Enterovirus infections of barrier cells.
The human gastrointestinal (GI) tract is a complex organ, with an epithelial surface that must provide a protective and immunological barrier in a complex and diverse microbial environment. Enteroviruses are leading causes of human infections worldwide, particularly in infants and children, and infect primarily via the fecal-oral route. These viruses, which include poliovirus, coxsackieviruses, echoviruses, enterovirus D68 (EV-D68), and enterovirus 71 (EV71), are small, single-stranded RNA viruses belonging to the Picornaviridae family.
The events that surround enterovirus infections of the human GI epithelium remain poorly understood. Our laboratory is interested in developing models to better define the mechanisms associated with enterovirus infections in the GI tract. We are also interested in identifying the host factors and pathways that facilitate enterovirus entry, replication, and spread from the GI epithelium.
Good CA, Wells AI, and Coyne CB. Type III interferon signaling restricts enterovirus 71 infection of goblet cells. Science Advances 2019 Mar 6;5(3). PMID: 30854425.
Morosky S, Wells A, Lemon K, Evans E, Schamus S, Bakkenist CJ, Coyne CB. The neonatal Fc receptor is a pan-echovirus receptor. Proceedings of the National Academy of Science, 2019 2019 Feb 26;116(9):3758-3763. PMID: 30808762.
Drummond CG, Bolock, AM, Congrong M, Luke CJ, Good, M, and Coyne, CB. Enteroviruses infect human enteroids and induce antiviral signaling in a cell-lineage specific manner. Proceedings of the National Academy of Science 2017, Feb 14;114(7):1672-1677. PMID: 28137842.
Bramley JC, Drummond CG, Lennemann NJ, Good CA, Kim KS, and Coyne CB. A Three-Dimensional Cell Culture System To Model RNA Virus Infections at the Blood-Brain Barrier. mSphere. 2017 Jun 21;2(3). pii: e00206-17. PMID: 28656176.
Drummond CG, Nickerson CA, and Coyne CB. A three-dimensional cell culture model to study enterovirus infection of polarized intestinal epithelial cells. mSphere 2016 Jan 1(1).
Harris KG, Morosky SA, Drummond CG, Patel M, Kim C, Stolz, DB, Bergelson JM, Cherry S, and Coyne CB. RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells. Cell Host & Microbe, Volume 18, Issue 2, p221–232, 2015.
Antimicrobial signaling at the maternal-fetal interface.
The placenta is unlike any other human organ. Given its essential role in protecting the fetus, the placenta must function as a barrier and conduit between the maternal and fetal environments and serve as an active immunological tissue that responds to microbes present in the maternal circulation. Our research program asks two central questions:
What are the mechanisms by which the placenta restricts the vertical transmission of microorganisms?
How do microorganisms associated with congenital disease breach the placental barrier?
Our studies have established a new and important paradigm – that in addition to its role as a physical barrier, the placenta is a dynamic and highly reactive chemical barrier that uses multiple classes of molecules, including type III interferons and microRNAs, to protect the fetus and maternal host from viral infections. However, our investigations continue to probe important questions to learn if there are differences in the mechanisms employed by the placenta to restrict microbial access at different stages of gestation and to understand what mechanisms are used by the placenta to defend against non-viral pathogens. Further, we hope to define the influence of the systemic maternal immune response on placental antimicrobial defenses.
Ander SE, Rudzki EN, Arora N, Sadovsky Y, Coyne CB, Boyle JP. Human Placental Syncytiotrophoblasts Restrict Toxoplasma gondii Attachment and Replication and Respond to Infection by Producing Immunomodulatory Chemokines. mBio 2018 Jan 9;9(1). PMID: 29317509.
Yockey LJ, Jurado KA, Arora N, Millet A, Rakib T, Milano KM, Hastings AK, Fikrig E, Kong Y, Horvath TL, Weatherbee S, Kliman HJ, Coyne CB, Iwasaki A. Type I interferons instigate fetal demise after Zika virus infection. Science Immunology 2018 Jan 5;3(19) PMID: 29305462.
Jagger BW, Miner JJ, Cao B, Arora N, Smith AM, Kovacs A, Mysorekar IU, Coyne CB, and Diamond MS. Gestational stage and IFN-l signaling influence ZIKV infection in utero. 2017 Cell Host & Microbe Sep 13;22(3):366-376 PMID: 28910635.
Corry J, Arora N, Good C, Sadovsky Y, and Coyne CB. Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal-fetal interface. 2017 Proceedings of the National Academy of Science Aug 29;114(35):9433-9438 PMID: 28784796.
Bayer A, Lennemann NJ, Ouyang Y, Bramley JC, Morosky S, Marques Jr. E, Cherry S, Sadovsky Y, and Coyne CB. Human Placental Trophoblasts Produce Type III Interferons that Confer Protection Against Zika Virus Infection. Cell Host & Microbe 2016 Apr 5. PMID: 27066743.
McConkey C, Delorme-Axford E, Nickerson CA, Kim KS, Sadovsky Y, Boyle JP, and Coyne CB. A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. Science Advances. 2016 Mar 4;2(3). PMID: 26973875.
Delorme-Axford E, Donker RB, Mouillet JF, Chu T, Bayer A, Ouyang Y, Wang T, Stolz DB, Sarkar SN, Morelli AE, Sadovsky Y, and Coyne CB. Human placental trophoblasts confer viral resistance to recipient cells. Proceedings of the National Academy of Sciences, 2013, 2013 Jul 16;110(29):12048-53. Cozzarelli Prize for best Biomedical Sciences (Class IV) publication in PNAS in 2013.
Cell biology of RNA virus replication.
RNA viruses usurp a variety of host cell pathways to facilitate their replication. One of the key missions of the Coyne Lab is identifying the pathways targeted by RNA viruses (including enteroviruses and flaviviruses) to promote their replication and spread.
An obligate step in the life cycle of positive sense RNA viruses is the formation of membrane-enriched organelles, termed replication organelles, that provide the structural support for viral replication. Multiple mechanisms have been proposed for the generation of these membranes, including manipulation of the host autophagic pathway, a process that removes damaged organelles via the formation of double membrane bound vesicles. Current studies in the laboratory are focused on the identification and characterization of novel regulators of host cell authophagy and on the identification of mechanisms employed by RNA viruses to specifically modulate the host autophagic pathway.
Lennemann, NJ and Coyne, CB. Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B. Autophagy 2017 2017 Feb;13(2):322-332. PMID: 28102736.
Morosky S, Lennemann NJ, and Coyne CB. BPIFB6 regulates secretory pathway trafficking and enterovirus replication. J. Virology. 2016 Mar 9. PMID: 26962226.
Shu Q, Lenneman N, Sarkar SN, Sadovsly Y, and Coyne CB. ADAP2 is an interferon stimulated gene that alters virus entry. PLoS Pathogens, 2015 Sep 15;11 (9). PMID:
Delorme-Axford E, Morosky S, Bomberger J, Stolz DB, Jackson WT, and Coyne CB. BPIFB3 regulates autophagy and Coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery. MBio. 2014 Dec 9;5(6):e02147.