Oral Presentation The Prato Conference on the Pathogenesis of Bacterial Infections of Animals 2016

Strength lies in calmness: the role of Interferon-β in the host defense against Mycobacterium avium subspecies paratuberculosis infection (#30)

Nanthapon Ruangkiattikul 1 , Andreas Nerlich 1 , Stefan Lienenklaus 2 , Julia Spanier 3 , Siegfried Weiss 2 , Ralph Goethe 1
  1. Institute for Microbiology, University of Veterinary Medicine Hannover, University of Veterinary Medicine Hannover, Hannover, Germany
  2. Department of Molecular Immunology , Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
  3. Institute for Experimental Infection Research, , TWINCORE Centre for Experimental and Clinical Infection Research, 30625, Hannover, Germany

Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of paratuberculosis (Johne’s disease), a chronic intestinal inflammation in ruminants. The disease affects the productivity in cattle industry due to high morbidity and mortality worldwide. The pathogenicity of MAP is nearly unresolved. Our previous results indicated that MAP persists in the host by suppressing host pro-inflammatory responses.

In the present study, we addressed the role of interferon-β (IFN-β), an important mediator in antimicrobial defense, in response to MAP infections. Using murine macrophages, we found that MAP-infected macrophages exhibited a substantially lower Ifnb expression than macrophages infected with the non-pathogenic Mycobacterium smegmatis (MSM). Induction of Ifnb in both mycobacterial species was dependent on bacterial viability and the cGAS-STING-TBK1-IRF3/IRF7 activation pathway. The higher phosphorylation of TBK1 in MSM infected macrophages indicated that MSM more efficiently activates the shared signaling cascade.

After intra-peritoneal infection of mice, we found that the activation of host Ifnb upon MSM infection correlated with effective killing of MSM. In contrast, in MAP-infected cells weak Ifnb induction correlated with high granuloma numbers in the livers and survival of MAP. Infection of mice lacking the type I interferon receptor IFNAR led to increased survival of MSM. Vice versa, treatment of MAP infected wildtype mice with the IFN-β inducer poly(I:C) reduced MAP survival indicating the essential relevance of IFN-β in mycobacterial clearance.

Overall, our results strongly suggest that the weak IFN-β response of MAP-infected macrophages is a specific immune evasion mechanism that contributes to the persistence of MAP.