Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF

Abstract

k Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-B activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF.T umor necrosis factor (TNF) is critical for resistance against intracellular bacterial infections; however, its dysregulation may be associated with the development of human immunopathologies (1-5). Anti-TNF therapies have shown their efficacy for the treatment of autoimmune inflammatory diseases, such as rheumatoid arthritis and Crohn's disease, and are being explored for the treatment of other severe human pathologies, such as chronic obstructive pulmonary disease (6-8). However, the complete blockade of TNF has confirmed the essential role of TNF in the control of tuberculosis (TB) infection, as treated patients develop both TB and nontuberculous mycobacterial diseases (9-12). TB is still a major health problem newly affecting in its active form nearly 9 million people every year. One-third of the global population is considered to be infected by Mycobacterium tuberculosis in a latent form (13). M. bovis BCG is used for vaccination in countries with a high TB incidence and appears to control severe forms of tuberculosis in children but fails to prevent TB in adults (14).TNF is initially synthesized as a membrane protein released under activation by infectious and inflammatory stimuli. Two types of TNF inhibitors blocking membrane and soluble TNF are currently used to treat inflammatory diseases and comprise anti-TNF antibodies (infliximab, adalimumab, certolizumab, etc.) and soluble TNF receptor 2 (sTNFR2; etanercept) (15). These drugs have distinct neutralization efficacies in human diseases, and they are associated with distinct risks of TB reactivation,...

Altered composition and functional profile of high-density lipoprotein in leprosy patients

“…Hepatocyte damage is commonly triggered during inflammations promoted by chronic exposition to cytokines like TNF (tumor necrosis factor) [93,94]. TNF is a typical pro-inflammatory cytokine released by Kupffer cells in hepatic granulomas induced by BCG (M. bovis Calmette-Guérin) and M. tuberculosis, to keep their morphological structure in the hepatic environment [95,96]. High levels of TNF and interleukin-1β in hepatic environment can negatively regulate APOA1 gene expression via nuclear receptors LXRs (liver X receptor), FXRs (farnesoid X receptor) and PPARα (peroxisome proliferator-activated receptor α) in hepatocytes [97][98][99], and maybe leading the modulation on ApoA-I expression in leprosy patients.…”

Novel functions of inactive rhomboid proteins in immunity and disease

“…TNF often acts in synergy with other key cytokines such as IFN‐γ produced by T cells to heighten the microbicidal killing inside the phagosomes of activated Mϕs, which is vital for efficient eradication of bacterial pathogens such as Listeria monocytogenes or Mtb . The importance of TNF is evidently highlighted by the severely immunocompromised response and increased morbidity in Tnf ‐deficient mice in response to these pathogenic bacteria as well as to viral pathogens such as influenza, the HSV, and the vesicular stomatitis virus (VSV) …”

Can we design a better anti-cytokine therapy?

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