"Metabolism" uncovers the "truth" of Zika virus infection

Around 2016, the Zika virus ravaged the world and became an international public health emergency
.
Especially when pregnant women are infected with Zika virus, it can cause severe microcephaly in newborns

From the perspective of metabolism, the team of Professor Hu Zeping from the School of Pharmacy of Tsinghua University and collaborators took the lead in revealing the significant metabolic reprogramming of nicotinamide adenine dinucleotide (hereinafter referred to as NAD+) in the brain tissue of microcephaly caused by Zika virus infection.
It is proposed that targeting NAD+ metabolism can improve microcephaly caused by Zika virus infection
.
The relevant research results were published in the journal Nature-Metabolism on August 12

Open the treatment window

In May 2015, the Zika virus outbreak in South America caused 1.
5 million infections in just 8 months, of which the suspected cases of neonatal microcephaly surged to 3,894
.
Then, the World Health Organization announced that Zika virus has constituted a "public health emergency of international concern

Behind the "microcephaly" is the dramatic changes in the substances in the living body, and metabolism is the basic biological process that produces biological substances and bio-energy

In the past, scientists have conducted some explorations on the infection mechanism of Zika virus, but most of them are based on in vitro cell line models, and some host proteins or signal pathways related to Zika virus have also been discovered
.

"We still don't know how Zika virus infection causes molecular changes in the host.
From the perspective of metabolism, we can better understand the molecular mechanism of microcephaly caused by Zika virus infection, and then develop potential strategies to treat the disease
.
" Hu Zeping told "China Science Daily"

For a long time, Hu Zeping’s team has been committed to the development of new metabolomics and metabolic flow analysis technologies, and the development of multi-omics big data integration strategies based on artificial intelligence (AI), and applied them to cancer, viral infectious diseases, and heart diseases.
Research on the metabolic remodeling of pathological processes such as vascular diseases, and physiological processes such as stem cells, development and aging
.
They created a highly sensitive and highly accurate broad-spectrum targeted metabolomics technology, developed a highly sensitive dynamic metabolic flow analysis technology for multiple key metabolic pathways, and explained the effects of tumors, viral infectious diseases and other diseases.

Hu Zeping said that using the developed new metabolomics and metabolic flow analysis technologies, the team has carried out extensive domestic and international cooperation to explain the metabolic remodeling and molecular mechanisms of malignant melanoma, hematopoietic stem cells, lung cancer, and heart regeneration.
Reveals new targets and new strategies for potential treatments
.

These foundations have provided good technical means and research experience for unveiling the "black hands" behind the "microcephaly" induced by Zika virus
.

"Metabolism" reveals the molecular mechanism of microcephaly

In recent years, multi-omics data sorting strategies and related technologies have been widely used in the interpretation of molecular mechanisms, the discovery of drug targets, and precision medicine
.

Hu Zeping’s team took the lead in the world to use multi-omics data integration analysis strategy to conduct a panoramic study on microcephaly caused by Zika virus infection, and systematically described Zika virus infection from the level of RNA, protein and metabolites.
The molecular map of microcephaly
.

Through the integration of transcriptomics and proteomics data, the researchers found that the metabolism of Zika virus-infected mice brain tissue has undergone significant changes
.

What caused the changes in metabolism? The researchers further analyzed the proteomics data and metabolomics and found that the oxidative phosphorylation, tricarboxylic acid cycle and other metabolisms closely related to mitochondrial metabolism in the brain tissue of Zika virus-infected mice have undergone significant changes
.
More importantly, metabolomics analysis found that NAD+ and its related precursor metabolites in the brain tissue of Zika virus-infected mice have undergone drastic changes, and further combined with transcriptome and proteome data, they interactively verified from different perspectives The NAD+ metabolic reprogramming process

Coenzyme NAD+ exists in all living cells and participates in many important physiological processes of the living organism.
Its abnormal metabolism will seriously affect the health of the body's cells and tissues
.
Metabolic reprogramming means that the virus “hijacks” the metabolism of the infected host cell to obtain the vital substances and energy needed for survival and growth, as well as “protection” from immune surveillance

The above studies indicate that NAD+ metabolic reprogramming is likely to be the potential molecular mechanism and intervention target of microcephaly caused by Zika virus infection
.

In order to further verify this scientific hypothesis, the researchers supplemented NAD+ and its important precursor substance nicotinamide ribose (NR) in mice, and found that microcephaly related indicators (including cell apoptosis, Brain weight, body weight, survival time, etc.
) have been significantly improved
.

"These studies not only provide powerful big data resources for clinical understanding of the molecular mechanism of microcephaly caused by Zika virus infection, but also propose the potential value of intervention in NAD+ metabolism in its clinical treatment and drug development
.
At present, NAD+-related Supplements have received extensive attention in the field of anti-aging.
Our research provides new inspiration and clues for the application of NAD+ in the clinical treatment of
Zika virus infection .
" Hu Zeping said
.

In-depth research to promote clinical

Scientific research does not happen overnight
.
Hu Zeping said that starting from a biological phenomenon, discovering a problem, analyzing a problem, and then solving a problem, this process is full of unknowns, hardships and challenges, but it is a very interesting process
.

"When a certain scientific problem is solved, or even a
small'bug ' in an experiment, the sense of satisfaction and gain is incomparable to anything else .
" Hu Zeping shared that in the verification experiment stage, one needs Considering the actual clinical medication mode, on the one hand, due to the fact that pregnant mice are easily interfered by external stimuli, the fetal mice are small, there are problems such as limited drug delivery methods and experimental operation difficulties.
After repeated discussions and preliminary experiments, they finally formulated the pregnancy The dosage regimen of adding drinking water to mice combined with intraperitoneal injection of their newborn mice allowed the experiment to proceed smoothly
.

International colleagues agree that this work is very novel and interesting and can attract the interest of a broad audience in the metabolic field.
They believe that “this is a rich multi-omics research masterpiece” and “provides a large amount of data resources and science for other Zika virus-related research.
Hypothesis” and “found a new therapeutic strategy that can be further developed as a drug target”
.

However, Hu Zeping accepts that it is limited by objective factors such as experimental conditions and time.
In this study, they only confirmed in mice that supplementing NAD+ or NR can improve microcephaly caused by Zika virus infection
.
However, whether this improvement effect can be better through the optimization of experimental protocols, such as combined use with antiviral drugs, still needs to be explored
.

"Whether this work has guiding significance for clinical medication or treatment, in the future, if conditions permit, we hope to continue to explore in depth and achieve clinical transformation
.
" Hu Zeping said
.
(Source: China Science News Han Yangmei)

Related paper information: https://doi.
org/10.
1038/s42255-021-00437-0