This is unpublished

Hladik Lab

Publications

Elucidation of the earliest steps how human immunodeficiency virus penetrates the female genital mucosa and establishes infection. Exact knowledge about how someone is infected with HIV helps in devising strategies to prevent infection.

Characterization of messenger nucleic acids carried by extracellular vesicles in semen. Semen carries trillions of these ultra-tiny vesicles. When they enter the female genital tract during intercourse, molecules carried by these vesicles deliver messages to cells in the recipient mucosa. These messages influence a range of processes ranging from immune defenses against sexually transmitted infections to tolerance of the mother towards a developing fetus.

Development of a new genetic assay to measure the latent HIV reservoir, which will be an essential tool for clinical trials that aim to cure HIV infection.

Vojtech Lab

Publications

  • Vojtech L, Zhang M, Davé V, Levy C, Hughes SM, et al. (2019) Extracellular vesicles in human semen modulate antigen-presenting cell function and decrease downstream antiviral T cell responses. PLOS ONE 14(10):e0223901. PMCID: PMC6797208
  • Wang P, Gornalusse G, Pandey U, Hladik F, and Vojtech L. Potent restriction of sexual Zika virus infection by the lipid fraction of extracellular vesicles in semen. Frontiers in Microbiology, 2020 September; 11:2391. doi: 10.3389/fmicb.2020.574054. PMCID: PMC7550675.
  • Vojtech, L, Woo, S, Hughes S, Levy C, Ballweber L, Sauteraud RP, Strobl J, Westerberg K, Gottardo R, Tewari M, Hladik F.  Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Research, 2014;42:7290-7304. PMID: 24838567. PMCID: PMC4066774.

Adams Waldorf Lab

Pregnancy immunology and preterm labor therapeutics

My early work focused on reproductive immunology, autoimmune diseases in pregnancy, maternal-fetal tolerance and maternal-fetal cell trafficking during pregnancy. This work led to the discovery that persistent fetal microchimerism is common in the apheresis products for stem cell transplantation from women donors, which has implications for transplantation and development of graft-versus-host disease. We have also used systems biology to integrate mRNA and miRNA transcriptomics analyses from the placenta, uterus and fetal organs to investigate mechanistic relationships between infection, fetal injury and preterm birth. Our work has linked mRNA and miRNA gene networks to inflammatory injury several pathogens and the ensuing developmental arrest of the placental chorioamniotic membranes, fetal lung and heart. Our laboratory is also known for testing immunotherapeutics for the prevention of preterm labor in our nonhuman primate model.

