Proteomics-based identification of plasma proteins and their association with the host–pathogen interaction in chronic typhoid carriers

Kumar, Abhai; Singh, Smita; Ahirwar, Suneel Kumar; Nath, Gopal

doi:10.1016/j.ijid.2013.10.008

Cited by 16 publications

(15 citation statements)

References 44 publications

(40 reference statements)

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“…Our data show that furinA/FURIN expression is upregulated in the host in response to a mycobacterial infection and the Th1 hallmark cytokine IL-12 (15). FURIN is also secreted from macrophages in response to LPS activation (14), and it can be measured from serum (66). Therefore, in the future it will be interesting to assess whether serum FURIN levels can be used as an infection biomarker to mirror mycobacterial growth and the activation of Th1 type immune responses.…”

Section: Discussionmentioning

confidence: 85%

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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Section: Discussionmentioning

confidence: 85%

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

et al. 2015

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“…Recent findings show that not only IL-12 and TCR signals in T cells, but also LPS stimulation in macrophages can upregulate FURIN (10, 38). FURIN is also secreted from cells upon immune activation, and elevated serum levels were recently found in chronic typhoid carriers (39). Assessing serum FURIN levels has thus potential to become a future biomarker in detecting the activation of immune systems in host.…”

Section: Discussionmentioning

confidence: 99%

Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii

Oksanen

Aittomäki

Janković

et al. 2014

The Journal of Immunology

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The proprotein convertase subtilisin/kexin (PCSK) enzymes proteolytically convert immature proproteins into bioactive molecules and thereby they serve as key regulators of cellular homeostasis. The archetype PCSK, FURIN is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in T helper 1 type cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGFβ-1 in vivo, but FURIN’s role in cell-mediated immunity and Th polarization has remained elusive. Here, we show that T-cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4 receptor subunit alpha (IL-4Rα) on cell surface, sensitized IL-4/STAT6 signaling and a propensity to polarize towards the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass-spectrometry we further identify an association with a cytoskeleton modifying RAC/DOCK2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to down-regulate IL-4Rα cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T-cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance.

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“…Although S. Typhi was not detected in the single stool sample obtained in the late phase from these individuals, such data may support the possibility that host biomarkers beyond antibodies may be used to identify carriers [68]. Similarly, another study comparing the proteome in the blood of chronic carriers, patients with acute typhoid fever, and healthy individuals identified changes in serum proteins that may be indicative of the chronic carrier state [69]. These and related studies suggest that development of an assay(s) to identify carriers is theoretically possible, although for maximal public health utility, any such assay(s) would need to be minimally or non363 invasive, inexpensive, practical, and easily applied in the field among target populations to identify a relatively few asymptomatic individuals.…”

Section: In Search Of Diagnostic Markers For Salmonella Carriagementioning

confidence: 99%

Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence

Gunn

Marshall

Baker

et al. 2014

Trends in Microbiology

246

242

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Typhoid (enteric fever) remains a major cause of morbidity and mortality worldwide, causing over 21 million new infections annually, with the majority of deaths occurring in young children. As typhoid fever-causing Salmonella have no known environmental reservoir, the chronic, asymptomatic carrier state is thought to be a key feature of continued maintenance of the bacterium within human populations. In spite of the importance of this disease to public health, our understanding of the molecular mechanisms that catalyze carriage, as well as our ability to reliably identify and treat the Salmonella carrier state, have only recently begun to advance.

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Proteomics-based identification of plasma proteins and their association with the host–pathogen interaction in chronic typhoid carriers

Abstract: Through proteomics techniques, this study identified four proteins in the chronic typhoid carrier host that may have a role in the disease pathogenesis of enteric fever.

Cited by 16 publications

References 44 publications

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

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

Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii

Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence

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