Supplementing NAD+ Curtails Zika-Related Birth Defects, Promoting Newborn Mice Survival
New research points to exploiting NAD+ levels to develop therapeutic strategies against the Zika virus and other mosquito-borne diseases.
Not only are mosquitos pesky and annoying, but they have also affected innumerable lives by transmitting pernicious diseases. One of the most recent mosquito-borne diseases comes from the Zika virus, linked to drastic head size reductions (microcephaly) in newborns of pregnant women. Finding new ways to counter the handicapping effects of the virus has become paramount to preserve these newborns’ quality of life.
New research from Hu and colleagues published in Nature Metabolism demonstrated profoundly abnormal nicotinamide adenine dinucleotide (NAD+) metabolism with Zika infection in newborn mice. The Tsinghua University-based research team then boosted NAD+ levels by injecting the molecule or its precursor nicotinamide riboside (NR) in Zika-infected mouse pups. By increasing NAD+ levels, these treatments preserved neurons, brain weight, and improved overall survival for the infected mouse pups. Hu and colleagues’ study shows that the Zika virus dramatically alters NAD+ metabolism and that increasing its levels can counter the virus’s microcephaly-inducing effects.
Viruses Reprogram Host Metabolism
Viruses reprogram infected host metabolism through many unique strategies specific for each virus to achieve rapid proliferation. With that in mind, Hu and colleagues wanted to uncover how Zika reprograms its host cells so they could target these metabolic changes with antiviral therapy. The Chinese researchers examined gene activity, protein production, and metabolite profiles of Zika-infected mouse pups to uncover how the Zika virus reprograms the host cells.
Their gene activity analysis showed that infecting the embryonic mice increased the abundance of brain immune cells that dispose of the dead, dying, injured, or diseased neurons. What’s more, this analysis of gene activity also indicated a reduced abundance of cells that produce neurons along with reduced numbers of neurons, which aligns with Zika infections driving reduced brain weights and volumes. Similarly, their protein abundance analyses showed reduced levels of proteins associated with metabolic reactions that involve NAD+. This finding hinted that NAD+ might play a crucial role in Zika virus-induced microcephaly.
In search of evidence that Zika reprograms NAD+ metabolism and that targeting NAD+ might provide a way to minimize microcephaly, Hu and colleagues looked at the molecule’s levels in the brain. They found that the virus substantially reduces NAD+ abundance in mouse pup brains while increasing levels of its precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). These findings came from altered NAD+ metabolism that goes hand-in-hand with a greater abundance of NAD+-consuming proteins.
Increasing NAD+ Levels Preserves the Newborn Mouse Brain with Zika Infection
Since Hu and colleagues saw that NAD+-consuming proteins become more abundant and deplete NAD+ with Zika infection, they decided to test whether boosting NAD+ can preserve the brain. They found that increasing NAD+ levels by injecting NAD+ or its precursor NR maintained brain weight and volume in infected mouse pups, and NR also helped their survival. These findings provide compelling evidence that NAD+ metabolism represents a targetable pathway to counter the Zika virus’s effects in newborns, at least in mice.