  • Adams KM, Lambert NC, Heimfeld S, Tylee TS, Pang JM, Erickson TD, Nelson JL.  Male DNA in female donor apheresis and CD34-enriched products. Blood 2003; 102(10):3845-3847.
  • Adams KM, Nelson JL. Microchimerism:  an investigative frontier in autoimmunity and transplantation.  JAMA 2004; 291(9):1127-1131.
  • McCartney SA, Kapur R, Liggitt HD, Baldessari A, Coleman M, Orvis A, Ogle J, Katz R, Rajagopal L, Adams Waldorf KM. Cytokine Response in Amniotic Fluid is a Superior Predictor of Fetal Lung Injury Compared to Maternal Plasma or Placental Histopathology in a Nonhuman Primate Model. Am J Obstet Gynecol  2021 Jan 4;S0002-9378(20)32631-4. doi: 10.1016/j.ajog.2020.12.1214. Online ahead of print. PMID: 33412130. PMCID pending.
  • Coleman M, Orvis A, Wu T-Y, Dacanay M, Merillat S, Ogle J, Baldessari A, Kretzer NM, Munson J, Boros-Rausch A, Shynlova S, Lye S, Rajagopal L, Adams Waldorf KM. A Broad Spectrum Chemokine Inhibitor Prevents Preterm Labor but not Microbial Invasion of the Amniotic Cavity or Neonatal Morbidity in a Nonhuman Primate Model. Front Immunol 2020 Apr 30;11:770. doi: 10.3389/fimmu.2020.00770. eCollection 2020. PMCID: PMC7203489
  • Mitchell TM, Macdonald J, Srinouanpranchanh S, Bammler T, Merillat S, Boldenow E, Coleman M, Agnew K, Baldessari A, Stencel-Baerenwald JE, Tisoncik-Go J, Green RR, Gale MJ, Rajagopal L*, Adams Waldorf KM*. Evidence of cardiac involvement in the fetal inflammatory response syndrome: disruption of gene networks programming cardiac development in the nonhuman primates. Am J Obstet Gynecol 2018; 218(4): 438.e1-438.e16. PMCID:PMC6070341. *co-corresponding authors, **Editor’s Choice.
  • Vanderhoeven J, Bierle CJ, Kapur RP, McAdams RM, Beyer RP, Bammler TK, Farin FM, Bansal A, Spencer M, Deng M, Gravett MG, Rubens CE, Trucer M, Rajagopal L, Adams Waldorf KM.  Group B Streptococcal infection of the choriodecidua induces dysfunction of the cytokeratin network in amniotic epithelium: a pathway to membrane weakening. PLoS Path 2014; 10(3):e1003920. PMCID: PMC3946355.
  • McAdams RM, Bierle CJ, Boldenow E, Weed S, Tsai J, Beyer RP, MacDonald JW, Bammler TK, Liggitt HD, Farin FM, Vanderhoeven J, Rajagopal L, Adams Waldorf KM. Choriodecidual Group B Streptococcal infection induces miR-155-5p in the fetal lung in Macaca nemestrina.  Infect Immun 2015; 83(10): 3909-17. PMCID: PMC4567641.
  • Weed S, Liggitt HD, Johnson B, Tsai J, Beyer RP, Bammler TK, Kretzer NM, Parker E, Vanderhoeven JP, Bierle CJ, Rajagopal L, Adams Waldorf KM. MicroRNA Signature of Epithelial-mesenchymal Transition in Group B Streptococcal Infection of the Placental Chorioamniotic Membranes. J Infect Dis 2020; 71(15):879-881. PMID: 32296817. PMCID: PMC7184504

Zika virus injury of the fetal brain, in vivo molecular characterization of neuroprogenitor loss

We were the first to demonstrate that a maternal Zika virus infection could cause fetal brain injury in a nonhuman primate model, which we demonstrated through clinical imaging (MRI and ultrasound), neuropathology and in vivo molecular characterization on late neurogenic niches in the hippocampus. This work was significant, because it showed that loss of neuronal progenitor cells can occur in the absence of the prenatal diagnosis of microcephaly and be exceedingly difficult to detect clinically. Our work has provided the foundation for testing therapeutics and vaccines to prevent the vertical transmission of Zika virus, because we understand how to detect common and subtle viral injuries to neuroprogenitor cells in the fetal brain.

  • Adams Waldorf KM, Nelson BR*, Stencel-Baerenwald JE*, Studholme C*, Kapur RP*, Armistead B*, Walker CL*, Merillat S*, Vornhagen J*, Tisoncik-Go J*, Baldessari A, Coleman M, Dighe MK, Shaw DWW, Roby JA, Santana-Ufret V, Boldenow E, Li JW, Gao X, Davis MA, Swanstrom JA, Jensen K, Widman DG, Baric RS, Medwid JT, Hanley KA, Ogle J, Gough GM, Lee W, English C, Durning WM, Thiel J, Gatenby C, Dewey EC, Fairgrieve MR, Hodge RD, Grant RF, Kuller L, Dobyns WB, Hevner RF, Gale M, Rajagopal L. Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 2018; 24(3):368-374. PMID: 29400709. PMCID: PMC5839998
  • Adams Waldorf KM, Stencel-Baerenwald JE*, Kapur RP*, Studholme C*, Boldenow E*, Vornhagen J, Baldessari A, Dighe MK, Thiel J, Merillat S, Armistead B, Tisoncik-Go J, Green RR, Davis MA, Dewey EC, Fairgrieve MR, Gatenby JC, Richards T, Garden GA, Diamond MS, Juul SE, Grant RF, Kuller L, Shaw DWW, Ogle J, Gough GM, Lee W, English C, Hevner RF, Dobyns WB, Gale Jr. M#, Rajagopal L#.  Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med 2016; 22: 1256-9. *shared contribution, #co-corresponding authors. PMCID: PMC5365281.
  • Dudley DM, Van Rompay KK, Coffey LL, Ardeshir A, Keesler RI, Grigsby PL, Steinbach RJ, Hirsch AJ, MacAllister RP, Hodge T, Streblow DN, Tardif S, Patterson JL, Tamhankar M, Seferovic M, Aagard KM, Sanchez-San Martin C, Chiu CY, Panganiban AT*, Veazey RS, Wang X , Maness NJ, Gilbert MH, Bohm RP, Adams Waldorf KM*, Gale Jr. M, Rajagopal L, Hotchkiss CE, Mohr EL, Capuano SV, Friedrich TC, Golos TG, O’Connor DH*. Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nat Med 2018; 24(8): 1104-1107. PMCID: PMC29967348. *Note Dr. Adams Waldorf’s role as co-corresponding author.
  • Walker CL, Merriam AA, Ohuma EO, Dighe MK, Gale M, Rajagopal L, Papageorghiou AT, Gyamfi-Bannerman C*, Adams Waldorf KM*. Femur-Sparing Pattern of Abnormal Fetal Growth in Pregnant Women from New York City after Maternal Zika Virus Infection. Am J Obstet Gynecol 2018; 219(2): 187.e1-187.e20 PMCID: PMC6066422. *co-corresponding authors, #equal contribution.

