Metabonomic analysis of different mice showed that liver arginase-1 is the source of plasma arginase in Plasmodium infection

Infection can destroy the host's metabolism, but the factors that determine the nature and extent of metabolic changes are not fully understood
.

In order to determine the relationship between host metabolism and disease severity, we conducted plasma metabolomics studies on 8 micePlasmodium Chabadie-Infected mouse strains with different disease phenotypes
.
We have identified plasma metabolic biomarkers for different physical properties and severity of malaria
.
The subset of metabolic changes, including plasma arginine depletion, matches the plasma metabolome of human malaria patients, indicating a new link between the pathology and metabolism of human malaria
.
In our malaria mice, liver damage (release of liver arginase-1 (Arg1)) enters the circulation and is related to plasma arginine depletion
.
We confirmed that liver Arg1 is the main source of increased plasma arginase activity in our model, which helps to further study liver damage in human malaria patients
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More broadly, our method demonstrates how to use phenotypic diversity to identify and verify the relationship between metabolism and the pathophysiology of infectious diseases
.

importance

Malaria is a serious and sometimes fatal infectious disease endemic to tropical and subtropical regions
.
An effective vaccine against malariaPlasmodiumParasites are still elusive, and malaria treatment often fails to prevent serious diseases
.
Small molecules that target host metabolism have recently become drug candidates for the treatment of malaria and other diseases
.
However, our limited understanding of how metabolites affect pathophysiology limits our ability to develop new metabolite therapies
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By providing a rich data set of metabolite-pathology correlations and verifying one of the correlations, our work is an important step towards the use of metabolism to alleviate diseases
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In particular, we foundP, Chabadie-Infected mice release liver arginase-1 into the circulation, where it may deplete plasma arginine, a candidate treatment for malaria that relieves blood vessel pressure
.
Our data suggests that liver damage may hinder efforts to increase arginine levels in human malaria patients
.

Introduction

Malaria is a serious infectious disease caused by Plasmodium.

Plasmodium
.
The deadliest species of mankind isPlasmodium falciparumAccording to statistics from the World Health Organization, 405,000 people died in 2018 (https:// data-src=").
Malarial pathologies range from uncomplicated fever and anemia to severe and sometimes fatal conditions, including severe anemia, metabolic acidosis, acute kidney injury, multiorgan failure, respiratory distress, and cerebral malaria (">The pathology of malaria ranges from simple fever and anemia to serious and even fatal diseases, including severe anemia, metabolic acidosis, acute kidney injury, multiple organ failure, respiratory distress and cerebral malaria (1–5).

Changes in host metabolism are often accompanied by malaria and are usually associated with severe systemic diseases or organ-specific diseases
.

For example, liver cell damage leads to increased levels of the metabolic enzymes aspartate and alanine aminotransferase (AST and ALT) in plasma (6,7) Renal insufficiency can also lead to changes in plasma metabolism, the most notable feature is the increase in plasma urea and creatinine (8,9) The dysfunction of any organ may lead to organ failure and other system complications (7).
Hypoglycemia(10) Metabolic acidosis (5) And other metabolic changes are also accompanied by serious diseases
.
However, the relationship between metabolic changes and the physical and physiological nature and extent of malaria remains unclear
.

In recent years, metabolites have become an important regulator of the pathophysiology of infection
.

For example, controlling glycolysis can change the severity of malaria (11,12) Control the tissue damage of other infections (13) Other metabolic indicators, including iron (14)Immune regulatory metabolic enzymes, such as arginase (15–17) And metabolic hormones (18) Has a high potential to reduce pathology during infection
.
There is no doubt that many metabolic therapies have not yet been discovered
.

Reveal the metabolic process in

PlasmodiumAfter infection, we have recently identified hundreds of plasma metabolites.
When C57BL/6 mice are infected, these metabolites will change significantly.
Plasmodium Chabadie(19)
.

Many of these metabolites also change in human malaria (
4,5,19–22) However, the causes and consequences of these metabolic changes are still unknown

Here, we collected different inbred lines, deliberately introduced mutations, and then measured the mutations

In order to link the pathophysiology of malaria with the metabolic changes of the host, we measured plasma metabolites and markers of pathology and immune response in 8 patients

P, Chabadie-The founder strain of the infection
.
Using principal component analysis, we found the magnitude of the metabolic responseP, ChabadieInfection is directly related to the severity of the disease
.
Through correlation analysis, we found that arginine deficiency is a specific marker of liver damage caused by malaria
.
We have identified more candidate molecules for future research
.
We showed thisP, Chabadie-Induced liver injury releases arginine depleting liver arginase-1 (Arg1) into the circulation, which explains the increase in plasma arginase activity in our model, and may also explain the plasma of human malaria patients Causes of elevated arginase
.
Our findings support the use of different mice to understand the link between metabolism during infection and disease severity, and promote further research on the metabolic consequences of human malaria liver damage
.