Murine enterocytes infected with murine rotavirus. Red is rotavirus, green is EdU and blue is nuclei.
About the Estes Lab
Our lab is interested in several facets of viral infections in the gastrointestinal tract. Lab members are studying underlying mechanisms of viral replication, pathogenesis, and virus-host interactions of two common enteric viral infections, norovirus and rotavirus. In addition, we have several projects on vaccine development and developing therapeutics that limit severe disease caused by these viruses. The lab is also interested in the genomic basis of infectious diseases and in understanding how the intestine repairs following infection.
The use of intestinal organoid cultures is a foundation for most of the studies in the lab. These cultures are derived from stem cells isolated from human intestinal tissue. The stem cells are propagated in vitro and form mature intestinal epithelium upon growth factor manipulation. In order to increase the complexity of this human biomimetic model, we are integrating engineered platforms that incorporate mechanoinduction, immune and neuronal cells, and the microbiome.
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The Estes lab is involved in providing organoids through the Texas Medical Center Gastrointestinal Models Core. Intestinal organoids support replication of previously uncultivable enteric viruses. Image shows a human jejunal organoid monolayer infected with GII.4 norovirus. Red is villin, green is norovirus VP1 and blue are nuclei.
Stem cells isolated from human intestinal tissue grow in vitro and differentiate into specialized cells that mimic the human intestine. Image shows 3D human jejunal intestinal organoid infected with human rotavirus. Red is rotavirus, green is E-cadherin and blue are nuclei.
Targeted mutation via reverse engineering answers critical questions about viral replication. Image shows MA104 cells infected with wildtype or NSP2 mutant rotavirus. Wildtype rotavirus replicates in viroplasms (left) but NSP2 mutant rotavirus delays formation of viroplasms (right). Red is rotavirus NSP2, green is rotavirus NSP5, and blue are nuclei.
Selected References
Human norovirus exhibits strain-specific sensitivity to host interferon pathways in human intestinal enteroids.
Lin SC, Qu L, Ettayebi K, Crawford SE, Blutt SE, Robertson MJ, Zeng XL, Tenge VR, Ayyar BV, Karandikar UC, Yu X, Coarfa C, Atmar RL, Ramani S, Estes MK. Proc Natl Acad Sci U S A. 2020 Sep 9:202010834. doi: 10.1073/pnas.2010834117.
A genetically engineered rotavirus NSP2 phosphorylation mutant impaired in viroplasm formation and replication shows an early interaction between vNSP2 and cellular lipid droplets.
Criglar JM, Crawford SE, Zhao B, Smith HG, Stossi F, Estes MK. J Virol. 2020 May 27:JVI.00972-20. doi: 10.1128/JVI.00972-20.
Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids.
Murakami K, Tenge VR, Karandikar UC, Lin SC, Ramani S, Ettayebi K, Crawford SE, Zeng XL, Neill FH, Ayyar BV, Katayama K, Graham DY, Bieberich E, Atmar RL, Estes MK.Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1700-1710. doi: 10.1073/pnas.1910138117.
Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation.
Zou WY, Blutt SE, Zeng XL, Chen MS, Lo YH, Castillo-Azofeifa D, Klein OD, Shroyer NF, Donowitz M, Estes MK.Cell Rep. 2018 Jan 23;22(4):1003-1015. doi: 10.1016/j.celrep.2017.12.093.
A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection.
Saxena K, Simon LM, Zeng XL, Blutt SE, Crawford SE, Sastri NP, Karandikar UC, Ajami NJ, Zachos NC, Kovbasnjuk O, Donowitz M, Conner ME, Shaw CA, Estes MK.Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E570-E579. doi: 10.1073/pnas.1615422114.
Replication of human noroviruses in stem cell-derived human enteroids.
Ettayebi K, Crawford SE, Murakami K, Broughman JR, Karandikar U, Tenge VR, Neill FH, Blutt SE, Zeng XL, Qu L, Kou B, Opekun AR, Burrin D, Graham DY, Ramani S, Atmar RL, Estes MK. Science. 2016 Sep 23;353(6306):1387-1393. doi: 10.1126/science.aaf5211.
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