Abstract
The glycolytic enzyme and bacterial virulence factor of Listeria monocytogenes, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Lmo2459), ADP-ribosylated the small GTPase, Rab5a, and blocked phagosome maturation. This inhibitory activity localized within the NAD binding domain of GAPDH at the N-terminal 1–22 peptides, also conferred listeriosis protection when used in dendritic cell-based vaccines. In this study, we explore GAPDH of Listeria, Mycobacterium, and Streptococcus spp. taxonomic groups to search for epitopes that confer broad protection against pathogenic strains of these bacteria. GAPDH multivalent epitopes are selected if they induce inhibitory actions and wide-ranging immune responses. Proteomic isolation of GAPDH from dendritic cells infected with Listeria, Mycobacterium, or Streptococcus confirmed similar enzymatic, Rab5a inhibitory and immune stimulation abilities. We identified by bioinformatics and functional analyses GAPDH N-terminal 1–22 peptides from Listeria, Mycobacterium, and Streptococcus that shared 95% sequence homology, enzymatic activity, and B and T cell immune domains. Sera obtained from patients or mice infected with hypervirulent pathogenic Listeria, Mycobacterium, or Streptococcus presented high levels of anti-GAPDH 1–22 antibodies and Th2 cytokines. Monocyte derived dendritic cells from healthy donors loaded with GAPDH 1–22 peptides from Listeria, Mycobacterium, or Streptococcus showed activation patterns that correspond to cross-immunity abilities. In summary, GAPDH 1–22 peptides appeared as putative candidates to include in multivalent dendritic based vaccine platforms for Listeria, Mycobacterium, or Streptococcus.
Highlights
Re-emerging pathogens causing severe meningitis in adults belong to the bacterial genus Listeria, Mycobacterium, and Streptococcus
The abilities of bacterial glyceraldehyde-3phosphate dehydrogenase (GAPDH) from Listeria monocytogenes (LM), Mycobacterium tuberculosis (MTB), or Streptococcus pneumoniae (SP) to bind to cell surface or intracellular proteins predicted they might share binding domains that contribute to virulence and immune responses
Proteins eluted from Blue-sepharose columns matched with GAPDH and enolase for LM, MTB, and SP, and two additional proteins were eluted in the case of MTB, the heat-shock protein 70 (Hsp70), and the elongator factor 60 (EF60) (Table 1, column c)
Summary
Re-emerging pathogens causing severe meningitis in adults belong to the bacterial genus Listeria, Mycobacterium, and Streptococcus. Listeriosis arose recently as a re-emerging infectious disease, and only experimental dendritic-based vaccines have been reported, with no development at the clinical practice (Kono et al, 2012; Calderon-Gonzalez et al, 2014; Calderon-Gonzalez et al, 2015; Torres et al, 2016) For this reason, developing vaccines that protect the adults against re-emerging bacterial infections would avoid the high mortality and morbidity they cause, as well as diminish the cost of antibiotics use in our health care systems. It will be worthy to prepare multivalent vaccine designs that might confer broad protection against these three bacterial genera In this regard, the toxins involved in host membrane disruption such as listeriolysin O (LLO) of Listeria monocytogenes (LM) (Nguyen et al, 2019), pneumolysin (PLY) of Streptococcus pneumoniae (SP) (Los et al, 2013) or mycobacteria factors of the ESX-1 secretion system such as ESAT-6, and CFP-10 of Mycobacterium tuberculosis (MTB) (Smith et al, 2008) have similar virulence factors. The glycolytic enzyme, glyceraldehyde-3phosphate dehydrogenase (GAPDH) of the above-mentioned bacterial pathogens can attach to cell surface immune-related proteins (i.e., lactoferrin, fibrinogen, plasmin, or C1q) or intracellular GTPases involved in trafficking (AlvarezDominguez et al, 2008; Terrasse et al, 2012; Boradia et al, 2014; Ireton et al, 2014; Malhotra et al, 2017; Moreau et al, 2017; Myllymäki et al, 2017), contributing to their virulence and to the identification of pathogen broad immunogenic epitopes to design multivalent vaccines
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