Abstract
BackgroundTumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia. Here we investigated the role of membrane TNF for host resistance in knock-in mice with a non-cleavable and regulated allele (mem-TNF).MethodsC57BL/6, TNF KO and mem-TNF mice were infected with M. tuberculosis H37Rv (Mtb at 100 CFU by intranasal administration) and the survival, bacterial load, lung pathology and immunological parameters were investigated. Bone marrow and lymphocytes transfers were used to test the role of membrane TNF to confer resistance to TNF KO mice.ResultsWhile TNF-KO mice succumbed to infection within 4–5 weeks, mem-TNF mice recruited normally T cells and macrophages, developed mature granuloma in the lung and controlled acute Mtb infection. However, during the chronic phase of infection mem-TNF mice succumbed to disseminated infection with necrotic pneumonia at about 150 days. Reconstitution of irradiated TNF-KO mice with mem-TNF derived bone marrow cells, but not with lymphocytes, conferred host resistance to Mtb infection in TNF-KO mice.ConclusionMembrane expressed TNF is sufficient to allow cell-cell signalling and control of acute Mtb infection. Bone marrow cells, but not lymphocytes from mem-TNF mice confer resistance to infection in TNF-KO mice. Long-term infection control with chronic inflammation likely disrupting TNF mediated cell-cell signalling, additionally requires soluble TNF.
Highlights
Tumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia
We show that membrane TNF substitutes soluble TNF to recruit and activate macrophages and T cells, to generate granuloma and control acute infection, but is insufficient to control the chronic phase of infection
While bone marrow derived macrophages (BMDM) secrete high TNF levels in response to M. bovis BCG and M. tuberculosis (Mtb) infection or to LPS, TNF is undetectable in culture supernatants of Bone marrow derived macrophages (BMDM) from TNF-KO and strongly defective in membrane TNF (mem-TNF) mice (Fig 1A), the latter express TNF on the membrane of activated macrophages and T-cells as shown before [19]
Summary
Tumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia. We investigated the role of membrane TNF for host resistance in knock-in mice with a non-cleavable and regulated allele (mem-TNF). The transgenic overexpression of membrane TNF (mem-TNF) demonstrated an in vivo role in the control of Listeria and mycobacterial infection [20,21]. These studies have been performed on TNF/lymphotoxin (LT) deficient background, and since lymphotoxin is implicated into TB resistance, do not address the role of membrane TNF only [20,21]. The recent generation of a mouse with functional, normally regulated and expressed membrane-bound TNF, obtained by knocking-in an uncleavable ∆1–9,K11E TNF allele, represents a major advance and allowed interesting insights in the role of membrane TNF in lymphoid structure maintenance and inflammation [19]
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