The TatD-like DNase of Plasmodium is a virulence factor and a potential malaria vaccine candidate

Abstract

Neutrophil extracellular traps (NETs), composed primarily of DNA and proteases, are released from activated neutrophils and contribute to the innate immune response by capturing pathogens. Plasmodium falciparum, the causative agent of severe malaria, thrives in its host by counteracting immune elimination. Here, we report the discovery of a novel virulence factor of P. falciparum, a TatD-like DNase (PfTatD) that is expressed primarily in the asexual blood stage and is likely utilized by the parasite to counteract NETs. PfTatD exhibits typical deoxyribonuclease activity, and its expression is higher in virulent parasites than in avirulent parasites. A P. berghei TatD-knockout parasite displays reduced pathogenicity in mice. Mice immunized with recombinant TatD exhibit increased immunity against lethal challenge. Our results suggest that the TatD-like DNase is an essential factor for the survival of malarial parasites in the host and is a potential malaria vaccine candidate.

Genomic Comparisons Reveal Microevolutionary Differences in Mycobacterium abscessus Subspecies

“…The twin-arginine translocation (tat) system has been shown to play an important role in the virulence of Yersinia pseudotuberculosis ( Lavander et al, 2006 ) and has been associated with E. coli meningitis ( Siddiqui et al, 2012 ). Although the function of the tatD component is not fully known, it has been reported to be the virulence factor in Plasmodium and a potential vaccine candidate for malaria ( Chang et al, 2016 ). We had previously reported thymidylate kinase and 30S ribosomal protein S3 as being suitable for the distinction of M. massiliense from other mycobacteria including other subspecies of the M. abscessus complex ( Tan et al, 2015 ).…”

Malaria Parasites: The Great Escape

“…During infection, multiple parasite toxins are released at the time of iRBC rupture. These toxins include the malaria pigment, a by-product of heme degradation by the parasite (76–78), glycophosphatidylinositol (GPI) moieties that are present in many merozoite proteins, a TatD-like DNase (79), a tyrosine-tRNA synthase (80), or lipids extracted from P. vivax schizonts (81). Protection from disease by anti-toxins antibodies has been demonstrated experimentally using synthetic glycans mimicking GPI (82).…”

A structural study of TatD from Staphylococcus aureus elucidates a putative DNA-binding mode of a Mg2+-dependent nuclease

“…TatD is a protein that is widely presented and conserved in various species, both prokaryotes and eukaryotes (Wang et al, 2018), and it is also involved in the DNA-repair system, in apoptotic cell death and in cleaving neutrophil extracellular traps (Chang et al, 2016;Chen, Shen et al, 2014;Gannavaram & Debrabant, 2012;Qiu et al, 2005). A variety of genes encoding TatD-like proteins, including a single conserved TatD domain consisting of approximately 250 amino acids, have been reported (Chen, Li et al, 2014).…”

“…A variety of genes encoding TatD-like proteins, including a single conserved TatD domain consisting of approximately 250 amino acids, have been reported (Chen, Li et al, 2014). However, while these proteins have been widely investigated in Gramnegative bacteria (Chen, Li et al, 2014;Matos et al, 2009;Chang et al, 2016), represented by Escherichia coli, little has been reported regarding the structural and functional properties of TatD-like proteins in Gram-positive bacteria. SAV0491, a putative deoxyribonuclease from the Grampositive bacterium Staphylococcus aureus (Mu50 strain), shares sequence identities of 30% and 34% with the TatD proteins from E. coli and Homo sapiens, respectively.…”