Abstract
ABSTRACTMycobacterium tuberculosis remains one of the most problematic infectious agents, owing to its highly developed mechanisms to evade host immune responses combined with the increasing emergence of antibiotic resistance. Host-directed therapies aiming to optimize immune responses to improve bacterial eradication or to limit excessive inflammation are a new strategy for the treatment of tuberculosis. In this study, we have established a zebrafish-Mycobacterium marinum natural host-pathogen model system to study induced protective immune responses in mycobacterial infection. We show that priming adult zebrafish with heat-killed Listeria monocytogenes (HKLm) at 1 day prior to M. marinum infection leads to significantly decreased mycobacterial loads in the infected zebrafish. Using rag1−/− fish, we show that the protective immunity conferred by HKLm priming can be induced through innate immunity alone. At 24 h post-infection, HKLm priming leads to a significant increase in the expression levels of macrophage-expressed gene 1 (mpeg1), tumor necrosis factor α (tnfa) and nitric oxide synthase 2b (nos2b), whereas superoxide dismutase 2 (sod2) expression is downregulated, implying that HKLm priming increases the number of macrophages and boosts intracellular killing mechanisms. The protective effects of HKLm are abolished when the injected material is pretreated with nucleases or proteinase K. Importantly, HKLm priming significantly increases the frequency of clearance of M. marinum infection by evoking sterilizing immunity (25 vs 3.7%, P=0.0021). In this study, immune priming is successfully used to induce sterilizing immunity against mycobacterial infection. This model provides a promising new platform for elucidating the mechanisms underlying sterilizing immunity and to develop host-directed treatment or prevention strategies against tuberculosis.This article has an associated First Person interview with the first author of the paper.
Highlights
Tuberculosis (TB) is an airborne respiratory disease caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb)
Immune activation by heat-killed L. monocytogenes leads to lower mycobacterial burdens in adult zebrafish In this study, we set out to investigate protective immune responses at the early stages of an M. marinum infection
Our hypothesis is that the right immune activation at the early stages of an infection prevents mycobacterial evasion strategies and leads to protective immune responses, increased killing of mycobacteria or even clearing of mycobacteria
Summary
Tuberculosis (TB) is an airborne respiratory disease caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb). A 7-43% proportion of heavily exposed individuals are able to clear the infection before the onset of adaptive immunity, resulting in negative tuberculin skin tests and interferon-gamma (Ifnγ) release assays (reviewed in Verrall et al, 2014) With this in mind, it should be possible to shift the balance of host-pathogen interactions in favor of the host by directing the immune response to the right immune activation at the early stages of infection, when the bacterial loads are rather small. We have used the zebrafish model to test whether the number of individuals sterilizing the infection can be increased through injection with different priming agents to circumvent mycobacterial virulence strategies, which generally lead to persistent, latent infections (Parikka et al, 2012). We show that the adult zebrafish is a feasible model for deciphering the mechanisms of sterilizing immunity, knowledge of which is crucial for the development of new preventive strategies and adjunctive therapies against TB
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