"Metabolism" uncovers the "truth" of microcephaly caused by Zika virus

"Metabolism" uncovers the "truth" of microcephaly caused by Zika virus

It is expected to bring new targets and new strategies for potential treatments

"Metabolism" uncovers the "truth" of microcephaly caused by Zika virus "Metabolism" uncovers the "truth" of microcephaly caused by Zika virus isexpected to bring new potential therapeutic targets and new strategies It is expected to bring new targets and new strategies for potential treatments

■ Our reporter Han Yangmei

Our reporter Han Yangmei Our reporter Han Yangmei

Zika virus is mainly transmitted by mosquito bites.
People infected with Zika virus may develop fever, skin rash, joint pain and other symptoms similar to dengue fever
.

Infection of Zika virus in pregnant women may damage the nervous system of the fetus, leading to neonatal microcephaly and other diseases

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 that Zika virus infection causes significant nicotinamide adenine dinucleotide (hereinafter referred to as NAD+) metabolism in the brain tissue of children with microcephaly.
Programming and proposed that targeting NAD+ metabolism can improve microcephaly caused by viral infection
.

On August 12, related research results were published in "Nature-Metabolism"

Open the treatment window

Open the treatment window

In May 2015, the Zika virus that broke out in South America caused 1.
5 million infections in just 8 months, among which 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 microcephaly is the dramatic changes in the substances in the living body, and metabolism is the basic biological process of the production of biological substances and energy
.

However, the molecular mechanism of microcephaly caused by Zika virus infection is still unclear, especially the interaction between the virus and the host and the regulatory relationship is still unclear

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

"We still don't know how Zika virus infection causes molecular changes in the host

With years of accumulation, Hu Zeping's team has 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 tumors and viral infectious diseases.
Metabolic molecular regulation mechanism of various diseases
.

Hu Zeping said that using new metabonomics and metabolic flow analysis technologies, researchers have respectively explained the metabolic remodeling and molecular mechanisms of malignant melanoma, hematopoietic stem cells, lung cancer, and heart regeneration, revealing new potential therapeutic targets and new strategies

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

"Metabolism" reveals the molecular mechanism of microcephaly

"Metabolism" reveals the molecular mechanism of microcephaly

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

The researchers found through the integration of transcriptomics and proteomics data that the metabolism of the brain tissue of mice infected with Zika virus has undergone significant changes
.

What caused the changes in metabolism? The researchers further analyzed the proteomics data and metabolomics and found that the metabolism of mitochondrial metabolism, such as oxidative phosphorylation and tricarboxylic acid cycle, in the brain tissue of the infected mice, has undergone significant changes
.

More importantly, metabolomics analysis found that the NAD+ and its related precursor metabolites in the brain tissues of these mice had drastic changes

The researchers said that the coenzyme NAD+ exists in all living cells and participates in many important physiological processes of the living body.
Its abnormal metabolism will seriously affect the health of the body's cells and tissues
.

Metabolic reprogramming means that by "hijacking" the metabolism of the infected host cell, the virus obtains 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 may be the potential molecular mechanism and intervention target of microcephaly caused by Zika virus infection
.

In order to test this 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) caused by Zika virus infection , Weight, survival time, etc.
) have been significantly improved
.

"These studies not only provide big data resources for clinical understanding of the molecular mechanism of microcephaly caused by Zika virus infection, but also point out the potential value of intervention in NAD+ metabolism in related treatments and drug development
.
At present, NAD+-related supplements are in The anti-aging field has received widespread attention.
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

In-depth research to promote clinical

Scientific research cannot be accomplished overnight
.
Hu Zeping said that starting from a biological phenomenon, the process of discovering, analyzing, and solving problems is full of unknowns, hardships and challenges, but it is also a very interesting process
.

"When a scientific problem or even a
small'error ' in an experiment is solved, the sense of satisfaction and gain is indescribable .
" Hu Zeping said
.
For example, in the verification experiment stage, they need to consider the actual clinical medication method on the one hand, and on the other hand, because pregnant rats are susceptible to external stimuli and the fetal rats are small, there are problems such as limited dosing methods and difficulty in experimental operations
.
After repeated discussions and pre-experimental explorations, the research team finally formulated a dosage regimen of drinking water for pregnant mice, combined with its intraperitoneal injection of newborn mice, to make the experiment go smoothly
.

International colleagues agree that this work is very novel and interesting.
They believe that “this is a masterpiece of multi-omics research” and “provides a large number of data resources and scientific hypotheses for other Zika virus-related research”, and “discovered a new kind of research.
The treatment strategy that can be further developed as a drug target"
.

However, Hu Zeping said that due to 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 the experimental protocol, such as the combined use of antiviral drugs, needs to continue to be explored
.

"In the future, if conditions permit, we hope to continue to explore in depth and achieve clinical transformation
.
" Hu Zeping said
.

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

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