TNF-Mediated Compensatory Immunity to Mycobacterium avium in the Absence of Macrophage Activation by IFN-γ

Abstract

Granuloma formation is a hallmark of several infectious diseases, including those caused by Mycobacterium sp. These structures are composed of accumulations of inflammatory cells, and it has been shown that cytokines such as IFN-g and TNF-a are required for granuloma assembly during M. avium infections in mice. Macrophages (MFs) insensitive to IFN-g (MIIG) mice have MFs, monocytes, and dendritic cells that are unresponsive to IFN-g. We observed that although IFN-g 2/2 mice present an exacerbated infection, the same is not true for MIIG animals, where the same levels of protection as the wild-type animals were observed in the liver and partial protection in the spleen. Unlike IFN-g 2/2 mice, MIIG mice still develop well-defined granulomas, suggesting that IFN-g-mediated MF activation is not required for granuloma assembly. This work also shows that MIIG animals exhibit increased cell recruitment with higher CD4 + T cells numbers as well as increased IFN-g and TNF-a expression, suggesting that TNF-a may have a role in protection and may compensate the lack of MF response to IFN-g in the MIIG model. TNF-a-deficient MIIG mice (MIIG.TNF-a 2/2) exhibited increased bacterial burdens when compared with MIIG mice. These results suggest that in the absence of IFN-g signaling in MFs, TNF-a has a protective role against M. avium.

Exacerbation of Mycobacterium avium pulmonary infection by comorbid allergic asthma is associated with diminished mycobacterium-specific Th17 responses

“…did not show exacerbated lesions). This result is in line with previous studies that showed that immunodeficient mice or IFN-γ −/mice developed increased bacterial burdens without exacerbated lung pathology and that failure of granuloma formation via macrophages and lymphocytes made the mice susceptible to Mav infection [45][46][47]. Therefore, we postulate that our results at 10 w.p.i.…”

The double‐edged sword of Tregs in M tuberculosis, M avium, and M. abscessus infection

“…93 This highlights an essential difference between Mtb bacterial control with IFNγ and M avium control with TNFα. 94 More recent studies have shown that mice can control M avium infections independently of macrophage activation by IFNγ, with TNFα compensating for the lack of IFNγ activation by IFNγ. 94 Moreover, the M avium granuloma development forms without the aid of IFNγ activation of macrophages.…”

“…94 More recent studies have shown that mice can control M avium infections independently of macrophage activation by IFNγ, with TNFα compensating for the lack of IFNγ activation by IFNγ. 94 Moreover, the M avium granuloma development forms without the aid of IFNγ activation of macrophages. 94 Early studies showed that M avium strains could show different morphotypes, which could impact the strain's virulence properties.…”

“…94 Moreover, the M avium granuloma development forms without the aid of IFNγ activation of macrophages. 94 Early studies showed that M avium strains could show different morphotypes, which could impact the strain's virulence properties. It was…”

“…At this time, the role of Th1 cytokines began to be investigated, and an early study suggested that TNF‐α was more effective than IFN‐γ in growth inhibition 93 . This highlights an essential difference between Mtb bacterial control with IFN‐γ and M avium control with TNF‐α 94 …”