A defect in the synthesis of Interferon-γ by the T cells of Complement-C5 deficient mice leads to enhanced susceptibility for tuberculosis

Abstract

Interferon-γ (IFNγ) plays a major role during host defense against Mycobacterium tuberculosis (Mtb). T cells produce IFNγ in response to IL-12 and IL-18 secreted from Mtb infected macrophages. IFNγ in turn, induces nitric oxide secretion in macrophages that kills Mtb. IFNγ knock-out mice are thus hyper-susceptible to tuberculosis. We reported earlier that Complement C5 deficient (C5-/-) congenic mice are more susceptible to tuberculosis and showed reduced IL-12 synthesis in their macrophages. Using C5-/- congenic mice that carry a deletion in the C5 gene and the wild type C5+/+ mice, we demonstrate here that, the C5-/-derived CD3+ T cells, have an additional defect in the synthesis of IFNγ. C5-/- T cells produced lower levels of IFNγ upon stimulation by antigen presenting cells (APCs) infected with Mtb or when stimulated directly with a combination of IL-12 and IL-18. The latter was in part due to a reduced phosphorylation of STAT-4 following IL-12/IL-18 stimulation. Addition of C5a peptide to IL-12/IL-18 partially restored STAT4 phosphorylation and IFNγ synthesis in C5-/- T cells indicating that IL-12/IL-18 mediated signaling within CD3+ T cells involves C5a peptide. Finally, C5-/- T cells derived from M.bovis BCG or Mtb infected mice showed a reduced expression of T-bet (T-box expressed in T cells) transcription factor, which correlated well with a reduced T cell secretion of IFNγ. Since T-bet mediated IFNγ synthesis facilitates Th1 expansion, C5-/- mouse derived T cells appear to have an intrinsic defect in the production of IFNγ, which is related to C5 deficiency and this may explain their increased susceptibility to infection with Mtb and BCG.

Lack of Long-Lasting Hydrosalpinx in A/J Mice Correlates with Rapid but Transient Chlamydial Ascension and Neutrophil Recruitment in the Oviduct following Intravaginal Inoculation with Chlamydia muridarum

“…Alternatively, a second hypothesis is that A/J mice are genetically defective in responding to chlamydial infection with a hydrosalpinx-causing prolonged inflammatory response, which is inconsistent with the equally robust pyosalpinx we detected in both A/J and CBA/J mice. Interestingly, A/J mice are known to be deficient in complement component 5 (C5) (36,37). Since C5 has been found to play significant roles in various inflammatory pathologies and anti-C5 therapy has been shown to reduce the severity of autoimmune pathologies (38,39), it is possible that A/J mice are not able to develop long-lasting hydrosalpinx if C5 is required for the conversion of early hydrosalpinx into long-lasting hydrosalpinx.…”

Nitric Oxide and KLF4 Protein Epigenetically Modify Class II Transactivator to Repress Major Histocompatibility Complex II Expression during Mycobacterium bovis Bacillus Calmette-Guérin Infection

“…Importantly, IFN-␥ null mice are readily susceptible to mycobacterial infections as macrophages display diminished activation and expression of inducible nitric-oxide synthase (iNOS)/ nitric oxide (NO) (11,12). Furthermore, human subjects deficient for IFN-␥ receptor or IFN-␥ exhibit heightened susceptibility to pathogenic mycobacterial infections (13).…”

Importância do componente C5 do sistema complemento para o controle de leptospirose in vivo em modelos murinos.

“…Contudo, além desse papel protetor, C5 também é responsável por aumentar o grau de lesão em diferentes modelos experimentais (Pritchard et al, 2007). Devido a capacidade de C5a estimular e atrair diversos tipos celulares para o sítio de inflamação (Liu et al, 2013;Mashruwala et al, 2011;Mollnes et al, 2002;Moulton et al, 2007;Snyderman et al, 1971;Ward, Zvaifler, 1971) …”

“…Camundongos C5 deficientes possuem menor atividade de linfócitos T CD4 + , macrófagos e células dendríticas (Liu et al, 2013;Mashruwala et al, 2011;Moulton et al, 2007). Macrófagos e células dendríticas desses animais produzem menores quantidades de IL-12p70 que as células de animais C5 normais.…”

“…Macrófagos e células dendríticas desses animais produzem menores quantidades de IL-12p70 que as células de animais C5 normais. Essa pequena produção de IL-12(p70) junto à ausência de C5a leva a menor ativação dos linfócitos T CD4 + , resultando em menor produção de IFN- por essas células (Mashruwala et al, 2011;Moulton et al, 2007). Essa maior dificuldade em organizar uma resposta Th1 pode explicar a maior susceptibilidade de camundongos C5 deficientes a bactérias do gênero Mycobacterium.…”