This is an administrative supplement to the parent R01 AI052116 ?SPATIOTEMPORAL CONTROL OF T CELL SYNAPSE STABILIZATION AND SIGNALING? which for my entire career has been my central grant for studies of T cell interactions leading to tolerance or activation. Here, we apply our considerable immune and tissue-immune experience towards generating and exploiting a RapidPath platform to find rapid actionable immunotherapeutic targets for COVID-19 patients for limiting damage due to SARS-CoV-2 infections.
In aim 1 of this study, we will build a lung plus virus plus immune platform in which the role of specific T cells of different activation status ?alone and through their modulation of myeloids cells?will be assessed in the response of damage to lung epithelium plus/minus endothelium (organoid, with Roose/Gordon and lung slice with Looney). This supplement will interact intensely with parallel studies of those labs and also with ongoing studies that will also leverage RapidPath but are not in this first cohort of applications. This will provide `best in class' model systems in human biology and will leverage our collective expertise.
In aim 2 of this study, we will test a panel of immunomodulatory drugs to determine if acute exposure to them can modulate lung damage, likely through modulating myeloid biology. The net result will be validated immunotherapeutic paths in robust pre-clinical human systems that recapitulate key features of COVID-19.
The SARS coronavirus-2 (SARS-CoV-2) has rapidly emerged over four months leading to a critical pandemic of coronavirus disease (COVID-19) with over 1M cases worldwide and 258,000 cases in the US alone as of April 3. This project will utilize a deep knowledge of T cell-myeloid biology to identify and rank immunotherapeutics that will be clinically useful to modulate the severity of catastrophic lung damage in the context of SARS-CoV-2.
| Krummel, Matthew F; Mahale, Jagdish N; Uhl, Lion F K et al. (2018) Paracrine costimulation of IFN-? signaling by integrins modulates CD8 T cell differentiation. Proc Natl Acad Sci U S A 115:11585-11590 |
| Cai, En; Marchuk, Kyle; Beemiller, Peter et al. (2017) Visualizing dynamic microvillar search and stabilization during ligand detection by T cells. Science 356: |
| Mujal, Adriana M; Gilden, Julia K; Gérard, Audrey et al. (2016) A septin requirement differentiates autonomous and contact-facilitated T cell proliferation. Nat Immunol 17:315-22 |
| Krummel, Matthew F; Bartumeus, Frederic; Gérard, Audrey (2016) T cell migration, search strategies and mechanisms. Nat Rev Immunol 16:193-201 |
| Pinkard, Henry; Stuurman, Nico; Corbin, Kaitlin et al. (2016) Micro-Magellan: open-source, sample-adaptive, acquisition software for optical microscopy. Nat Methods 13:807-809 |
| Pinkard, Henry; Corbin, Kaitlin; Krummel, Matthew F (2016) Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. PLoS One 11:e0150430 |
| Mujal, Adriana M; Krummel, Matthew (2015) The subtle hands of self-reactivity in peripheral T cells. Nat Immunol 16:10-1 |
| Krummel, Matthew F; Friedman, Rachel S; Jacobelli, Jordan (2014) Modes and mechanisms of T cell motility: roles for confinement and Myosin-IIA. Curr Opin Cell Biol 30:9-16 |
| Corbin, Kaitlin; Pinkard, Henry; Peck, Sebastian et al. (2014) Assessing and benchmarking multiphoton microscopes for biologists. Methods Cell Biol 123:135-51 |
| Gérard, Audrey; Patino-Lopez, Genaro; Beemiller, Peter et al. (2014) Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Cell 158:492-505 |
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