A baculovirus-conjugated mimotope vaccine targeting Mycobacterium tuberculosis lipoarabinomannan

Shin, Hyun Jin; Franco, Luis H.; Nair, Vidhya R.; Collins, Angela C.; Shiloh, Michael U.

doi:10.1371/journal.pone.0185945

Cited by 9 publications

(8 citation statements)

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“…FcMBL was able to detect both LPS and LTA from all 6 bacterial species tested in both buffer and blood, although detection sensitivity was consistently higher in buffer. In addition, we explored whether FcMBL binds to the antigenic PAMPs, LAM, PIM 1,2 , and PIM 6 from M. tuberculosis H37Rv because these are active virulence factors associated with TB pathogenesis, and hence, they are critically important targets for point-of-care diagnostic and vaccine applications 35– 38 . We found that FcMBL can detect LAM and PIM 6 , but not PIM 1,2 , in buffer, urine, and blood; this difference in binding is likely due to the fact that PIM 1,2 has 4 fewer branched mannose residues than PIM 6 39 .…”

Section: Discussionmentioning

confidence: 99%

Broad-spectrum capture of clinical pathogens using engineered Fc-mannose-binding lectin enhanced by antibiotic treatment

et al. 2019

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Background: Fc-mannose-binding lectin (FcMBL), an engineered version of the blood opsonin MBL that contains the carbohydrate recognition domain (CRD) and flexible neck regions of MBL fused to the Fc portion of human IgG1, has been shown to bind various microbes and pathogen-associated molecular patterns (PAMPs). FcMBL has also been used to create an enzyme-linked lectin sorbent assay (ELLecSA) for use as a rapid (<1 h) diagnostic of bloodstream infections. Methods: Here we extended this work by using the ELLecSA to test FcMBL’s ability to bind to more than 190 different isolates from over 95 different pathogen species. Results: FcMBL bound to 85% of the isolates and 97 of the 112 (87%) different pathogen species tested, including bacteria, fungi, viral antigens and parasites. FcMBL also bound to PAMPs including, lipopolysaccharide endotoxin (LPS) and lipoteichoic acid (LTA) from Gram-negative and Gram-positive bacteria, as well as lipoarabinomannan (LAM) and phosphatidylinositol mannoside 6 (PIM6) from Mycobacterium tuberculosis. Conclusions: The efficiency of pathogen detection and variation between binding of different strains of the same species could be improved by treating the bacteria with antibiotics, or mechanical disruption using a bead mill, prior to FcMBL capture to reveal previously concealed binding sites within the bacterial cell wall. As FcMBL can bind to pathogens and PAMPs in urine as well as blood, its broad-binding capability could be leveraged to develop a variety of clinically relevant technologies, including infectious disease diagnostics, therapeutics, and vaccines.

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Section: Discussionmentioning

confidence: 99%

Broad-spectrum capture of clinical pathogens using engineered Fc-mannose-binding lectin enhanced by antibiotic treatment

et al. 2019

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“…These studies demonstrated significant Ab-based protection against Mtb. More recently, other conjugate formulations including synthetic LAM OS [71] or a baculovirus-conjugated mimotope vaccine [72] have also demonstrated substantial immunogenicity. Similarly, ssDNA aptamers were developed to suppress the immunomodulatory properties of LAM leading to control of bacterial replication in animal models [73,74].…”

Section: Evidence Of Ab Efficacy In Tb Vaccine Studiesmentioning

confidence: 99%

Updates on antibody functions in Mycobacterium tuberculosis infection and their relevance for developing a vaccine against tuberculosis

Achkar

Prados-Rosales

2018

Current Opinion in Immunology

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A more effective vaccine to control tuberculosis (TB), a major global public health problem, is urgently needed. Current vaccine candidates focus predominantly on eliciting cell-mediated immunity but other arms of the immune system also contribute to protection against TB. We review here recent studies that enhance our current knowledge of antibody-mediated functions against Mycobacterium tuberculosis. These findings, which contribute to the increasing evidence that antibodies have a protective role against TB, include demonstrations that firstly distinct human antibody Fc glycosylation patterns, found in latent M. tuberculosis infection but not in active TB, influence the efficacy of the host to control M. tuberculosis infection, secondly antibody isotype influences human antibody functions, and thirdly that antibodies targeting M. tuberculosis surface antigens are protective. We discuss these findings in the context of TB vaccine development and highlight the need for further research on antibody-mediated immunity in M. tuberculosis infection.

