Sickness-induced anorexia is a conserved behavior induced during infections. Here, we report that an intestinal pathogen, Salmonella Typhimurium, inhibits anorexia by manipulating the gut-brain axis. ...Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP, prevented anorexia caused by IL-1β-mediated signaling to the hypothalamus via the vagus nerve. Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts, suggesting that there are trade-offs between transmission and virulence. These results clarify the complex and contextual role of anorexia in host-pathogen interactions and suggest that microbes have evolved mechanisms to modulate sickness-induced behaviors to promote health of their host and their transmission at the expense of virulence.
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•Feeding status of host regulates pathogen virulence and transmission•Pathogen inhibition of IL-1β prevents anorexia via the gut-brain axis•Pathogen inhibition of anorexia promotes host survival and pathogen transmission•Sickness-induced anorexia creates trade-offs between virulence and transmission
Pathogens can interfere with the gut-brain circuits that control host anorexia during infection to promote host survival while facilitating disease transmission.
Infections and inflammation can lead to cachexia and wasting of skeletal muscle and fat tissue by as yet poorly understood mechanisms. We observed that gut colonization of mice by a strain of ...Escherichia coli prevents wasting triggered by infections or physical damage to the intestine. During intestinal infection with the pathogen Salmonella Typhimurium or pneumonic infection with Burkholderia thailandensis, the presence of this E. coli did not alter changes in host metabolism, caloric uptake, or inflammation but instead sustained signaling of the insulin-like growth factor 1/phosphatidylinositol 3-kinase/AKT pathway in skeletal muscle, which is required for prevention of muscle wasting. This effect was dependent on engagement of the NLRC4 inflammasome. Therefore, this commensal promotes tolerance to diverse diseases.
Pathogen virulence exists on a continuum. The strategies that drive symptomatic or asymptomatic infections remain largely unknown. We took advantage of the concept of lethal dose 50 (LD50) to ask ...which component of individual non-genetic variation between hosts defines whether they survive or succumb to infection. Using the enteric pathogen Citrobacter, we found no difference in pathogen burdens between healthy and symptomatic populations. Iron metabolism-related genes were induced in asymptomatic hosts compared to symptomatic or naive mice. Dietary iron conferred complete protection without influencing pathogen burdens, even at 1000× the lethal dose of Citrobacter. Dietary iron induced insulin resistance, increasing glucose levels in the intestine that were necessary and sufficient to suppress pathogen virulence. A short course of dietary iron drove the selection of attenuated Citrobacter strains that can transmit and asymptomatically colonize naive hosts, demonstrating that environmental factors and cooperative metabolic strategies can drive conversion of pathogens toward commensalism.
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•Lethal dose 50 can be used to identify cooperative defense mechanisms•Dietary iron promotes cooperative defenses against a lethal enteric infection•Insulin resistance reduces gut glucose absorption•Cooperative defenses drive selection for attenuated pathogen strains
Defense strategies that are cooperative rather than antagonistic can promote asymptomatic infection and select for reduced virulence in a bacterial pathogen.
Abstract
Physiological responses that occur during infection are most often thought of in terms of effectors of microbial destruction through the execution of resistance mechanisms, due to a direct ...action of the microbe, or are maladaptive consequences of host–pathogen interplay. However, an examination of the cellular and organ-level consequences of one such response, thermoregulation that leads to fever or hypothermia, reveals that these actions cannot be readily explained within the traditional paradigms of microbial killing or maladaptive consequences of host–pathogen interactions. In this review, the concept of disease tolerance is applied to thermoregulation during infection, inflammation and trauma, and we discuss the physiological consequences of thermoregulation during disease including tissue susceptibility to damage, inflammation, behavior and toxin neutralization.
In this review, the concept of disease tolerance is applied to thermoregulation during infection, inflammation and trauma, and the authors discuss the physiological consequences of thermoregulation during disease including tissue susceptibility to damage, inflammation, behavior and toxin neutralization.
Since the 1870s, the primary motor cortex (M1) has been known to have a somatotopic organization, with different regions of cortex participating in control of face, arm, and leg movements. Through ...the middle of the 20th century, it seemed possible that the principle of somatotopic organization extended to the detailed representation of different body parts within each of the three major representations. The arm region of M1, for example, was thought to contain a well-ordered, point-to-point representation of the movements or muscles of the thumb, index, middle, ring, and little fingers, the wrist, elbow, and shoulder, as conveyed by the iconic homunculus and simiusculus. In the last quarter of the 20th century, however, experimental evidence has accumulated indicating that within-limb somatotopy in M1 is not spatially discrete nor sequentially ordered. Rather, beneath gradual somatotopic gradients of representation, the representations of different smaller body parts or muscles each are distributed widely within the face, arm, or leg representation, such that the representations of any two smaller parts overlap extensively. Appreciation of this underlying organization will be essential to further understanding of the contribution to control of movement made by M1. Because no single experiment disproves a well-ordered within-limb somatotopic organization in M1, here I review the accumulated evidence, using a framework of six major features that constrain the somatotopic organization of M1: convergence of output, divergence of output, horizontal interconnections, distributed activation, effects of lesions, and ability to reorganize. Review of the classic experiments that led to development of the homunculus and simiusculus shows that these data too were consistent with distributed within-limb somatotopy. I conclude with speculations on what the constrained somatotopy of M1 might tell us about its contribution to control of movement.
