# NIH grant: Elucidating the molecular nature and evolutionary conservation of RNA pathogen-associated molecular patterns (PAMPs) across the poxvirus family (1R21AI198990-01) — retained record

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NIH grant 1R21AI198990-01: Elucidating the molecular nature and evolutionary conservation of RNA pathogen-associated molecular patterns (PAMPs) across the poxvirus family
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Don Brad Gammon. Award: $209499.
Start: 2026-06-23T00:00:00.
PROJECT SUMMARY
 Poxviruses cause disease in disparate eukaryotic hosts, including insects and humans. However, the
molecular identity and evolutionary conservation of the RNA pathogen-associated molecular patterns (PAMPs)
they generate are poorly defined. Although poxviruses are DNA viruses, infection produces immunostimulatory
RNAs sensed by host pattern recognition receptors (PRRs), activating innate immunity. The precise nature and
conservation of these RNA PAMPs, and how host and viral factors regulate them, remain unknown. Addressing
this is essential for understanding host-virus coevolution and could inform new antiviral or vaccine strategies.
Our long-term goal is to define the PAMPs that trigger innate immune responses during poxvirus infection across
animal hosts. The objective of this proposal is to define the nature and conservation of RNA PAMPs generated
during poxvirus infection, focusing on the regulatory roles of host and viral DUSP11 RNA triphosphatases. We
hypothesize that poxvirus infection generates or unveils RNA PAMPs of viral and/or host origin that are
recognized by PRRs, and that DUSP11 enzymes mask their immunogenicity in both mammals and insects.
 We will test this hypothesis via two specific aims: Aim 1: Define the RNA PAMPs generated during
mammalian poxvirus infection. We will infect mammalian cells with vaccinia virus, isolate infection-induced
RNAs, and use biochemical, sequencing, and functional assays to identify and characterize immunostimulatory
RNAs. We will determine their features, ability to activate RIG-I, and how host DUSP11 shapes their abundance
and immunogenicity. Aim 2: Develop an insect poxvirus system to determine if RNA PAMPs are conserved
across poxviruses. Using entomopoxviruses and mutants lacking vDUSP11, we will characterize RNA PAMPs
generated during insect infection and compare their features and regulation to those in mammals.
 This project leverages advances in RNA biochemistry and sequencing, and our discovery that both
vertebrate and insect poxviruses encode DUSP11 homologs that dephosphorylate RNA PAMPs to evade
immune detection. Our expected contribution is a molecular map of RNA PAMPs in both mammals and insects,
and new insight into how DUSP11 enzymes regulate their immunogenicity. This research is significant because
it will provide the first systematic identification of RNA PAMPs in poxvirus infection, reveal evolutionary
conservation of immune evasion mechanisms, and enable targeting of conserved immune pathways for vaccine
and antiviral development. The project is innovative in that it directly interrogates the identity, structure, and
conservation of RNA PAMPs across anciently diverged poxviruses using viral and host DUSP11 mutants as tools
essential to map immunogenic RNAs. These results will be important because by resolving how poxviruses
generate and mask immunogenic RNAs, we will advance understanding of host-pathogen coevolution and PRR
function and possibly reveal strategies for broad-spectrum antiviral intervention and vaccine adjuvant design.
```



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