Group B Streptococcus perinatal infections and host-pathogen interactions

Group B Streptococci (GBS) are b-hemolytic, gram-positive bacteria that cause infections in pregnancy and human newborns. Conservatively, it is estimated that Group B Streptococcus results in approximately 400,000 maternal-fetal-infant infections and 147,00 stillbirths and infant deaths annually. The mechanisms that govern GBS invasion of the pregnant uterus, preterm birth and fetal infections infections are largely unknown and insufficiently studied. We were the first to show that a choriodecidual GBS infection could induce fetal lung injury prior to labor, mediated by cytokine production of placenta in the course of resolving the infection. Our team discovered that the molecular basis of GBS hemolytic activity is the ornithine rhamnolipid pigment. We were able to show that a hypervirulent GBS (expressing pigment) can circumvent neutrophils in the placenta by rapidly trafficking through the membranes and evading neutrophil extracellular traps. We have also described the mechanism by which GBS can ascend into the uterus to induce preterm labor (epithelial-to-mesenchymal transition resulting in epithelial sloughing which promotes bacterial invasion). This is the first mechanistic explanation for how bacteria ascend into the uterus to induce intra-amniotic infection, preterm birth and fetal injury.

  • Whidbey C, Harrell MI, Burnside K, Ngo L, Becraft AK, Iyer LM, Aravind L, Hitti J, Adams Waldorf KM, Rajagopal L. A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta. J Exp Med 2013; 210(6):1265-81. PMCID: PMC3674703.
  • Boldenow E, Gendrin C*, Ngo L*, Bierle C*, Vornhagen J*, Coleman M, Merillat S, Armistead B, Whidbey C, Alishetti V, Santana-Ufret V, Ogle J, Gough M, Srinouanprachanh S, Macdonald JW, Bammler TK, Bansal A, Liggitt HD, Rajagopal L#, Adams Waldorf KM#. A bacterial hemolytic lipid toxin circumvents neutrophils and neutrophil extracellular traps to promote GBS invasion, fetal injury and preterm labor in nonhuman primates. Sci Immunol 2016; 1(4): (doi:10.1126/sciimmunol.aah4576). PMCID: PMC5089172. *shared contribution, #co-corresponding authors
  • Vornhagen J, Armistead B, Santana-Ufret V, Gendrin C, Merillat S, Coleman M, Quach P, Boldenow E, Alishetti V, Leonhard-Melief C, Ngo LY, Whidbey C, Doran KS, Curtis C, Adams Waldorf KM, Nance E, Rajagopal L. Group B Streptococcus exploits vaginal epithelial exfoliation for ascending infection and fetal injury. J Clin Invest 2018; 128(5):1985-1999. PMCID: PMC5919824.
  • Coleman M, Armistead B, Orvis A, Quach P, Brokaw A, Gendrin C, Ogle J, Merillat S, Dacanay M, Wu T-Y, Munson J, Baldessari A, Vornhagen J, Furuta A, Nguyen S, Adams Waldorf KM*, Rajagopal L*. Hyaluronidase impairs neutrophil function and promotes Group B Streptococcus invasion, cervical ripening and preterm labor in pregnant nonhuman primates. mBio 2020; Apr 3: 770. PMID: 32425945. PMCID: PMC7203489. *co-corresponding authors