Antibiotic-induced disease tolerance

AbstractChagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi protozoa. Over 8 million people worldwide are T. cruzi-positive, 20-30% of which will develop cardiomyopathy, megaoesophagus and/or megacolon. The mechanisms leading to gastrointestinal (GI) symptom development are however poorly understood. To address this issue, we systematically characterized the spatial impact of experimental T. cruzi infection on the microbiome and metabolome across the GI tract. The largest microbiota perturbations were observed in the proximal large intestine in both acute and chronic disease, with chronic-stage effects also observed in the cecum. Strikingly, metabolomic impact of acute-to-chronic stage transition differed depending on the organ, with persistent large-scale effects of infection primarily in the oesophagus and large intestine, providing a potential mechanism for GI pathology tropism in CD. Infection particularly affected acylcarnitine and lipid metabolism. Building on these observations, treatment of infected mice with carnitine-supplemented drinking water prevented acute-stage mortality with no changes in parasite burden. Overall, these results identified a new mechanism of disease tolerance in CD, with potential for the development of new therapeutic regimens. More broadly, these results highlight the potential of spatially-resolved metabolomic approaches to provide insight into disease pathogenesis, with translational applications for infectious disease drug development.

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Cachexia and fibrosis are costs of chronic IL-1R-mediated disease tolerance in T. gondii infection

10.1101/783316 ◽

2019 ◽

Author(s):

Stephanie J. Melchor ◽

Jessica A. Hatter ◽

Erika A. LaTorre Castillo ◽

Claire M. Saunders ◽

Kari A. Byrnes ◽

...

Keyword(s):

Muscle Wasting ◽

Parasite Burden ◽

Protozoan Parasite ◽

Disease Tolerance ◽

Muscle Fibrosis ◽

Tissue Integrity ◽

Hepatocyte Necrosis ◽

The Cost

AbstractCachexia is an immune-metabolic disease of progressive muscle wasting that impairs patient survival and quality of life across a range of chronic diseases. T. gondii is a protozoan parasite that causes lifelong infection in many warm-blooded organisms, including humans and mice. Here we show that mice infected with T. gondii develop robust, sustained cachexia and perivascular fibrosis in metabolic tissues. Consistent with an emerging role for the IL-1 axis in disease tolerance, we show that mice deficient in the Type 1 IL-1 receptor (IL-1R) have more severe acute muscle wasting, adipocyte and hepatocyte necrosis, independent of parasite burden. Unexpectedly, IL-1R-/- mice rapidly recover from acute disease, despite sustained parasite infection, and are protected from chronic cachexia as well as perivascular liver and muscle fibrosis. These data are consistent with a model where IL-1R signaling benefits cell survival and tissue integrity over short periods of inflammation, but sustained reliance on IL-1 mediated tolerance programs come at the cost of fibrosis and cachexia.SummaryIL-1R signaling drives a disease tolerance program that protects mice from tissue pathology during acute Toxoplasma gondii infection. However, extended IL-1R signaling drives chronic cachexia and perivascular fibrosis in the liver and skeletal muscle.

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Major Genetic Changes in Wheat with Potential to Affect Disease Tolerance

Phytopathology ◽

10.1094/phyto-96-0680 ◽

2006 ◽

Vol 96 (7) ◽

pp. 680-688 ◽

Cited By ~ 24

Author(s):

M. J. Foulkes ◽

N. D. Paveley ◽

A. Worland ◽

S. J. Welham ◽

J. Thomas ◽

...

Keyword(s):

Genetic Background ◽

Field Experiments ◽

Flag Leaf ◽

Soluble Carbohydrate ◽

Potential Yield ◽

Genetic Changes ◽

Septoria Leaf Blotch ◽

Disease Tolerance ◽

The United Kingdom ◽

Canopy Area

Selection through plant breeding has resulted in most elite winter wheat germplasm in the United Kingdom containing the Rht-D1b semi-dwarfing allele, the 1BL.1RS chromosome arm translocation with rye, and an allele conferring suppression of awns. Near-isogenic lines (NILs) were used to test whether these major genetic changes have had any effect on disease tolerance. The ability of the NILs to tolerate epidemics of Septoria leaf blotch or stripe rust was measured in four field experiments over two seasons. Tolerance was quantified as yield loss per unit of green canopy area lost to disease. There was a trend for the presence of the 1BL.1RS translocation to decrease tolerance; however, this was not consistent across experiments and there was no effect of semi-dwarfing. The awned NIL exhibited decreased tolerance compared with the unawned NIL. There were significant differences in tolerance between the cultivar backgrounds in which the NILs were developed. Tolerance was lower in the modern genetic background of Weston, released in 1996, than in the genetic background of Maris Hunstman, released in 1972. The data suggest that certain physiological traits were associated with the tolerance differences among the backgrounds in these experiments. Potential yield, accumulation of stem soluble carbohydrate reserves, and grain sink capacity were negatively correlated with tolerance, whereas flag leaf area was positively correlated.

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