HypervirulentM. tuberculosisW/Beijing Strains Upregulate Type I IFNs and Increase Expression of Negative Regulators of the Jak-Stat Pathway

Abstract

The role of type I interferons (IFNs) in the host response to bacterial infections is controversial. Here, we examined the role of IFN-alpha/beta in the murine response to infection with Mycobacterium tuberculosis, using wildtype mice, mice with impaired signaling through the type I IFN receptor (IFNAR), and mice treated to reduce levels of type I IFNs. In this study, we used virulent clinical isolates of M. tuberculosis, including HN878, W4, and CDC1551. Our results indicate that higher levels of type I IFNs are induced by the HN878 and W4 strains. Induction of type I IFNs was associated with lower levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin- 12 (IL-12) and reduced T cell activation, and associated with decreased survival of the mice infected with HN878 or W4 relative to infection with CDC1551. Infection of mice with HN878 and W4 was also associated with relatively higher levels of mRNA for a number of negative regulators of the Jak-Stat signaling pathway, such as suppressors of cytokine signaling (SOCS) 1, 4, and 5, CD45, protein inhibitor of activated Stat1 (PIAS1), protein tyrosine phosphatase nonreceptor type 1 (Ptpn1), and protein tyrosine phosphatase nonreceptor type substrate 1 (Ptpns1). Taken together, these results suggest that increased type I IFNs may be deleterious for survival of M. tuberculosis-infected mice in association with reduced Th1 immunity.

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…This finding suggests that type I IFNs are detrimental only when IFN-g-dependent immune mechanisms are activated. In line with this work, M. tuberculosis strains known to trigger high levels of type I IFN also induce increased levels of the negative regulator of IFN signaling, suppressor of cytokine signaling 1 (SOCS1) (81). Moreover, Ifnar1 2/2 mouse macrophages express lower levels of Socs1 during mycobacterial infection, and IFN-g-activated Socs1 2/2 macrophages have lower intracellular bacteria as a result of the increased IFN-g signaling (91).…”

“…Indeed, infection of mice with hypervirulent clinical isolates results in higher type I IFN production compared with less virulent laboratory strains, and the increased type I IFN levels are associated with reduced expression of Th1 cytokines TNF-a and IL-12 (79)(80)(81). Importantly, Ifnar1 2/2 mice and Irf3 2/2 mice (unable to induce IFN-b) demonstrate lower bacterial burden compared with WT animals (71,79,81). Furthermore, intranasal treatment of mice with the type I IFN inducer poly I:C exacerbated pulmonary TB in WT, but not Ifnar1 2/2 , mice (82).…”

Avaliação da virulência micobacteriana e modulação da resposta imune durante a infecção por isolados clínicos de Mycobacterium bovis e Mycobacterium tuberculosis.

“…Porém, Neste estudo, foi verificada formação de intensa necrose tecidual nos camundongos deficientes em TNF-, IL-12, IFN-, iNOS, células T e camundongos SCID e, necrose tecidual branda nos camundongos deficientes em IL-1, IL-6, IL-10, TCD4 + , células TCD8 + e células T (Gil et al, 2006). Embora, Florido et al (2004) (Manca et al, 2005). Quando os camundongos infectados foram tratados com anti-IFN, a resposta imune do tipo Th1 foi restaurada e, consequentemente, observado o aumento da sobrevivência dos animais (Manca et al, 2001;Manca et al, 2005).…”

“…Embora, Florido et al (2004) (Manca et al, 2005). Quando os camundongos infectados foram tratados com anti-IFN, a resposta imune do tipo Th1 foi restaurada e, consequentemente, observado o aumento da sobrevivência dos animais (Manca et al, 2001;Manca et al, 2005). Reed et al (2004) mostraram que a falha da resposta imune durante a infecção pelo isolado HN878 era devida à expressão de PGL.…”

“…Ordway et al (2007) mostraram que o isolado clínico de genótipo Beijing HN878 foi capaz de induzir ativação exacerbada da resposta imune do tipo Th1, seguida de regulação negativa desta resposta em camundongos C57BL/6. A mortalidade nestes animais foi semelhante à observada por Manca et al (2001Manca et al ( , 2005 e Reed et al (2004). Foi confirmado, por Ordway et al (2007), que na ausência de IFN tipo 1 há o aumento da sobrevivência dos animais devido à ativação da resposta imune do tipo Th1 e baixa contagem bacilar no pulmão.…”