Guanylate binding proteins contained in the murine chromosome 3 are important to control mycobacterial infection

Abstract

Guanylate binding proteins (GBPs) are important effector molecules of autonomous response induced by proinflammatory stimuli, mainly IFNs. The murine GBPs clustered in chromo some 3 (GBPchr3) contains the majority of human homologous GBPs. Despite intense efforts, mycobacterial-promoted diseases are still a major public health problem. However, the com bined importance of GBPchr3 during mycobacterial infection has been overlooked. This study addresses the influence of the GBPchr3 in host immunity against mycobacterial infection to elucidate the relationship between cell-intrinsic immunity and triggering of an efficient anti mycobacterial immune response. Here we show that all GBPchr3 are up-regulated in lungs of mice during Mycobacterium bovis BCG infection, resembling tissue expression of IFN-𝛾. Mice defi cient in GBPchr3 (GBPchr3−/−) were more susceptible to infection, displaying diminished expres sion of autophagy-related genes (LC3B, ULK1, and ATG5) in lungs. Additionally, there was reduced proinflammatory cytokine production complementary to diminished numbers of myeloid cells in spleens of GBPchr3−/−. Higher bacterial burden in GBPchr3−/− animals correlated with increased number of tissue granulomas. Furthermore, absence of GBPchr3 hampered activation and pro duction of TNF-𝛼 and IL-12 by dendritic cells. Concerning macrophages, lack of GBPs impaired their antimicrobial function, diminishing autophagy induction and intracellular killing efficiency. In contrast, single GBP2 deficiency did not contribute to in vivo bacterial control. In conclusion, this study shows that GBPchr3 are important not only to stimulate cell-intrinsic immunity but also for inducing an efficient immune response to control mycobacterial infection in vivo.