Inhibition of type I interferon signaling abrogates early Mycobacterium bovis infection

Abstract

BackgroundMycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice.MethodsC57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay.ResultsWe observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice.ConclusionsAltogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

“…Not only does the death of infected macrophages release the pathogen to infect other cells, but the release of host cell contents may trigger tissue-damaging inflammation. Absence of Ifnar1 in 129S2 mice markedly reduced migration of inflammatory monocytes and neutrophils to the lungs (Dorhoi et al, 2014), and prophylaxis with anti-IFNAR1 mAb protected mice subsequently infected with virulent Mycobacterium bovis (Wang et al, 2019). Type I IFNs impaired the activation of macrophages by type II IFN (IFN-γ; Yoshida et al, 1988), which is essential for controlling TB in mice (Cooper et al, 1993;Flynn et al, 1993) and people (Jouanguy et al, 1996;Jouanguy et al, 1997), and this was also seen in the context of infection with Listeria monocytogenes (Rayamajhi et al, 2010) and Mycobacterium leprae (Teles et al, 2013).…”

Mycobacterial Infection of Precision-Cut Lung Slices Reveals Type 1 Interferon Pathway Is Locally Induced by Mycobacterium bovis but Not M. tuberculosis in a Cattle Breed

“…Autophagy antagonizes inflammasome activation to the benefit of Mb survival (65,66). In C57BL/6 mice treated with IFNAR1 blocking Ab and infected with Mb, the recruitment of neutrophils was reduced, but the pro-inflammatory profile of MPs was increased, leading to a reduced bacillary burden (67). No impact on T-cells was observed in this in vivo model, revealing a role of type I IFN signaling during the innate phase of the host response to infection.…”

National consensus statement by the Austrian Societies for Rheumatology, Pulmonology, Infectiology, Dermatology and Gastroenterology regarding the management of latent tuberculosis and the associated utilization of biologic and targeted synthetic disease modifying antirheumatic drugs (DMARDs)

“…Interferon alpha seems to play a role in the cellular response to mycobacteria infection. Since it is involved in the balance between host defense and inflammatory reactions, the effect of blocking its function is not totally clear yet [32][33][34]. In the phase II and III studies on anifrolumab, LTBI was an exclusion criterion, like in other studies assessing the efficacy of biologicals.…”