Parental obesity is associated with altered hematopoiesis and impaired viral immunity in offspring

The prevalence of obesity among adults of childbearing age has tripled worldwide since 1975. Obesity during pregnancy has been linked to impaired neonatal immunity and a higher risk of infections in childhood but the causal mechanisms have not been defined. Using a mouse model of diet-induced obesity, we documented impaired antiviral immunity in the offspring of obese mice, corresponding with reduced cell-mediated immune responses. This included lower frequencies of Tbet+ CD4+ T helper 1 cells and a decrease in cytotoxic CD8+ T cells in the lungs of mice infected with respiratory Sendai virus, and confirmed in spleens from mice infected with LCMV. Consistent with impaired cellular immunity, single-cell transcriptomic analysis of bone marrow revealed altered hematopoiesis in these offspring, with evidence of interferon-induced skewing toward myelopoiesis at the expense of lymphocyte development. Our studies provide an in-depth transcriptomic profile of immune cell progenitors in the bone marrow paired with mature innate and adaptive immune cell populations in lymph nodes at single-cell resolution. Results suggest that compromised immune protection from viral infections in the offspring of obese mice stems from altered lymphocyte development that is influenced by inflammatory interferon signaling in bone marrow.