A fundamentally important question in biology is how individual cells within multicellular organisms cooperate to form tissues, organs and a complete organism. One approach to address this complex question is to use simple model systems that exhibit many of the traits found in tissues. Myxococcus xanthus is one such system where, for instance, in response to starvation thousands of cells aggregate, move rhythmically and build fruiting bodies in which vegetative cells differentiate into spores. In M. xanthus we discovered a novel platform that mediates social interactions. This behavior involves kin recognition in which cells identify clonemates and exchange outer membranes (OM) proteins and lipids. Recognition in outer membrane exchange (OME) is mediated by a polymorphic cell surface receptor called TraA and its partner protein TraB. Only cells that bear identical or very similar alleles of traA will recognize one another for OME. Depending of conditions the exchange of OM content leads to beneficial or harmful outcomes. In genetic models we showed that OME can result in cooperative repair of damaged cells. Here, healthy cells replenish mutant cells with missing components that restores their fitness. In other examples, OME leads to antagonisms when polymorphic toxins are transferred and the recipient cells do not contain cognate immunity proteins. Although OME involves the apparent transfer of hundreds of different cellular components with complex social consequences, this system is amendable to powerful approaches that can be applied to bacterial research. This proposal addresses three goals.
In Aim 1 we will investigate OM fusion as the mechanism for exchange by using microscopy, genetic and biochemical methods to define the dynamic functions of TraA and TraB.
Aim 2 will also use a combination of approaches to define the molecular basis of TraA kin recognition and how it interacts with TraB.
Aim 3 will investigate a second pathway that allows toxins delivered by OME to enter the cytoplasm. Our preliminary data suggests that this kin discrimination system impacts strain diversification and population structures found in natural soil habitats. This hypothesis will be tested by genetic and bioinformatic experiments. Last, the ability of OME to repair damage that is inflicted on stressed cells will be tested. These studies will lead to a molecular understanding of the mechanisms of kin recognition and OME, as well as a deeper insights into how a socially sophisticated bacterium transitions from individuals into a cooperative multicellular tissue.

Public Health Relevance

Individual cells can interact with other cells to perform multicellular functions that are found in tissues, organs and animals. How cells cooperate in these multicellular communities is a fundamental question in biology. The failure of cells to properly interact in humans leads to devastating diseases such as cancer. This proposal investigates a new paradigm for how cells recognize their clonemates, transfer their cellular cargo and perform social behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101449-07
Application #
9557492
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Sledjeski, Darren D
Project Start
2012-05-01
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Wyoming
Department
Biochemistry
Type
Earth Sciences/Resources
DUNS #
069690956
City
Laramie
State
WY
Country
United States
Zip Code
82071
Troselj, Vera; Treuner-Lange, Anke; S√łgaard-Andersen, Lotte et al. (2018) Physiological Heterogeneity Triggers Sibling Conflict Mediated by the Type VI Secretion System in an Aggregative Multicellular Bacterium. MBio 9:
Troselj, Vera; Cao, Pengbo; Wall, Daniel (2018) Cell-cell recognition and social networking in bacteria. Environ Microbiol 20:923-933
Troselj, Vera; Wall, Daniel (2018) Metabolic disharmony and sibling conflict mediated by T6SS. Microb Cell 5:256-258
Cao, Pengbo; Wall, Daniel (2017) Self-identity reprogrammed by a single residue switch in a cell surface receptor of a social bacterium. Proc Natl Acad Sci U S A 114:3732-3737
Vassallo, Christopher N; Cao, Pengbo; Conklin, Austin et al. (2017) Infectious polymorphic toxins delivered by outer membrane exchange discriminate kin in myxobacteria. Elife 6:
Wall, Daniel (2016) Kin Recognition in Bacteria. Annu Rev Microbiol 70:143-60
Dey, Arup; Vassallo, Christopher N; Conklin, Austin C et al. (2016) Sibling Rivalry in Myxococcus xanthus Is Mediated by Kin Recognition and a Polyploid Prophage. J Bacteriol 198:994-1004
Vassallo, Christopher N; Wall, Daniel (2016) Tissue repair in myxobacteria: A cooperative strategy to heal cellular damage. Bioessays 38:306-15
Cao, Pengbo; Dey, Arup; Vassallo, Christopher N et al. (2015) How Myxobacteria Cooperate. J Mol Biol 427:3709-21
Vassallo, Christopher; Pathak, Darshankumar T; Cao, Pengbo et al. (2015) Cell rejuvenation and social behaviors promoted by LPS exchange in myxobacteria. Proc Natl Acad Sci U S A 112:E2939-46

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