Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses
Encounters between immune cells and invading bacteria ultimately determine the course of infection. These interactions are usually measured in populations of cells, masking cell-to-cell variation that may be important for infection outcome. To characterize the gene expression variation that underlie...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2016
|
| Online Access: | http://hdl.handle.net/1721.1/105325 https://orcid.org/0000-0003-2616-4030 https://orcid.org/0000-0001-8567-2049 |
| _version_ | 1811082090476732416 |
|---|---|
| author | Avraham, Roi Brown, Douglas Penaranda, Cristina Jijon, Humberto B. Trombetta, John J. Satija, Rahul Xavier, Ramnik J. Hung, Deborah T. Haseley, Nathan Scott Shalek, Alexander K Regev, Aviv |
| author2 | Institute for Medical Engineering and Science |
| author_facet | Institute for Medical Engineering and Science Avraham, Roi Brown, Douglas Penaranda, Cristina Jijon, Humberto B. Trombetta, John J. Satija, Rahul Xavier, Ramnik J. Hung, Deborah T. Haseley, Nathan Scott Shalek, Alexander K Regev, Aviv |
| author_sort | Avraham, Roi |
| collection | MIT |
| description | Encounters between immune cells and invading bacteria ultimately determine the course of infection. These interactions are usually measured in populations of cells, masking cell-to-cell variation that may be important for infection outcome. To characterize the gene expression variation that underlies distinct infection outcomes and monitor infection phenotypes, we developed an experimental system that combines single-cell RNA-seq with fluorescent markers. Probing the responses of individual macrophages to invading Salmonella, we find that variation between individual infected host cells is determined by the heterogeneous activity of bacterial factors in individual infecting bacteria. We illustrate how variable PhoPQ activity in the population of invading bacteria drives variable host type I IFN responses by modifying LPS in a subset of bacteria. This work demonstrates a causative link between host and bacterial variability, with cell-to-cell variation between different bacteria being sufficient to drive radically different host immune responses. This co-variation has implications for host-pathogen dynamics in vivo. |
| first_indexed | 2024-09-23T11:57:25Z |
| format | Article |
| id | mit-1721.1/105325 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:57:25Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1053252022-10-01T07:16:52Z Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses Avraham, Roi Brown, Douglas Penaranda, Cristina Jijon, Humberto B. Trombetta, John J. Satija, Rahul Xavier, Ramnik J. Hung, Deborah T. Haseley, Nathan Scott Shalek, Alexander K Regev, Aviv Institute for Medical Engineering and Science Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Ragon Institute of MGH, MIT and Harvard Haseley, Nathan Scott Shalek, Alexander K Regev, Aviv Encounters between immune cells and invading bacteria ultimately determine the course of infection. These interactions are usually measured in populations of cells, masking cell-to-cell variation that may be important for infection outcome. To characterize the gene expression variation that underlies distinct infection outcomes and monitor infection phenotypes, we developed an experimental system that combines single-cell RNA-seq with fluorescent markers. Probing the responses of individual macrophages to invading Salmonella, we find that variation between individual infected host cells is determined by the heterogeneous activity of bacterial factors in individual infecting bacteria. We illustrate how variable PhoPQ activity in the population of invading bacteria drives variable host type I IFN responses by modifying LPS in a subset of bacteria. This work demonstrates a causative link between host and bacterial variability, with cell-to-cell variation between different bacteria being sufficient to drive radically different host immune responses. This co-variation has implications for host-pathogen dynamics in vivo. National Institutes of Health (U.S.) (grant HG002295) National Institutes of Health (U.S.) (grant DK043351) National Institutes of Health (U.S.) (grant NIH U19AI109725) National Institutes of Health (U.S.) (grant NIH F32 HD075541-02) National Human Genome Research Institute (U.S.) ((CEGS) Center of Cell Circuits (P50 HG006193)) Klarman Cell Observatory 2016-11-14T20:35:28Z 2016-11-14T20:35:28Z 2015-09 2015-05 Article http://purl.org/eprint/type/JournalArticle 00928674 http://hdl.handle.net/1721.1/105325 Avraham, Roi, Nathan Haseley, Douglas Brown, Cristina Penaranda, Humberto B. Jijon, John J. Trombetta, Rahul Satija, Alex K. Shalek, Ramnik J. Xavier, Aviv Regev, and Deborah T. Hung. “Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses.” Cell 162, no. 6 (September 2015): 1309-1321. https://orcid.org/0000-0003-2616-4030 https://orcid.org/0000-0001-8567-2049 en_US http://dx.doi.org/10.1016/j.cell.2015.08.027 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Avraham, Roi Brown, Douglas Penaranda, Cristina Jijon, Humberto B. Trombetta, John J. Satija, Rahul Xavier, Ramnik J. Hung, Deborah T. Haseley, Nathan Scott Shalek, Alexander K Regev, Aviv Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses |
| title | Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses |
| title_full | Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses |
| title_fullStr | Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses |
| title_full_unstemmed | Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses |
| title_short | Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses |
| title_sort | pathogen cell to cell variability drives heterogeneity in host immune responses |
| url | http://hdl.handle.net/1721.1/105325 https://orcid.org/0000-0003-2616-4030 https://orcid.org/0000-0001-8567-2049 |
| work_keys_str_mv | AT avrahamroi pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT browndouglas pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT penarandacristina pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT jijonhumbertob pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT trombettajohnj pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT satijarahul pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT xavierramnikj pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT hungdeboraht pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT haseleynathanscott pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT shalekalexanderk pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses AT regevaviv pathogencelltocellvariabilitydrivesheterogeneityinhostimmuneresponses |