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“…FcMBL was able to detect both LPS and LTA from all 6 bacterial species tested in both buffer and blood, although detection sensitivity was consistently higher in buffer. In addition, we explored whether FcMBL binds to the antigenic PAMPs, LAM, PIM 1,2 , and PIM 6 from M. tuberculosis H37Rv because these are active virulence factors associated with TB pathogenesis, and hence, they are critically important targets for point-of-care diagnostic and vaccine applications [33–36]. We found that FcMBL can detect LAM and PIM 6 , but not PIM 1,2 , in buffer, urine, and blood; this difference in binding is likely due to the fact that PIM 1,2 has 4 fewer branched mannose residues than PIM 6 [37].…”

Section: Discussionmentioning

confidence: 99%

Broad spectrum capture of clinical pathogens using engineered Fc-Mannose-Binding Lectin (FcMBL) enhanced by antibiotic treatment

Seiler¹,

Cartwright²,

Dinis³

et al. 2018

Preprint

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25FcMBL, an engineered version of the blood opsonin mannose-binding 26 lectin (MBL) that contains the carbohydrate recognition domain (CRD) and27 flexible neck regions of MBL fused to the Fc portion of human IgG1, has been 28 shown to bind various microbes and pathogen-associated molecular patterns 29 (PAMPs). FcMBL also has been used to create an enzyme-linked lectin sorbent 30 assay (ELLecSA) for use as a rapid ( 1 hr) diagnostic of bloodstream infections.31 Here we extended this work by using the ELLecSA to test FcMBL's ability to bind 32 to more than 200 different isolates from over 100 different pathogen species. 33 FcMBL bound to 86% of the isolates and 110 of the 122 (90%) different pathogen 34 species tested, including bacteria, fungi, viruses, and parasites. It also bound to 35 PAMPs including, lipopolysaccharide endotoxin (LPS) and lipoteichoic acid (LTA) 36 from Gram-negative and Gram-positive bacteria, as well as lipoarabinomannan 37 (LAM) and phosphatidylinositol mannoside 6 (PIM 6 ) from Mycobacterium 38 tuberculosis. The efficiency of pathogen detection and variation between binding 39 of different strains of the same species also could be improved by treating the 40 bacteria with antibiotics prior to FcMBL capture to reveal previously concealed 41 binding sites within the bacterial cell wall. As FcMBL can bind to pathogens and 42 PAMPs in urine as well as blood, its broad-binding capability could be leveraged 43 to develop a variety of clinically relevant technologies, including infectious 44 disease diagnostics, therapeutics, and vaccines. 45 46 3 47 Introduction 48 49 Mannose-binding lectin (MBL) is a key host-defense protein associated 50 with the lectin pathway of the innate immune system [1], and deficiency of MBL 51 can lead to increased susceptibility to a wide-spectrum of infectious diseases [2-52 4]. MBL functions as a calcium-dependent, pattern-recognition opsonin that binds 53 a range of carbohydrate molecules associated with the surfaces or cell walls of 54 many different types of pathogens [5]. Collectively these microbial surface 55 carbohydrate molecules, including for example, lipoteichoic acid (LTA) and 56 lipopolysaccharide endotoxin (LPS), are referred to as pathogen-associated 57 molecular patterns (PAMPs) [6,7]. MBL has the intrinsic ability to distinguish 58 foreign PAMPs from self, subsequently activating the complement system and 59 providing protection via antibody-dependent and independent mechanisms [8,9]. 60 Due to the evolutionary conserved recognition carbohydrate moieties of 61 PAMPs, MBL is a broad spectrum opsonin that can bind over 90 different species 62 of pathogens, including Gram-negative and Gram-positive bacteria, fungi, 63 viruses, and parasites [10-14]. MBL binding to these various pathogens has been 64 demonstrated by means of flow cytometry [14,15], radio-immunoassay [13,16], 65 enzyme-linked immunosorbent assay (ELISA) [13,17], immunofluorescence and 66 scanning electron microscopy (SEM) [18], and Saccharomyces cerevisiae-67 induced MBL activation and ...

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A baculovirus-conjugated mimotope vaccine targeting Mycobacterium tuberculosis lipoarabinomannan

Cited by 9 publications

References 55 publications

Broad-spectrum capture of clinical pathogens using engineered Fc-mannose-binding lectin enhanced by antibiotic treatment

Broad-spectrum capture of clinical pathogens using engineered Fc-mannose-binding lectin enhanced by antibiotic treatment

Updates on antibody functions in Mycobacterium tuberculosis infection and their relevance for developing a vaccine against tuberculosis

Broad spectrum capture of clinical pathogens using engineered Fc-Mannose-Binding Lectin (FcMBL) enhanced by antibiotic treatment

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