Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Background The COVID-19 pandemic has focused research on the detrimental impact of neuroinvasive single-strand RNA (ssRNA) viruses. Those viruses cause a wide range of human diseases ranging from mild to severe life-threatening conditions, and host factors such as age, sex, and the expression of virus receptors can influence the severity of the infection. For example, older adults and males have a bias for severe disease with COVID-19 infection, but females have a higher risk of Long-COVID. However, there is a gap in understanding the expression of receptors for ssRNA viruses in the human brain and how that expression varies by age and sex. Here, we studied the expression of ssRNA virus receptors in the human brain and compared lifespan changes in females and males to identify age- and sex-specific book patterns. Methods We used a publicly available transcriptomic database of human brain development to characterize the development of 67 viral host factor genes for 10 ssRNA virus families. A data-driven approach was applied to characterize the lifespan trajectories for those ssRNA receptors using samples from 15 brain areas (n=700, F=306, M=394, age range:4 mo-82 yrs). Then, high-dimensional trajectory analyses and visualizations, including tSNE, were used to compare lifespan changes for females and males among the 15 brain areas. Results Unsupervised hierarchical clustering of the 2010 trajectories identified 25 different patterns with a range of sex bias from ones with only female data to ones with only male data. Differential Expression Sliding Window Analysis (DE-SWAN) found a brain-wide pattern of virus receptor sex differences in childhood, before puberty. The virus families had a range of sexual dimorphism, with the Pneumoveridae family being the most dimorphic. Finally, high dimensional visualization of ssRNA virus receptor development in the 15 brain areas showed that the cortex is distinct for females and males. Conclusions Females are often described as developing precociously relative to males, but our findings paint a different picture. Instead, we found that sex differences in virus receptor development in the human brain do not reflect simply linear shifts and are best described as females and males following distinct high-dimensional trajectories. Highlights Plain english summary The COVID-19 pandemic has drawn attention to viruses that can affect the brain, causing various brain-related health issues. Age, sex, and the expression of virus receptors can influence the severity of these infections. For example, older adults and males tend to experience more severe COVID-19 symptoms, while women are more prone to long-lasting effects. However, little is known about virus receptors in the human brain, their age-related changes, and potential sex differences. To address this, we studied the development of 67 genes related to brain-infecting viruses and analyzed data from 15 brain regions in individuals of various ages. Our findings revealed that these genes develop differently in females and males, with the most differences observed in childhood before puberty. Some virus families exhibited more pronounced sex distinctions, notably pneumonia-related virus receptors. Contrary to the belief that females mature more quickly, our study suggests that virus receptors have unique developmental trajectories for females and males. ### Competing Interest Statement The authors have declared no competing interest.