Exploring the Impact of Paternal Immune Activation on Offspring Immunity to Viral Infection

The consequences of maternal immune activation (MIA) are currently being explored and already show that inflammation during gestation can influence offspring behavior and immunity. However, the influence of paternal immune activation (PIA) on offspring is an understudied topic. Limited studies have shown that paternal immune activation, either through pathogen exposure or stimulation of the immune system with synthetic molecules before conception results in altered offspring behavior. Moreover, these events influence the epigenetic information within the sperm. Yet, we lack understanding of how immune stimulation alters the expression of epigenetic molecules within germ cells and if PIA can also shape offspring immune development. With this in mind, I sought to understand how immune stimulation due to viral infection in male parents could influence offspring immunity. First, I evaluated the impact of viral infection (Zika virus) or immune stimulation with a viral mimetic (Poly (I:C)) on the small RNAs, a carrier of epigenetic information, within sperm. I determined that immune stimulation, with or without viral replication resulted in an altered sperm small RNA profile. I have explored the impact of these modifications have on offspring at two developmental stages: during embryonic development and in juvenile aged offspring. Using sperm from Poly (I:C) treated males to fertilize naïve eggs, I found that gene expression in morula stage embryos was altered, indicating the sperm small RNA profile established by PIA influences early embryonic development. Moreover, when juvenile offspring sired by Poly (I:C) treated males were infected with influenza, I found these offspring had a higher survival rate and fewer signs of infection. Importantly, this is the first evidence that PIA may confer resistance to viral infection to offspring. Taken together, my central hypothesis is that proinflammatory cytokines induced during PIA lead to changes in the sperm small RNA profile which program early embryonic gene expression and confer lasting viral resistance to offspring through altered immune function. For my first aim, I will evaluate if this resistance to infection lasts into adult hood and what differences in offspring immunobiology allow for this resistance. For my second aim, I will determine if paternal immune activation modifies the sperm small RNA profile though cytokine signaling and if these cytokines induced changes are responsible for the offspring phenotypes I have observed. Completion of this proposal will provide new understanding into how paternal immune activation can impact offspring immunity. This study will provide key insights to developmental immunobiology and directly challenge our current interpretation of the evolutionary arms race between host and pathogen. Project Number: 1F31AI191458-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Taylor Miller-Ensminger | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $50,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07C-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19145801A1