Transgenic zebrafish larva showing blood vessels in red and blood vessel cell nuclei in green. Credit: Daniel Castranova, Weinstein Lab, NICHD/NIH (CC BY-NC-ND 2.0)
Sex differences can influence physiological responses to exercise, stress or immune responses. For example, males are often more susceptible to viral infections due to hormonal and chromosomal influences.
While primary sex determination in mammals is strictly linked to chromosomes, other animals, such as fish, can have a very fluid sex determination, with some fish species lacking sex chromosomes completely. This diversity provides a unique system to study how sexual dimorphism affects immune responses, independent of classical sex-linked pathways.
Long-Feng et al. used a fish model with alternative sex determination to test whether non-sex-chromosome genes can affect immune differences between males and females, without the influence of sex chromosomes or hormones. Using genetic and biochemical methods, the researchers demonstrated that male zebrafish are more resistant than females to virus, despite the absence of sex chromosomes. They identified an enzyme called Cyp17a2 to be responsible for this difference, which was present in high amounts in males.
This enzyme is usually involved in steroid hormone production, but in species such as zebrafish, it regulates stress hormone production. The experiments revealed that Cyp17a2 boosts antiviral defense in males in two ways. First, it strengthens the fish’s immune signaling by stabilizing a protein known as STING. It does this by adding ubiquitin, a chemical tag that helps the protein to work properly. Second, it directly suppresses viral replication by promoting the breakdown of a viral protein. Moreover, male fish genetically engineered to lack this protein showed reduced immune responses. Overall, these findings suggest that Cyp17a2 is an immune regulator that connects male-specific traits to antiviral defenses.
By studying a vertebrate model with alternative sex determination, Long-Feng et al. challenged the mammal-centric view of immune sexual dimorphism that centers on sex chromosomes and hormones and provided new insight into how sex-specific immunity may have evolved. The results prompt reconsideration of the unique mechanisms underlying sex-based immune differences in fish. They may also inform the development of sex-specific strategies to improve disease resistance in economically important fish. Future work should assess the evolutionary conservation of this pathway across vertebrates and explore whether targeting the Cyp17a2 and STING could offer new approaches to antiviral therapy, although clinical applications remain speculative.
