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Principal Investigator: Mehul Shamal Suthar
Organization: EMORY UNIVERSITY
Fiscal Year: 2021
Award: $757,655
Funding agency: National Institute of Allergy and Infectious Diseases
Humoral immunity is an essential component of the immune response to flavivirus infection. Primary infection generates a robust neutralizing antibody response that mediates viral control and protection. It is becoming increasingly apparent that secondary infection with a closely related flavivirus strain can result in immunological cross-reactivity; however, the consequences to infection outcome are hotly debated and controversial. Zika virus (ZIKV) is a mosquito-borne flavivirus, which has a high degree of sequence and structural homology to Dengue virus (DENV), and is responsible for continuing epidemics of fetal congenital malformations within the Americas since its introduction to Brazil in 2015. Prior flavivirus exposure has been strongly associated with generation of cross-reactive antibodies that bind to and/or neutralize ZIKV. A unique aspect of ZIKV pathogenesis is the ability of the virus to seed infection within the placenta, however, the mechanisms of transplacental ZIKV infection are not well understood. The overall goal of this proposal is to understand how cross-reactive antibodies facilitate ZIKV transcytosis and seed infection of the placenta. The placenta is composed of anchoring chorionic villi, which penetrate the uterine wall, as well as floating chorionic villi that are bathed in maternal blood pooling in the intervillous space. Recent epidemiological observations found that between 20-50% of pregnant women with possible ZIKV exposure had detectable ZIKV RNA in the placenta. Another report found that ZIKV can persist in the placenta for over 200 days post mother onset of Zika symptoms. We discovered that Hofbauer cells, fetally- derived placental macrophages located within the villus stroma, are permissive for ZIKV infection. To identify a potential mechanism by which ZIKV gains access to the villous stroma, we recently evaluated the impact of cross-reactive dengue antibodies in mediating transplacental infection. Using an ex vivo placental explant model, we observed profound enhancement of ZIKV infection of human mid-gestation floating chorionic villi with ZIKV immune complexes generated using either DENV or ZIKV cross-reactive convalescent serum or monoclonal antibodies. Similar to histological analysis of placenta from infected pregnant mothers, ZIKV replicated exclusively within Hofbauer cells. Based on these observations, we hypothesize that the Fab fragment (specificity for ZIKV) and the Fc domain (affinity for FcRn and FcγR) of IgG impacts antibody-mediated ZIKV transplacental infection. Moreover, we believe that gestational age of the placenta dynamically influences the efficiency of ZIKV transcytosis and placental infection. Moreover, we believe that gestational age of the placenta dynamically impacts ZIKV transcytosis and placental infection. In this proposal, we seek to address the following outstanding questions: 1) How does IgG antibody specificity, affinity and Fc/FcRn interactions impact ZIKV transplacental infection? and 2) How does placental gestational age impacts antibody-mediated infection of Hofbauer cells? Our studies will likely reveal therapeutic targets and provide insights for development a vaccine to protect against ZIKV infection.
Terms: <21+ years old><7S Gamma Globulin><AIDP><Acute Autoimmune Neuropathy><Acute Infective Polyneuritis><Acute Inflammatory Demyelinating Polyradiculoneuropathy><Acute Inflammatory Polyneuropathy><Acute Inflammatory Polyradiculoneuropathy><Address><Adult><Adult Human><Affinity><Americas><Antibodies><Antibody Response><Antibody Specificity><Antigen Binding Fragment><Antigen-Antibody Complex><Autoregulation><Binding><Biologic Models><Biological Models><Biology><Birth Defects><Blood><Blood Reticuloendothelial System><Blood Serum><Brazil><Breakbone Fever Virus><Cell Body><Cells><Cells Placenta-Tissue><Chorionic villi><Chronologic Fetal Maturity><Clinical Treatment Moab><Congenital Abnormality><Congenital Anatomic Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Dengue><Dengue Virus><Dengue fever virus><Environment><Epidemic><Epidemiology><Fab Fragments><Fab Immunoglobulins><Fc Receptor><Fc domain><FcRn><FcRn neonatal transfer protein><Fetal Age><Flavivirus><Flavivirus Infections><Gases><Generations><Gestation><Gestational Age><Goals><Group B Arbovirus><Guillain Barré Syndrome><Guillaine-Barre Syndrome><Histologic><Histologically><Homeostasis><Host Factor><Host Factor Protein><Human><Humoral Immunities><IgG><IgG Receptors><IgG1><IgG2><IgG3><IgG4><Immune Complex><Immune response><Immunochemical Immunologic><Immunoglobulin G><Immunoglobulin G Receptor><Immunoglobulin, F(ab) Fragment><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infection><Inflammation><Inflammatory Response><Integration Host Factors><Landry's paralysis><Landry-Guillain-Barre Syndrome><Link><Mediating><Microcephaly><Miscarriage><Model System><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Mothers><Mφ><Neonatal><Normal Placentoma><Nutrient><Outcome><Pathway interactions><Physiological Homeostasis><Placenta><Placenta Embryonic Tissue><Placental Development><Placental Villi><Placentation><Placentome><Plant Embryos><Plant Zygotes><Play><Pregnancy><Pregnant Women><Primary Infection><Public Health><Reporting><Seeds><Serum><Specificity><Spontaneous abortion><Structure><Symptoms><Syncytiotrophoblast><System><Transportation><Uterus><Vascular blood supply><Villous><Villus><Viral><Viral Pathogenesis><Virion><Virus><Virus Particle><ZIKA><ZIKV><ZIKV infection><ZIKV positive><Zika Virus><Zika virus infection><acute idiopathic polyneuritis><acute post-infectious polyneuropathy><acute postinfectious polyneuropathy><adulthood><antibody receptor><antibody-based immunity><base><blood supply><cross reactivity><develop a vaccine><development of a vaccine><epidemiologic><epidemiological><expectant mother><expecting mother><fetal><fetal blood><gamma Fc Receptors><host response><immune system response><immunoresponse><insight><mAbs><mRNA seq><mRNA sequencing><mRNA-seq><mRNAseq><macrophage><micrencephaly><microencephaly><mosquito-borne><mosquitoborne><neonatal Fc receptor><neutralizing antibody><pathway><placenta infection><placental infection><pregnant mothers><receptor expression><secondary infection><seed><therapeutic target><transcytosis><vaccine development><vaccine formulation><vascular supply><viral RNA><virus RNA><virus envelope><virus pathogenesis><wasting><womb><zika infection><zika viral infection><zikav>