3D illustration of the bacterial pathogen Mycobacterium tuberculosis.
Image: 123rf
A study by computational bioengineers at Rice University and infectious disease experts at Rutgers New Jersey Medical School (NJMS) has revealed how Mycobacterium tuberculosis, the organism that causes TB, is able to resist our immune system and lie dormant for many years, before becoming active and pathological again. It has a genetic mechanism that enables it to resist stress and 'remember' how id did it, so it can do it again more quickly.
Creationists, for whom evolution by entirely natural processes must be dogmatically rejected, must attribute this ability to the intentional design of their putative intelligent [sic] designer, who is one and the same as the Christian god and allegedly omni-benevolent, only wanting a maximally good world for its creation. Why then it came up with this apparently malevolent design remains a mystery that I have yet to get a creationist to explain, other than by dismissing it as a mystery that we can't ever expect to understand, and calling me arrogant for "trying to understand the mind of God", whilst still pretending it is real science and a sound basis for investigating biology.
There’s some sort of peace treaty between the immune system and bacteria. The bacteria don’t grow, and the immune system doesn’t kill them. But if people get immunocompromised due to malnutrition or AIDS, the bacteria can be reactivated.
The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don’t have that much of a response, but if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back.
Hysteretic switches are known to be very slow, and this wasn’t. There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results.
We didn’t discover [Dnak], but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we’d observed. What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK.
When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network, so once there are enough unfolded proteins to ‘distract’ DnaK, the organism responds to the stress.
The immediate first step is to really try and see whether this hysteresis is important during the infection. Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host.
What the researcher found is explained in a Rice University press release:
The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don’t have that much of a response, but if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back.
Hysteretic switches are known to be very slow, and this wasn’t. There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results.
We didn’t discover [Dnak], but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we’d observed. What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK.
When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network, so once there are enough unfolded proteins to ‘distract’ DnaK, the organism responds to the stress.
The immediate first step is to really try and see whether this hysteresis is important during the infection. Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host.
Oleg Igoshin, corresponding author
Professor of bioengineering at Rice.
Professor of bioengineering at Rice.
Researchers have long suspected that the ability of TB bacteria to remain dormant, sometimes for decades, stems from their ability to behave based upon past experience. Latent TB is an enormous global problem. While TB kills about 1.5 million people each year, the World Health Organization estimates that 2-3 billion people are infected with a dormant form of the TB bacterium.The work was published in the open access journal of the American Society for Microbiology, mSystems, a few days ago.
[...]
One of the most likely candidates for a genetic switch that can toggle TB bacteria into a dormant state is a regulatory network that is activated by the stress caused by immune cell attacks. The network responds by activating several dozen genes the bacteria use to survive the stress. Based on a Rice computational model, Igoshin and his longtime Rutgers NJMS collaborator Maria Laura Gennaro and colleagues predicted just such a switch in 2010. According to the theory, the switch contained an ultrasensitive control mechanism that worked in combination with multiple feedback loops to allow hysteresis, or history-dependent behavior.
In later experiments, Gennaro’s team found no evidence of the predicted control mechanism in Mycobacterium smegmatis, a close relative of the TB bacterium. Since both organisms use the same regulatory network, it looked like the prediction was wrong. Finding out why took years of follow-up studies. Gennaro and Igoshin’s teams found that the TB bacterium, unlike their noninfectious cousins, had the hysteresis control mechanism, but it didn’t behave as expected.
[...]
Igoshin and study co-author Satyajit Rao, a Rice doctoral student who graduated last year, revisited the 2010 model and considered how it might be modified to explain the paradox. Studies within the past decade had found a protein called DnaK played a role in activating the stress-response network. Based on what was known about DnaK, Igoshin and Rao added it to their model of the dormant-active switch.
[...]
DnaK was known to play the role of chaperone in helping rid cells of unfolded proteins, but it plays an additional role in the stress-response network by keeping its sensor protein in an inactive state.
[...]
Gennaro and co-author Pratik Datta conducted experiments at NJMS to confirm DnaK behaved as predicted. But Igoshin said it is not clear how the findings might impact TB treatment or control strategies. For example, the switch responds to short-term biochemical changes inside the cell, and it’s unclear what connection, if any, it may have with long-term behaviors like TB latency, he said.
The interesting thing from the Creationism vs Science 'debate' is how part of what distinguishes the M. tuberculosis bacillus from its close relative, M. smegmatis, and a large part of what makes it highly pathological and a major killer, unlike its harmless close relative is this modification that has allowed it to set up home in our tissues and eventually kill us. A biologist would call this evolution but a Creationist would be obliged to call it 'intelligent [sic] design'.ABSTRACT
Dynamical properties of gene regulatory networks are tuned to ensure bacterial survival. In mycobacteria, the MprAB-σE network responds to the presence of stressors, such as surfactants that cause surface stress. Positive feedback loops in this network were previously predicted to cause hysteresis, i.e., different responses to identical stressor levels for prestressed and unstressed cells. Here, we show that hysteresis does not occur in nonpathogenic Mycobacterium smegmatis but does occur in Mycobacterium tuberculosis. However, the observed rapid temporal response in M. tuberculosis is inconsistent with the model predictions. To reconcile these observations, we implement a recently proposed mechanism for stress sensing, namely, the release of MprB from the inhibitory complex with the chaperone DnaK upon the stress exposure. Using modeling and parameter fitting, we demonstrate that this mechanism can accurately describe the experimental observations. Furthermore, we predict perturbations in DnaK expression that can strongly affect dynamical properties. Experiments with these perturbations agree with model predictions, confirming the role of DnaK in fast and sustained response.
IMPORTANCE Gene regulatory networks controlling stress response in mycobacterial species have been linked to persistence switches that enable bacterial dormancy within a host. However, the mechanistic basis of switching and stress sensing is not fully understood. In this paper, combining quantitative experiments and mathematical modeling, we uncover how interactions between two master regulators of stress response—the MprAB two-component system (TCS) and the alternative sigma factor σE—shape the dynamical properties of the surface stress network. The result show hysteresis (history dependence) in the response of the pathogenic bacterium M. tuberculosis to surface stress and lack of hysteresis in nonpathogenic M. smegmatis. Furthermore, to resolve the apparent contradiction between the existence of hysteresis and fast activation of the response, we utilize a recently proposed role of chaperone DnaK in stress sensing. These result leads to a novel system-level understanding of bacterial stress response dynamics.
Rao, Satyajit D.; Datta, Pratik; Gennaro, Maria Laura; Igoshin, Oleg A.
Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response
mSystems Feb 2021, 6 (1) e00979-20; DOI: 10.1128/mSystems.00979-20
Copyright: © 2021 The authors. Published by American Society for Microbiology Journals
Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
And again we have yet another instance of where compliance with dogma requires Creationists to deny the only explanation for this modification that doesn't leave their supposedly omni-benevolent deity, looking more like a malevolent, misanthropic, pestilential, evil genius than one any decent parent would encourage their children to praise.
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