Multiscale modeling of bacterial colonies: how pili mediate the dynamics of single cells and cellular aggregates

Abstract

Neisseria gonorrhoeae is the causative agent of one of the most common sexually transmitted diseases, gonorrhea. Over the past two decades there has been an alarming increase of reported gonorrhea cases where the bacteria were resistant to the most commonly used antibiotics thus prompting for alternative antimicrobial treatment strategies. The crucial step in this and many other bacterial infections is the formation of microcolonies, agglomerates consisting of up to several thousands of cells. The attachment and motility of cells on solid substrates as well as the cell–cell interactions are primarily mediated by type IV pili, long polymeric filaments protruding from the surface of cells. While the crucial role of pili in the assembly of microcolonies has been well recognized, the exact mechanisms of how they govern the formation and dynamics of microcolonies are still poorly understood. Here, we present a computational model of individual cells with explicit pili dynamics, force generation and pili–pili interactions. We employ the model to study a wide range of biological processes, such as the motility of individual cells on a surface, the heterogeneous cell motility within the large cell aggregates, and the merging dynamics and the self-assembly of microcolonies. The results of numerical simulations highlight the central role of pili generated forces in the formation of bacterial colonies and are in agreement with the available experimental observations. The model can quantify the behavior of multicellular bacterial colonies on biologically relevant temporal and spatial scales and can be easily adjusted to include the geometry and pili characteristics of various bacterial species. Ultimately, the combination of the microbiological experimental approach with the in silico model of bacterial colonies might provide new qualitative and quantitative insights on the development of bacterial infections and thus pave the way to new antimicrobial treatments.

Continuum theory of active phase separation in cellular aggregates

“…Multi-scale computer simulations have played an important role in the study of the physics of the formation of N. gonorrhoeae colonies [16][17][18]. Continuum approaches such as theories of active gels [19][20][21][22][23][24][25][26] so far do not capture important features of dense cellular aggregates.…”

Relative distance between tracers as a measure of diffusivity within moving aggregates

“…In order to compute not just the sum of the diffusion coefficients, but their values, it is necessary to track not just two but three cells The method based on MSRD measurements can, with some limitations, be used for non-uniform diffusivities, where, for example, the diffusion constant is a function of the distance from the center of the aggregate [1].…”

“…Often, tracers move within domains of finite size, for example individual molecules inside single cells [7,17,31] or individual cells within cell aggregates [1,32].…”

“…Examples range from microcolonies formed by bacteria [1,2] (see Fig. 1a) to eukaryotic cells forming aggregates [3][4][5] and tissues [6].…”

“…However, frequently cell aggregates or individual cells exhibit spatial translation and rotation [1,2]. This motion contributes to the MSD of tracers and makes it difficult to disentangle the diffusivity of the tracers.…”