Identification of Plasmodium falciparum proteoforms from liver stage models

Benjamin Winer; Kimberly A. Edgel; Xiaoyan Zou; Julie Sellau; Sri Hadiwidjojo; Lindsey S. Garver; Christin E. McDonough; Neil L. Kelleher; Paul M. Thomas; Eileen Villasante; Alexander Ploss; Vincent R. Gerbasi

doi:10.1186/s12936-019-3093-3

Identification of Plasmodium falciparum proteoforms from liver stage models

Benjamin Winer, Kimberly A. Edgel, Xiaoyan Zou, Julie Sellau, Sri Hadiwidjojo, Lindsey S. Garver, Christin E. McDonough, Neil L. Kelleher, Paul M. Thomas, Eileen Villasante, Alexander Ploss, Vincent R. Gerbasi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Background : Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. Methods: In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. Results: These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. Conclusions: This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.

Original language	English (US)
Article number	10
Journal	Malaria journal
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s12936-019-3093-3
State	Published - Jan 7 2020

Funding

This work was funded by the Bill and Melinda Gates Grand Challenges Explorations Round Nine Phase II awarded to VRG (OP1119033), the Military Infectious Diseases Research Program (VRG), the US Navy In-house Laboratory Independent Research Program (ILIR) supported by the Office for Naval Research (VRG), and the National Resource for Translational Proteomics NIH P41 GM108569 to NLK. A.P. is supported by a Burroughs Wellcome Fund Award (1015389) for Investigators in Pathogenesis and funds from Princeton University. B.Y.W. was supported by a training grant from the National Institutes of Healths (T32GM007388), is a recipient of an F31 NIH/National Research Service Award Ruth L. Kirschstein Predoctoral award from the National Institute of Allergy and Infectious Diseases and a graduate fellowship from the New Jersey Commission on Cancer Research.

Keywords

Antigen
Cell-mediated immunity
Liver stage
Proteomics
Top-down
Vaccine

ASJC Scopus subject areas

Parasitology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s12936-019-3093-3

Cite this

@article{15062eb979804b89bd4392e8e94ebfd8,

title = "Identification of Plasmodium falciparum proteoforms from liver stage models",

abstract = "Background : Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. Methods: In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. Results: These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. Conclusions: This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.",

keywords = "Antigen, Cell-mediated immunity, Liver stage, Proteomics, Top-down, Vaccine",

author = "Benjamin Winer and Edgel, {Kimberly A.} and Xiaoyan Zou and Julie Sellau and Sri Hadiwidjojo and Garver, {Lindsey S.} and McDonough, {Christin E.} and Kelleher, {Neil L.} and Thomas, {Paul M.} and Eileen Villasante and Alexander Ploss and Gerbasi, {Vincent R.}",

note = "Funding Information: This work was funded by the Bill and Melinda Gates Grand Challenges Explorations Round Nine Phase II awarded to VRG (OP1119033), the Military Infectious Diseases Research Program (VRG), the US Navy In-house Laboratory Independent Research Program (ILIR) supported by the Office for Naval Research (VRG), and the National Resource for Translational Proteomics NIH P41 GM108569 to NLK. A.P. is supported by a Burroughs Wellcome Fund Award (1015389) for Investigators in Pathogenesis and funds from Princeton University. B.Y.W. was supported by a training grant from the National Institutes of Healths (T32GM007388), is a recipient of an F31 NIH/National Research Service Award Ruth L. Kirschstein Predoctoral award from the National Institute of Allergy and Infectious Diseases and a graduate fellowship from the New Jersey Commission on Cancer Research. Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = jan,

day = "7",

doi = "10.1186/s12936-019-3093-3",

language = "English (US)",

volume = "19",

journal = "Malaria journal",

issn = "1475-2875",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Identification of Plasmodium falciparum proteoforms from liver stage models

AU - Winer, Benjamin

AU - Edgel, Kimberly A.

AU - Zou, Xiaoyan

AU - Sellau, Julie

AU - Hadiwidjojo, Sri

AU - Garver, Lindsey S.

AU - McDonough, Christin E.

AU - Kelleher, Neil L.

AU - Thomas, Paul M.

AU - Villasante, Eileen

AU - Ploss, Alexander

AU - Gerbasi, Vincent R.

N1 - Funding Information: This work was funded by the Bill and Melinda Gates Grand Challenges Explorations Round Nine Phase II awarded to VRG (OP1119033), the Military Infectious Diseases Research Program (VRG), the US Navy In-house Laboratory Independent Research Program (ILIR) supported by the Office for Naval Research (VRG), and the National Resource for Translational Proteomics NIH P41 GM108569 to NLK. A.P. is supported by a Burroughs Wellcome Fund Award (1015389) for Investigators in Pathogenesis and funds from Princeton University. B.Y.W. was supported by a training grant from the National Institutes of Healths (T32GM007388), is a recipient of an F31 NIH/National Research Service Award Ruth L. Kirschstein Predoctoral award from the National Institute of Allergy and Infectious Diseases and a graduate fellowship from the New Jersey Commission on Cancer Research. Publisher Copyright: © 2020 The Author(s).

PY - 2020/1/7

Y1 - 2020/1/7

N2 - Background : Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. Methods: In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. Results: These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. Conclusions: This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.

AB - Background : Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. Methods: In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. Results: These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. Conclusions: This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.

KW - Antigen

KW - Cell-mediated immunity

KW - Liver stage

KW - Proteomics

KW - Top-down

KW - Vaccine

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U2 - 10.1186/s12936-019-3093-3

DO - 10.1186/s12936-019-3093-3

M3 - Article

C2 - 31910830

AN - SCOPUS:85077683535

SN - 1475-2875

VL - 19

JO - Malaria journal

JF - Malaria journal

IS - 1

M1 - 10

ER -

Identification of Plasmodium falciparum proteoforms from liver stage models

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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