Inhibition of Type I Interferon Signaling abrogates Early Mycobacterium bovis Infection

Abstract

Background: Mycobacterium bovis (M. bovis) is the central causative agent of bovine tuberculosis; however, it also caused serious infection in human beings. Type I IFNs is a key factor in reducing viral multiplication and modulate host immune defense against viral infection. However, the regulatory pathways of type I IFN signaling during Mycobactrium bovis (M. bovis) infection are not yet fully explored. Here, we investigate the role of type I IFN signaling on the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection mice were sacrificed, for analysis of type I IFN signaling on the pathogenesis of M. bovis. qRT-PCR and ELISA was performed to detect the expression of type I IFNs and relative gene. M. bovis induced lung lesions and viable bacterial count was assessed by conducting histopathology and CFU assay. Results: We observed an abundant expression of type I IFNs in the blood 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, mediate the activation of macrophages toward a pro-inflammatory profile and regulate the inflammatory cytokine production; however, no impact on T cell recruitment and activation in the early acute phase of infection was observed. Additionally, blocking of type I IFN signaling reduces bacterial burden in infected mice than untreated infected mice. Conclusions: Altogether, our results reveal that type I IFN mediates a balance between infection-mediated inflammatory reactions and pathogen’s control mechanism of the host during M. bovis infection. Thus, modulating type I IFN signaling could be exploited as therapeutic strategies 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 ).…”

Impact of Type I Interferons on Susceptibility to Bacterial Pathogens

“…A reduction in neutrophil recruitment was observed in vivo along with reduced IL-10 and IL-6 and increased IFN-γ and IL-1β. In vitro, macrophages treated with αIFNAR1 induced decreased levels of M2 markers, such as Arg1, Ym1, and Mrc1, and increased expression of M1 markers such as Nos2 and Ifng, suggesting that type I IFN signaling mediates macrophage polarization toward an anti-inflammatory profile during M. bovis infection [55]. Another study found that macrophages deficient in either IFNAR or STAT exhibited increased viability compared with WT cells after infection with M. tuberculosis [56].…”

“…M. tuberculosis was also shown to inhibit autocrine type I IFN signaling (by 50-60%) via reduced phosphorylation of the IFNAR-associated protein kinases JAK1 and TYK2, leading to reduced phosphorylation of STAT1 and STAT2 [54], suggesting that the type I IFN response could be detrimental to the pathogen but this is a good example of how in vitro does not always correlate to in vivo. Murine models with the bovine turbercule bacilli, Mycobacterium bovis, are protected against infection when IFNAR is neutralized [55]. Both cellular and immune signaling differences were noted.…”

Mycobacterium smegmatis Resists the Bactericidal Activity of Hypochlorous Acid Produced in Neutrophil Phagosomes

“…Relatively little is known regarding neutrophil killing of mycobacteria, as the host immune response has been considered primarily a by guest on October 16, 2022 http://www.jimmunol.org/ Downloaded from macrophage-and adaptive immunity-driven process (21)(22)(23). However, abundant neutrophils are observed at sites of infection (1,24,25), and evidence suggests they play a role in clearance of mycobacterial infections, although they may also aid survival within the host (26)(27)(28)(29)(30).…”