os

    • Mixes with: vaginal transudate, exfoliated epithelial cells, bacterial secretions

    • In FRT, mucus lining is ~10 µm thick

    • CVM is home to microbiota that can produce enzymes to modulate it

    • Enzymes can degrade barrier properties of CVM

    Iwasaki, A., Nat Rev Immunol. 2010

  • The vaginal microbiota varies among women

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

    • Lactobacilli dominated: -Near monomicrobial Lactobacilli -pH < 4.0 • Polymicrobial culture/Bacterial Vaginosis (BV): -Overgrowth of many different mostly gram-negative species -pH > 4.5 -Recurrence rate >50% within 12 months -BV incidence rate 29.2% in the US -BV increased risk of HIV acquisition by 60% -Risk factor for adverse obstetric outcomes, PID, acquisition/transmission of STIs

    Lactobacillus-dominated

    Polymicrobial/BV

  • Methods

    Instead® menstrual cups

    • Donor Mucus Undiluted CVM can be obtained from self-administered collection device • mCherry fluorescently labeled HIV

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

    • Quantitative Microscopy Technique -Multiple Particle Tracking (MPT) -Obtain x, y positional data over time -Calculate Mean-Square Displacement (MSD)

  • HIV is diffusive in polymicrobial CVM

    Lactobacillus-dominated Polymicrobial/BV

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

  • HIV is diffusive in polymicrobial CVM

    10-3

    10-2

    10-1

    100

    101

    0.01 0.1 1 10

    Dis

    tanc

    e Tr

    avel

    ed

    (µm

    2 )

    Time Scale (s)

    Polymicrobial/BV

    Water

    Lactobacillus-dominated

    Polymicrobial/BV

    Lactobacillus-dominated

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

  • HIV is diffusive in CVM even after antibiotic treatment

    10-3

    10-2

    10-1

    100

    101

    0.01 0.1 1 10

    Dis

    tanc

    e Tr

    avel

    ed

    (µm

    2 )

    Time Scale (s)

    Before

    Water

    After

    • BV is treated with course of antibiotics (Metronidazole, Clindamycin, Tinidazole)

    • 1 month after treatment, HIV is still diffusive in CVM

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

  • CVM barrier properties similar between women with symptomatic and asymptomatic BV

    10-3

    10-2

    10-1

    100

    101

    0.01 0.1 1 10

    Dis

    tanc

    e Tr

    avel

    ed

    (µm

    2 )

    Time Scale (s)

    Symptomatic

    Water

    Asymptomatic

    Lactobacillus-dominated

    • Symptomatic - presented at a clinic for treatment

    • Asymptomatic - self-reported “healthy” and without vaginal symptoms

    • HIV diffusion was similar between these two groups

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

  • HIV diffusion correlated with pH and lactic acid concentration

    10-3

    10-2

    10-1

    100

    101

    3 3.5 4 4.5 5 5.5 6 6.5 7

    MSD

    at 1

    sec

    ond

    pH

    Lactobacillus-dominated

    Polymicrobial/BV

    10-3

    10-2

    10-1

    100

    101

    0 0.5 1 1.5 2M

    SD a

    t 1 s

    econ

    d% Lactic Acid

    Lactobacillus-dominated

    Polymicrobial/BV

    • HIV diffusion correlated with higher pH (>4.5)

    • Lactobacillus make lactic acid • Higher % lactic acid correlates with

    HIV trapping

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

  • Future Directions

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

    • Mechanisms by which BV-associated bacteria degrade CVM barrier properties

    • Prospective clinical study to understand how

    Depo-Provera may modulate the microbiota thus effecting the CVM barrier properties

  • Acknowledgements

    Funding R01HD062844

    Collaborators Richard Cone, Ph.D Kevin DeLong Sam Lai, Ph.D Craig Hendrix, MD Jenell Coleman Fennell, MD Ronald Schnaar, Ph.D

    The Center for Nanomedicine Laura Ensign-Hodges, Ph.D Elizabeth Nance, Ph.D. Jane Chisholm Kunal Parikh Ben Schuster, Ph.D. Taarika Babu Yoo Chun Kim, Ph.D. Jong Sung Park, Ph.D. Rezo Omiadze, M.D.

    Sumon Chattopadhyay Maggie Swierczewska, Ph.D. Tao Yu, Ph.D. Abhijit Date, Ph.D. Clark Zhang Raj Reddy, Ph.D. Xinglu Huang, Ph.D. Yi-An Lin, Ph.D. Emily Toler

    Gregg Duncan, Ph.D. Heena Soni, Ph.D. Yumin Oh, Ph.D. Siva Kambhampati, Ph.D. Panos Mastorakos, M.D. Fan Zhang Uri Soiberman, M.D. Namho Kim Elga Bandeira de Melo Marta Roig Pons

    Core faculty Justin Hanes, Ph.D. Rangaramanujam Kannan, Ph.D. Samuel Yiu, M.D. Ian Pitha, M.D., Ph.D. Jung Soo Suk, Ph.D. Qingguo Xu, Ph.D. Jie Fu, Ph.D. Seulki Lee, Ph.D. Manoj Mishra, Ph.D. Ogyi Park, Ph.D.

    CVM donors

    THE CENTER FOR NANOMEDICINE AT JOHNS HOPKINS

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