Association of hypothermia with increased mortality rate in SARS-CoV-2 infection

Fatteh, Naaz; Sutherland, Glen E.; Santos, Radleigh; Zeidan, Rita; Gastesi, A; Naranjo, Christopher D.

doi:10.1016/j.ijid.2021.05.031

“…While the clinical scores for all the surviving hACE2; Irgm1 −/− mice were fully restored to normal by 13 DPI, the hACE2 mice still displayed abnormal clinical scores ( Figure 1G ). Hypothermia (a rapid drop in body temperature) was found to be associated with the increased mortality rate in COVID-19 patients (Fatteh et al, 2021; Maait et al, 2021). We observed a rapid drop in temperature in hACE2 mice, but not in hACE2; Irgm1 −/− mice ( Figure 1H ).…”

Section: Resultsmentioning

confidence: 98%

“…The Irgm1 knockout mice displayed very mild clinical symptoms with none of the mice undergoing hypothermic conditions. A condition that was shown to be associated with enhanced mortality rates in humans (Fatteh et al, 2021; Maait et al, 2021) The viral load remained low in Irgm1 −/− mice throughout the experiments performed for different time points. The pathological changes in Irgm1 knockout mice were minor as compared to parental hACE2 mice, which showed severe lung consolidation and fibrosis with enhanced migration of neutrophils, T-Cells, and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Chauhan

¹

,

Kundu

²

,

Bal

³

et al. 2022

Preprint

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Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, however, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2; Irgm1-/-) and the other with dampened IFN-I response (hACE2; Ifnar1-/-) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2; Irgm1-/- mice were resistant to lethal SARS-CoV-2 (including delta variant) infection with substantially reduced cytokine storm and immunopathology in the lungs and brain. In striking contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2; Ifnar1-/- mice. Additionally, hACE2; Ifnar1-/- mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2; Irgm1-/- Ifnar1-/- double knockout mice or hACE2; Irgm1-/- mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2; Irgm1-/- mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against COVID-19.

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“…This is achieved, in part, through oxidation of fatty acids and activation of UCP1 ( Lee et al, 2015 ). A decrease in body temperature during sepsis is an independent predictor of mortality ( Rumbus et al, 2017 ; Fatteh et al, 2021 ). Therefore, given the importance of thermogenesis during sepsis and our findings that Acod1 deficiency impairs hepatic β-oxidation, we endeavored to determine if this has effects on BAT function.…”

Section: Resultsmentioning

confidence: 99%

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Mainali,

Buechler,

Otero

et al. 2024

eLife

1

0

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One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

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“…This is achieved, in part, through oxidation of fatty acids and activation of UCP1 28 . A decrease in body temperature during sepsis is an independent predictor of mortality 29,30 .…”

Section: Irg1 Deficiency Impairs the Thermogenic Program During Sepsismentioning

confidence: 99%

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Mainali,

Buechler,

Otero

et al. 2023

Preprint

View full text Add to dashboard Cite

One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

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Association of hypothermia with increased mortality rate in SARS-CoV-2 infection

Cited by 9 publications

References 22 publications

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

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