Adequate Th2-Type Response Associates with Restricted Bacterial Growth in Latent Mycobacterial Infection of Zebrafish

Hammaren, Milka; Oksanen, Kaisa; Nisula, Hanna; Luukinen, Hanna; Pesu, Marko; Rämet, Mika; Parikka, Mataleena

doi:10.1371/journal.ppat.1004190

Cited by 31 publications

(39 citation statements)

References 42 publications

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“…Recently the zebrafish tuberculosis model, using M. marinum , has been used to mimic aspects of LTBI due to its small size, rapid reproduction, formation of granulomas and advanced genetic tools, making it a suitable animal model for large-scale screening of novel therapeutic agents in early-stage preclinical studies. However, zebrafish are anatomically and physiologically different to humans and lack the clinical manifestations and symptoms of tuberculosis disease and moreover they cannot be infected with the pathogenic human strain M. tuberculosis [4,59–62]. …”

Section: Discussionmentioning

confidence: 99%

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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Animal models have long been used in tuberculosis research to understand disease pathogenesis and to evaluate novel vaccine candidates and anti-mycobacterial drugs. However, all have limitations and there is no single animal model which mimics all the aspects of mycobacterial pathogenesis seen in humans. Importantly mice, the most commonly used model, do not normally form granulomas, the hallmark of tuberculosis infection. Thus there is an urgent need for the development of new alternative in vivo models. The insect larvae, Galleria mellonella has been increasingly used as a successful, simple, widely available and cost-effective model to study microbial infections. Here we report for the first time that G. mellonella can be used as an infection model for members of the Mycobacterium tuberculosis complex. We demonstrate a dose-response for G. mellonella survival infected with different inocula of bioluminescent Mycobacterium bovis BCG lux, and demonstrate suppression of mycobacterial luminesence over 14 days. Histopathology staining and transmission electron microscopy of infected G. mellonella phagocytic haemocytes show internalization and aggregation of M. bovis BCG lux in granuloma-like structures, and increasing accumulation of lipid bodies within M. bovis BCG lux over time, characteristic of latent tuberculosis infection. Our results demonstrate that G. mellonella can act as a surrogate host to study the pathogenesis of mycobacterial infection and shed light on host-mycobacteria interactions, including latent tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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“…Although the Th1 type cell immune response is crucial in adaptive immunity against TB (5-8), other Th lymphocyte subsets, including Th2, Th17, and Treg cells, also regulate the magnitude of the host defense and survival (59)(60)(61)(62). We have previously shown that FURIN is dispensable for T cell development in mice but that it plays a role in CD4 ϩ T cell activation and polarization (15,18).…”

Section: Discussionmentioning

confidence: 99%

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

et al. 2015

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Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinA td204e/؉ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinuminfected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinA td204e/؉ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinA td204e/؉ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection.T uberculosis (TB) is an epidemic infectious disease caused by the mycobacterial species Mycobacterium tuberculosis (1, 2). Circa 13% of the individuals with active TB were simultaneous carriers of the human immunodeficiency virus (HIV), and almost one-third of TB-associated deaths occurred among HIV ϩ patients, demonstrating the critical role of cluster of differentiation 4 (CD4 ϩ ) T lymphocyte-mediated immunity in the control of M. tuberculosis infection (3, 4). More specifically, the adaptive immunity against TB is primarily mediated by T helper (Th) type 1 cells, as is suggested by the gene expression profile upon infection (5), as well as the infection-induced mortality of gamma interferon-deficient (6, 7) and interleukin-12 (IL-12)-deficient (8) mice.The proprotein convertase subtilisin/kexin (PCSK) enzymes are a family of serine endoproteases with nine members in humans: PCSK1 and -2, FURIN, PCSK4 to -7, membrane-bound transcription factor peptidase site 1 (MBTPS1), and PCSK9 (9). Typically, PCSKs convert precursor proteins (proproteins) into their biologically active forms by cleaving them at specific target motifs made up of the basic amino acids lysine and arginine (9, 10). FURIN was the first identified mammalian PCSK and is present in vertebrates and many invertebrates (11,12). A series of in vitro experiments have suggested a central role for FURIN in host defense because it proteolytically activates several immunoregulatory proproteins, such as membrane-inserted matrix metallo...

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“…In mammals T H 2 responses are characterized by increased expression of signature cytokines such as IL-4, IL-5 and IL-13 resulting in eosinophilia, mast cell activity, IgE production and mucosal changes (Jackson et al, 2009). While the teleost immune system is relatively understudied, T H 2-like cells and functional responses (involving teleost il4/ il13) have been observed in zebrafish and salmonids (see Balla et al, 2010;Takizawa et al, 2011;Hammarén et al, 2014) and might be predicted to also occur in the stickleback.…”

Section: Immunologymentioning

confidence: 99%

Hook, Line and Infection

Stewart

Jackson

Barber

et al. 2017

Advances in Parasitology

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The three-spined stickleback (Gasterosteus aculeatus) is a model organism with an extremely well-characterized ecology, evolutionary history, behavioural repertoire and parasitology that is coupled with published genomic data. These small temperate zone fish therefore provide an ideal experimental system to study common diseases of coldwater fish, including those of aquacultural importance. However, detailed information on the culture of stickleback parasites, the establishment and maintenance of infections and the quantification of host responses is scattered between primary and grey literature resources, some of which is not readily accessible. Our aim is to lay out a framework of techniques based on our experience to inform new and established laboratories about culture techniques and recent advances in the field. Here, essential knowledge on the biology, capture and laboratory maintenance of sticklebacks, and their commonly studied parasites is drawn together, highlighting recent advances in our understanding of the associated immune responses. In compiling this guide on the maintenance of sticklebacks and a range of common, taxonomically diverse parasites in the laboratory, we aim to engage a broader interdisciplinary community to consider this highly tractable model when addressing pressing questions in evolution, infection and aquaculture.

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Adequate Th2-Type Response Associates with Restricted Bacterial Growth in Latent Mycobacterial Infection of Zebrafish

Cited by 31 publications

References 42 publications

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

Hook, Line and Infection

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