35,829 research outputs found
The physicist's guide to one of biotechnology's hottest new topics: CRISPR-Cas
Clustered regularly interspaced short palindromic repeats (CRISPR) and
CRISPR-associated proteins (Cas) constitute a multi-functional, constantly
evolving immune system in bacteria and archaea cells. A heritable, molecular
memory is generated of phage, plasmids, or other mobile genetic elements that
attempt to attack the cell. This memory is used to recognize and interfere with
subsequent invasions from the same genetic elements. This versatile prokaryotic
tool has also been used to advance applications in biotechnology. Here we
review a large body of CRISPR-Cas research to explore themes of evolution and
selection, population dynamics, horizontal gene transfer, specific and
cross-reactive interactions, cost and regulation, non-immunological CRISPR
functions that boost host cell robustness, as well as applicable mechanisms for
efficient and specific genetic engineering. We offer future directions that can
be addressed by the physics community. Physical understanding of the CRISPR-Cas
system will advance uses in biotechnology, such as developing cell lines and
animal models, cell labeling and information storage, combatting antibiotic
resistance, and human therapeutics.Comment: 75 pages, 15 figures, Physical Biology (2018
Characterising two-pathogen competition in spatially structured environments
Different pathogens spreading in the same host population often generate
complex co-circulation dynamics because of the many possible interactions
between the pathogens and the host immune system, the host life cycle, and the
space structure of the population. Here we focus on the competition between two
acute infections and we address the role of host mobility and cross-immunity in
shaping possible dominance/co-dominance regimes. Host mobility is modelled as a
network of traveling flows connecting nodes of a metapopulation, and the
two-pathogen dynamics is simulated with a stochastic mechanistic approach.
Results depict a complex scenario where, according to the relation among the
epidemiological parameters of the two pathogens, mobility can either be
non-influential for the competition dynamics or play a critical role in
selecting the dominant pathogen. The characterisation of the parameter space
can be explained in terms of the trade-off between pathogen's spreading
velocity and its ability to diffuse in a sparse environment. Variations in the
cross-immunity level induce a transition between presence and absence of
competition. The present study disentangles the role of the relevant biological
and ecological factors in the competition dynamics, and provides relevant
insights into the spatial ecology of infectious diseases.Comment: 30 pages, 6 figures, 1 table. Final version accepted for publication
in Scientific Report
Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling
Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation
Model of host-pathogen Interaction dynamics links In vivo optical imaging and immune responses
Tracking disease progression in vivo is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for in vivo tracking of bacterial population development and therapeutic response. For a precise understanding of in vivo imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). We connect in vivo disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions
Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo
The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity
Drosophila as a model system to study nonautonomous mechanisms affecting tumour growth and cell death
The study of cancer has represented a central focus in medical research for over a century. The great complexity and constant evolution of the pathology require the use of multiple research model systems and interdisciplinary approaches. This is necessary in order to achieve a comprehensive understanding into the mechanisms driving disease initiation and progression, to aid the development of appropriate therapies. In recent decades, the fruit fly Drosophila melanogaster and its associated powerful genetic tools have become a very attractive model system to study tumour-intrinsic and non-tumour-derived processes that mediate tumour development in vivo. In this review, we will summarize recent work on Drosophila as a model system to study cancer biology. We will focus on the interactions between tumours and their microenvironment, including extrinsic mechanisms affecting tumour growth and how tumours impact systemic host physiology
High levels of cyclic-di-GMP in plant-associated Pseudomonas correlate with evasion of plant immunity
The plant innate immune system employs plasma membrane-localized receptors that specifically perceive pathogen/microbe-associated molecular patterns (PAMPs/MAMPs). This induces a defence response called pattern-triggered immunity (PTI) to fend off pathogen attack. Commensal bacteria are also exposed to potential immune recognition and must employ strategies to evade and/or suppress PTI to successfully colonize the plant. During plant infection, the flagellum has an ambiguous role, acting as both a virulence factor and also as a potent immunogen as a result of the recognition of its main building block, flagellin, by the plant pattern recognition receptors (PRRs), including FLAGELLIN SENSING2 (FLS2). Therefore, strict control of flagella synthesis is especially important for plant-associated bacteria. Here, we show that cyclic-di-GMP [bis-(3'-5')-cyclic di-guanosine monophosphate], a central regulator of bacterial lifestyle, is involved in the evasion of PTI. Elevated cyclic-di-GMP levels in the pathogen Pseudomonas syringae pv. tomato (Pto) DC3000, the opportunist P. aeruginosa PAO1 and the commensal P. protegens Pf-5 inhibit flagellin synthesis and help the bacteria to evade FLS2-mediated signalling in Nicotiana benthamiana and Arabidopsis thaliana. Despite this, high cellular cyclic-di-GMP concentrations were shown to drastically reduce the virulence of Pto DC3000 during plant infection. We propose that this is a result of reduced flagellar motility and/or additional pleiotropic effects of cyclic-di-GMP signalling on bacterial behaviour
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