A role played by sex in innate immune memory and disease severity
Authors:   , Earhart Alexander Parker 
Published: March 2024

While immunological memory has traditionally been understood to be solely within the purview of adaptive immunity, recent evidence has shown that a type of "memory" exists in innate immune cells, as a prior insult can lead to enhanced subsequent pro-inflammatory activity, such as cytokine release, against a broad range of secondary stimuli. However, innate immune responses can differ between females and males, as sex hormones can augment or reduce activity. This dissertation examines the influence of the female sex hormones 17?-estradiol and progesterone on innate immune memory, or 'trained immunity'. We hypothesized that progesterone would attenuate trained secondary responses. To this end, we found that infection by the opportunistic bacterium Burkholderia gladioli decreased survival in trained female adaptive immune- deficient mice, and that female mouse serum significantly attenuated trained secondary responses. This effect varied with serum from the different stages of the mouse estrous cycle and correlated with higher progesterone levels. We further showed that exogenous progesterone decreased trained responses, and glycolytic activity underlying trained immunity, while blocking its cognate nuclear receptor restored activity and rescued trained female mice from infection to the level of protection seen in males. This work suggests that the naturally cycling variability in progesterone levels may affect trained immunity and even protection against infections, possibly even during pregnancy though further studies are needed. This is the basis for a mechanism by which males can produce greater average trained immune responses than females, which protected males from opportunistic B. gladioli infection, but oppositely, might correlate with increased male morbidity from coronavirus disease 2019 (COVID-19). In early 2020, the COVID-19 viral pandemic shut down schools worldwide, although classes resumed in the Fall semester. We sought to track antibody seropositivity in the University of Missouri population during that semester, paying special attention to demographics including sex. As expected, antibody- positive cases increased throughout the duration of the semester, particularly among students. Older individuals, especially older men, had higher antibody concentrations after infection compared to women, although these levels declined more rapidly than those of women over time. We can correlate these observations with worldwide studies concluding that during the pandemic, men were shown to be more susceptible to severe morbidity and mortality than women, on average. We proposed application of an existing drug to attempt to alleviate morbidity in the most severe COVID-19 cases. COVID-19 is primarily a respiratory disease caused by a viral pathogen. Many severe respiratory viral infections, including influenza, are often characterized by high neutrophil infiltration into the lungs and production of neutrophil extracellular traps (NETs), comprised of DNA and inflammatory enzymes, which can clog the respiratory tracts. We hypothesized that severe COVID-19 patients had high lung neutrophil counts and NETs; and that treatment with the cystic fibrosis drug, dornase alfa, which breaks apart these clogging NETs, would improve disease outcomes. Indeed, we found that dornase alfa decreased NETs in the lungs and also improved lung characteristics in treated patients. Though we did not design the clinical trial to assess sex differences in our small cohort (n = 10 patients), together with the sex differences observed in the large data set sampling the MU community, and those reported worldwide, these findings imply an outsized role for innate immunity in severe respiratory infections. Although unexplored here, it is conceivable that training of innate cells and their precursors may have influenced immune hyperresponsiveness in COVID-19.