Females as compared to males display better general health status, longer life span and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This project will test the question of whether the presence of cellular mosaicism of X chromosome-linked protein variants in females represents a functionally adaptive cellular system that is advantageous during the host response to infections. Cells from females carry both parental X chromosomes (maternal, Xm and paternal, Xp) whereas males carry only one X chromosome that is derived from the mother (Xm). As the result of dosage compensation and random X inactivation, half of the cells from females express proteins either from Xm or Xp, respectively. Therefore, females are cellular mosaics for X-linked polymorphic proteins. Several genes encoding key regulatory and metabolic proteins involved in the innate immune response reside on the X chromosome. The study focuses on two X-linked proteins, the first, gp91phox (Cybb) is a critical protein component of the NADPH oxidase complex that produces superoxide anion required for bacterial killing;the second, IRAK1 (IL-1 receptor associated kinase-1) is an important component of TLR-mediated cell signaling pathway. The investigations will employ experimental models of endotoxemia and sepsis utilizing mouse strains that carry genetically silenced forms of these X-linked proteins. Changes in blood and bone marrow cell compositions as well as phagocyte infiltration into lung, spleen and liver will be tested following sepsis or endotoxemia. Observations will be compared between mosaics and single-population homo/hemizygous deficient or WT animals. Alterations in cell signaling, cytokine production and redox-dependent cell functions will also be determined and compared. We hypothesize that female mosaics will display acute heterogeneous functional adaptation that will be associated with improved outcome following sepsis or endotoxemia. This will be reflected in skewed cell composition and cell activation toward mosaic subpopulations expressing the advantageous alleles together with improved bacterial killing and survival. The studies will broaden our understanding of the cellular and biochemical mechanisms responsible for immuno-modulation by X- chromosome mosaicism and gender and may open new perspectives in treating the critically ill.
Small differences in the genetic makeup of individuals, called single nucleotide polymorphisms (SNPs), have been shown to alter the clinical outcomes after injury and infection. In the case of X-chromosome-linked SNPs, males and females are different because females carry both parental X-chromosomes and show cellular X-chromosome mosaicism whereas males carry only one X-chromosome. The studies will test the novel hypothesis that cellular mosaicism for X-linked genetic mutations can benefit the host during the immune response to infections. Better understanding of the protecting cellular mechanisms that are in effect during septic conditions could lead to advanced protocols in treating the critically ill.
