Indira U. Mysorekar, Ph.D.

Obstetrics and Gynecology
Pathology and Immunology

Developmental, Regenerative and Stem Cell Biology Program
Molecular Microbiology and Microbial Pathogenesis Program
Immunology Program
Molecular Genetics and Genomics Program

Research Abstract:

1) Maternal Fetal transmission of Zika Virus and host defense mechanisms in the Placenta:

The placenta is literally vital to the maintenance of mankind as it not only performs functions of the lung/GI/GU tract, it also moderates host defense of the fetus against infections in utero, which has long-term impact on the well-being of both the woman and the child. Our most recent work has focussed on Zika Virus (ZIKV), an emerging flavivirus that has become a global public health threat and which causes microcephaly, intrauterine growth restriction (IUGR), and spontaneous abortion during pregnancy. We study a model of in utero transmission of ZIKV and showed that ZIKV colonizes placental trophoblasts where it replicates and subsequently crosses the placental barrier to infect fetal endothelial cells, enters the fetal circulation ultimately leading to fetal brain damage and fetal demise.
We have also recently identified a key cellular‐molecular mechanism at the heart of how and why placentas regulate host defense against bacterial pathogens: the cellular autophagy pathway, and in particular, the autophagy gene Atg16l1, plays a critical role in the human and rodent placental host defense. Autophagy regulates ZIKV maternal fetal transmission and an autophagy inhibitor, Hydroxychloroquine, can limit adverse fetal outcomes.

2) Placental microbiome:

Our recent work has provided the first documentation of intracellular organisms present in the maternal basal plate of human placentas indicating that there is a ‘placental microbiome’. Our work has also identified the cellular location of these microbiota, which are the extravillous trophoblasts (EVTs) embedded in the maternal decidua. EVTs express human leukocyte antigen-G (HLA-G), a major histocompatibility complex protein involved in maternal-fetal tolerance. Ongoing work is defining specific members of the microbiota and their role in maintaining placental health.

3)Host mechanisms underlying persistent UTIs in young and aged mice:

Recurrent UTIs can be seeded from bacterial reservoirs harbored deep within the bladder wall. We have shown that the pathogens use the autophagy pathway to establish these reservoirs. Specifically, my lab has shown that one autophagy protein in particular, ATG16L1, is critical for bladder homeostasis and in pathogenesis of the UTI-causing bacteria UPEC. Mice deficient for Atg16l1 are resistant to UTIs. We showed that this is because Atg16l1−/− mice have a higher than normal pro-inflammatory response, and they lose the protective niche UPEC establish to persist indefinitely to seed recurrent UTIs. Furthermore, we have identified the cell type (macrophage) and the mechanism of bacterial control (inflammasome and IL-1beta signaling) that are important for the host-UPEC interactions during a UTI. Most recently, our work has shown that UPEC shuttles with ferritin-bound iron into the autophagosomal and lysosomal compartments within the bladder. These findings provide a mechanism by which the bacteria can persist and re-emerge to cause recurrent UTIs. We have identified a key role for the sex hormone estrogen in modulating urothelial regeneration. We`ve shown that the Bmp4 pathway is indirectly targeted by estrogenic signaling, and the WNT pathway is targeted by androgen signaling. Finally, we have shown that the postmenopausal low-estrogen condition is associated with increased presence of inflammatory macrophages and circulating levels of interleukin 6. Our work is providing new insights into the molecular interplay between estrogen and bladder host defense during a UTI and providing a foundation upon which to determine develop preventive interventions and treatments using estrogen and anti-IL-6 therapies that are optimized for menopausal women.

Selected Publications:

Selected Publications:

Miner JJ, Cao B, Govero J, Smith AM, Fernandez E, Cabrera OH, Garber C, Noll M, Klein RS, Noguchi KK, Mysorekar IU*, Diamond MS*. Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell 2016. DOI: (*Co-corresponding author)

Mysorekar IU* and Diamond MS*. Modeling Zika Virus Infection in Pregnancy. N Engl J Med. 2016 Jul 13. DOI: 10.1056/NEJMcibr1605445. PMID: 27433842. (*Co-corresponding authors)

Cao B, Macones C, Mysorekar IU. ATG16L1 governs placental infection risk and preterm birth in mice and women. JCI Insight, 2016 Dec 22;1(21):e86654. doi: 10.1172/jci.insight.86654

Cao B, Parnell LA, Diamond MS, and Mysorekar IU. Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice. J Exp Med, July 2017, DOI: 10.1084/jem.20170957

Stout MJ, Conlon B, Landeau M, Lee I, Bower C, Zhao Q, Roehl K, Nelson DM, Macones GA, Mysorekar IU. Identification of intracellular bacteria in human placenta basal plate in term and preterm gestations. Am J Obstet Gynecology. 2013. Jan 17. doi. S0002-9378. PMID: 23333552. PMCID: PMC3740162

Parnell LA, Briggs CA, Cao B, Delannoy-Bruno P, Schrieffer AE, Mysorekar IU. Microbial communities in placentas from term normal pregnancy exhibit spatially variable profiles. Sci Rep, 2017

Wang C*, Mendonsa GR*, Symington JW*, Zhang Q, Cadwell K, Virgin HW, Mysorekar IU. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. Proc Natl Acad Sci USA (2012). Jul 3;109(27):11008-13. PMID: 22715292. PMCID: PMC3390880.

Symington JW, Wang C, Twentyman J, Owusu-Boaitey N, Schwendener R, Núñez G, Schilling JD, Mysorekar IU. ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1β-dependent manner. Mucosal Immunol. 2015 Feb 11. doi: 10.1038/mi.2015.7. PMID: 25669147

Bauckman KA and Mysorekar IU. Ferritinophagy drives uropathogenic Escherichia coli persistence in bladder epithelial cells. Autophagy. 2016 May 3;12(5):850-63. Doi:10-1080-15548627.2016-1160176

Wang C, Symington JW, Ma E, Cao B, Mysorekar IU. Estrogenic modulation of uropathogenic Escherichia coli infection pathogenesis in a murine menopause model. Infect Immun. 2013, Mar;81(3):733-9. PMID: 23264047

Last Updated: 7/12/2017 10:00:35 AM

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