Abstract
Tuberculosis ranks as one of the world’s deadliest infectious diseases causing more than a million casualties annually. IL10 inhibits the function of Th1 type cells, and IL10 deficiency has been associated with an improved resistance against Mycobacterium tuberculosis infection in a mouse model. Here, we utilized M. marinum infection in the zebrafish (Danio rerio) as a model for studying Il10 in the host response against mycobacteria. Unchallenged, nonsense il10e46/e46 mutant zebrafish were fertile and phenotypically normal. Following a chronic mycobacterial infection, il10e46/e46 mutants showed enhanced survival compared to the controls. This was associated with an increased expression of the Th cell marker cd4-1 and a shift towards a Th1 type immune response, which was demonstrated by the upregulated expression of tbx21 and ifng1, as well as the down-regulation of gata3. In addition, at 8 weeks post infection il10e46/e46 mutant zebrafish had reduced expression levels of proinflammatory cytokines tnfb and il1b, presumably indicating slower progress of the infection. Altogether, our data show that Il10 can weaken the immune defense against M. marinum infection in zebrafish by restricting ifng1 response. Importantly, our findings support the relevance of M. marinum infection in zebrafish as a model for tuberculosis.
Highlights
More than 10 million new tuberculosis cases are estimated to emerge, leading to over a million casualties[1]
In any of the studied tissues il[10] mRNA expression did not differ between il10e46/e46 mutants and wild type (WT) zebrafish, suggesting that the effects of the mutation are only evident at the translational level
The exact mechanisms of the immune defense against M. tuberculosis are in many ways still unknown, disease progression has been studied in human samples, as well as with various model organisms in vivo
Summary
More than 10 million new tuberculosis cases are estimated to emerge, leading to over a million casualties[1]. In vivo mouse studies have shown that IL10 impairs the immune defense against M. tuberculosis by impeding host immunity at an early[13,14], and during later stages of an infection[15]. In these studies, the lack of functional IL10 signaling resulted in enhanced protection. While IL10 deficiency or receptor blockade has been associated with an enhanced protection against mycobacteria in mice, it has been reported that the lack of IL10 can eventually lead to harmful lung inflammation and to the progression of a mycobacterial disease in the mouse model[16]. The M. marinum infection model in adult zebrafish allows studying the adaptive response[35,36,37]
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