Defects of the Innate Immune System Contribute to Age-related Susceptibility to Mousepox

The elderly population is viewed as high risk to a variety of invasive infections. The accumulation of changes in the aged immune system results in impaired development and function, rendering the elderly more susceptible to mild infections (e.g., influenza). Like humans, aged mice exhibit age-induced susceptibility to various viruses. For example, aged C57BL/6 (B6) mice infected with ectromelia virus (ECTV) results in 100% lethality, whereas infection of young B6 mice results in no deaths. The loss in resistance is tied to fewer mature natural killer cells systemically as well as the impaired recruitment of NK cells to the draining lymph node (dLN). Therefore, it is vital to identify the mechanisms affecting NK cell maturation and recruitment in aged mice. We show that the integrin heterodimer α2β1 expressed on NK cells is not required for their maturation, recruitment to the dLN or effector function during ECTV infection. To date, the role of α2β1 in NK cell biology is largely unknown and we observe its reduction on aged NK cells. For the first time, we show α2β1 mediates proliferation of NK cells during ECTV and murine cytomegalovirus infections, but is dispensable for NK cell-mediated protection. We also show that altered NK cell recruitment during ECTV infection is because of reduced migratory dendritic cell (mDC) accumulation in the dLN. The effect of reduced mDC numbers is decreased production of interferon gamma (IFN-γ) by group one innate lymphoid cells (G1-ILCs), inflammatory monocyte recruitment (iMO), and production of the NK cell chemoattractant CXCL9 by iMOs. The lack of mDCs is independent of virulence, as attenuated ECTV does not restore iMOs or NK cell numbers nor does it increase IFN-γ or CXCL9 expression. Our findings highlight that defects in the innate immune system with age directly contribute to increased susceptibility to viruses. Conversely, the identification of innate immune defects provides targets for therapeutic intervention