An adult zebrafish model for preclinical tuberculosis vaccine development

Oksanen, Kaisa; Halfpenny, NJ; Sherwood, Eleanor; Harjula, Sanna-Kaisa E.; Hammaren, Milka; Ahava, Maarit J; Pajula, Elina; Lahtinen, Marika J.; Parikka, Mataleena; Rämet, Mika

doi:10.1016/j.vaccine.2013.08.093

Cited by 62 publications

(74 citation statements)

References 46 publications

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“…It has been shown [33] that there are professional antigen presenting cells capable of inducing antigen-specific T cell responses in zebrafish. In our recent publication [34], we have demonstrated the presence of specific and protective immune responses against M. marinum infection in zebrafish. We have shown that vaccination of zebrafish with the Bacillus Calmette-Guérin (BCG) increases survival of adult zebrafish from infection with M. marinum .…”

Section: Discussionmentioning

confidence: 90%

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

Hammaren

Oksanen²,

Nisula³

et al. 2014

PLoS Pathog

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Tuberculosis is still a major health problem worldwide. Currently it is not known what kind of immune responses lead to successful control and clearance of Mycobacterium tuberculosis. This gap in knowledge is reflected by the inability to develop sufficient diagnostic and therapeutic tools to fight tuberculosis. We have used the Mycobacterium marinum infection model in the adult zebrafish and taken advantage of heterogeneity of zebrafish population to dissect the characteristics of adaptive immune responses, some of which are associated with well-controlled latency or bacterial clearance while others with progressive infection. Differences in T cell responses between subpopulations were measured at the transcriptional level. It was discovered that a high total T cell level was usually associated with lower bacterial loads alongside with a T helper 2 (Th2)-type gene expression signature. At late time points, spontaneous reactivation with apparent symptoms was characterized by a low Th2/Th1 marker ratio and a substantial induction of foxp3 reflecting the level of regulatory T cells. Characteristic gata3/tbx21 has potential as a biomarker for the status of mycobacterial disease.

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Section: Discussionmentioning

confidence: 90%

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

Hammaren

Oksanen²,

Nisula³

et al. 2014

PLoS Pathog

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“…The presence of M. marinum in infected adult zebrafish was verified with a histological analysis and Ziehl-Neelsen staining (25,34). Uninfected controls were included to exclude background mycobacterial infection.…”

Section: Mo and M Marinum Coinjectionsmentioning

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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“…These granulomas are preferentially formed in fatty tissue and are most commonly found in the pancreas, adipose tissue, liver, spleen, and gonads (Swaim et al 2006;Parikka et al 2012;Oksanen et al 2013;Stoop et al 2013). The first granulomas can already be found in the first weeks postinfection (Swaim et al 2006;Parikka et al 2012).…”

Section: Pathology In Adult Fishmentioning

confidence: 99%

Animal Models of Tuberculosis: Zebrafish

Leeuwen

Sar

Bitter

2014

Cold Spring Harbor Perspectives in Medicine

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Correspondence: a.vandersar@vumc.nl Over the past decade the zebrafish (Danio rerio) has become an attractive new vertebrate model organism for studying mycobacterial pathogenesis. The combination of mediumthroughput screening and real-time in vivo visualization has allowed new ways to dissect host pathogenic interaction in a vertebrate host. Furthermore, genetic screens on the host and bacterial sides have elucidated new mechanisms involved in the initiation of granuloma formation and the importance of a balanced immune response for control of mycobacterial pathogens. This article will highlight the unique features of the zebrafish-Mycobacterium marinum infection model and its added value for tuberculosis research.

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An adult zebrafish model for preclinical tuberculosis vaccine development

Cited by 62 publications

References 46 publications

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

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

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

Animal Models of Tuberculosis: Zebrafish

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