To determine whether other digits move when normal humans attempt to move just one digit, we asked 10 right-handed subjects to move one finger at a time while we recorded the motion of all five ...digits simultaneously with both a video motion analysis system and an instrumented glove. We quantified the independence of the digits to compare (1) the different digits, (2) the right versus the left hand, and (3) movements at a self-paced frequency versus externally paced movements at 3 Hz. We also quantified the degree to which motion occurred at the proximal, middle, or distal joint of each digit. Even when asked to move just one finger, normal human subjects produced motion in other digits. Movements of the thumb, index finger, and little finger typically were more highly individuated than were movements of the middle or ring fingers. Fingers of the dominant hand were not more independent than were those of the nondominant hand. Self-paced movements made at approximately 2 Hz were more highly individuated than were externally paced movements at 3 Hz. Angular motion tended to be greatest at the middle joint of each digit, with increased angular motion at the proximal and distal joints during 3 Hz movements. Simultaneous motion of noninstructed digits may result in part from passive mechanical connections between the digits, in part from the organization of multitendoned finger muscles, and in part from distributed neural control of the hand.
We tested several techniques for decoding the activity of primary motor cortex (M1) neurons during movements of single fingers or pairs of fingers. We report that single finger movements can be ...decoded with >99% accuracy using as few as 30 neurons randomly selected from populations of task-related neurons recorded from the M1 hand representation. This number was reduced to 20 neurons or less when the neurons were not picked randomly but selected on the basis of their information content. We extended techniques for decoding single finger movements to the problem of decoding the simultaneous movement of two fingers. Movements of pairs of fingers were decoded with 90.9% accuracy from 100 neurons. The techniques we used to obtain these results can be applied, not only to movements of single fingers and pairs of fingers as reported here, but also to movements of arbitrary combinations of fingers. The remarkably small number of neurons needed to decode a relatively large repertoire of movements involving either one or two effectors is encouraging for the development of neural prosthetics that will control hand movements.
We investigated how damage to the motor cortex or corticospinal tract affects the selective activation of finger muscles in humans. We hypothesized that damage relatively restricted to the motor ...cortex or corticospinal tract would result in unselective muscle activations during an individuated finger movement task. People with pure motor hemiparesis attributed to ischemic cerebrovascular accident were tested. Pure motor hemiparetic and control subjects were studied making flexion/extension and then abduction/adduction finger movements. During the abduction/adduction movements, we recorded muscle activity from 3 intrinsic finger muscles: the abductor pollicis brevis, the first dorsal interosseus, and the abductor digit quinti. Each of these muscles acts as an agonist for only one of the abduction/adduction movements and might therefore be expected to be active in a highly selective manner. Motor cortex or corticospinal tract damage in people with pure motor hemiparesis reduced the selectivity of finger muscle activation during individuated abduction/adduction finger movements, resulting in reduced independence of these movements. Abduction/adduction movements showed a nonsignificant trend toward being less independent than flexion/extension movements in the affected hands of hemiparetic subjects. These changes in the selectivity of muscle activation and the consequent decrease in individuation of movement were correlated with decreased hand function. Our findings imply that, in humans, spared cerebral motor areas and descending pathways that remain might activate finger muscles, but cannot fully compensate for the highly selective control provided by the primary motor cortex and the crossed corticospinal system.
The purpose of this study was to quantify the long-term loss of independent finger movements in humans with lesions relatively restricted to motor cortex or corticospinal tract. We questioned whether ...damage to the motor cortex or corticospinal tract would permanently affect the ability to move each finger to the same degree or would affect some fingers more than others. People with pure motor hemiparesis due to ischemic cerebrovascular accident were used as our experimental sample. Pure motor hemiparetic and control subjects were tested for their ability to make cyclic flexion/extension movements of each finger independently. We recorded their finger joint motion using an instrumented glove. The fingers of control subjects and of the unaffected hands (ipsilateral to the lesion) of hemiparetic subjects moved relatively independently. The fingers of the affected hands (contralateral to the lesion) of hemiparetic subjects were differentially impaired in their ability to make independent finger movements. The independence of the thumb was normal; the independence of the index finger was slightly impaired, while the independence of the middle, ring, and little fingers was substantially impaired. The differential long-term effects of motor cortical or corticospinal damage on finger independence may result from rehabilitative training emphasizing tasks requiring independent thumb and index movements, and from a greater ability of the spared components of the neuromuscular system to control the thumb independently compared with the other four fingers.
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