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

The COVID-19 pandemic highlighted the detrimental impact of neuroinvasive single-stranded RNA (ssRNA) viruses. Those viruses cause a wide range of human diseases ranging from mild to severe life-threatening conditions. Host factors, including age, sex, and virus receptor expression, influence infection severity; yet, how sex and age shape the expression of ssRNA virus receptors in the human brain remains unclear. Here, we applied a data-driven computational workflow that integrates sex and age to characterize developmental patterns of ssRNA virus receptors in females and males across the human brain. Using a publicly available transcriptomic dataset spanning the lifespan, we analyzed 67 host receptor genes that mediate viral entry across 10 families of ssRNA viruses. Lifespan trajectories were generated, and high-dimensional analyses compared changes between sexes across 15 brain areas (n = 700, F = 306, M = 394; age range: 4 months-82 years), revealing spatiotemporal patterns of virus receptor expression. Unsupervised hierarchical clustering of the 2010 trajectories identified 25 different patterns spanning a range of sex bias from female-biased to male-biased expression. Differential expression analysis revealed a brain-wide pattern of sex differences in virus receptor expression during childhood, prior to puberty. Among virus families, Pneumoviridae was the most sexually dimorphic, and cortical brain areas had distinct developmental trajectories for females and males. While females are often described as developing precociously relative to males, our findings show that sex differences in virus receptor expression are not simple linear shifts, but follow complex high-dimensional trajectories, underscoring the importance of incorporating sex as a biological variable in studies of neuroinfectious disease vulnerability.