Poster Presentation Lorne Infection and Immunity 2023

Mouse GBP1 is detrimental for the host during Burkholderia thailandensis infection (#173)

Garrett Ng 1 2 , Si Ming Man 3 , Ian van Driel 4 , Elizabeth Hartland 1 2
  1. Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
  3. Division of Immunity, Inflammation, and Infection, The John Curtin School of Medical Research, The Australian National University, Acton, Australian Capital Territory, Australia
  4. Department of Biochemistry & Pharmacology, Bio21 Institute of Biotechnology and Molecular Science, University of Melbourne, Parkville, Victoria, Australia

Guanylate binding proteins (GBPs) are strongly induced by interferon-gamma (IFNγ) and bind a range of intracellular pathogens. GBPs are believed to mediate the release or binding of pathogen associated molecules to activate the inflammasome. Due to the rapid expansion of GBPs in mice (11 vs 7 in humans), individual murine GBPs are believed to have redundant and overlapping roles. Murine GBP1 arose from a duplication of murine GBP2, the direct homologue of human GBP2.

We initially investigated the relative contributions of IFNγ and mouse GBPs to B. thailandensis infection. Mice that lacked GBPs encoded on chromosome 3 (GBPΔchr3; GBP1, 2, 3, 5, 7) were highly susceptible to infection but mice that lacked several GBPs encoded on chromosome 5 (GBP4, 6, 8) were relatively similar to wildtype mice. GBP2 and GBP5 have been previously described to restrict B. thailandensis infection. Hence, we investigated if GBP1 had a role in infection.  Surprisingly, Gbp1-/- mice had the opposite phenotype to GBPΔchr3 or Gbp2-/- mice, and were more resistant to infection.

In conclusion, murine GBP1 has a unique role in the response to infection despite high similarity to GBP2. We believe this is the first demonstration of a GBP being detrimental to the host during infection. The divergent roles of murine GBP1 and GBP2 in B. thailandensis infection could be exploited to understand the different roles of GBP1 and GBP2.