Prediction of molecular mimicry candidates in human pathogenic bacteria

Abstract

Molecular mimicry of host proteins is a common strategy adopted by bacterial pathogens to interfere with and exploit host processes. Despite the availability of pathogen genomes, few studies have attempted to predict virulence-associated mimicry relationships directly from genomic sequences. Here, we analyzed the proteomes of 62 pathogenic and 66 non-pathogenic bacterial species, and screened for the top pathogen-specific or pathogen-enriched sequence similarities to human proteins. The screen identified approximately 100 potential mimicry relationships including well-characterized examples among the top-scoring hits (e.g., RalF, internalin, yopH, and others), with about 1/3 of predicted relationships supported by existing literature. Examination of homology to virulence factors, statistically enriched functions, and comparison with literature indicated that the detected mimics target key host structures (e.g., extracellular matrix, ECM) and pathways (e.g., cell adhesion, lipid metabolism, and immune signaling). The top-scoring and most widespread mimicry pattern detected among pathogens consisted of elevated sequence similarities to ECM proteins including collagens and leucine-rich repeat proteins. Unexpectedly, analysis of the pathogen counterparts of these proteins revealed that they have evolved independently in different species of bacterial pathogens from separate repeat amplifications. Thus, our analysis provides evidence for two classes of mimics: complex proteins such as enzymes that have been acquired by eukaryote-to-pathogen horizontal transfer, and simpler repeat proteins that have independently evolved to mimic the host ECM. Ultimately, computational detection of pathogen-specific and pathogen-enriched similarities to host proteins provides insights into potentially novel mimicry-mediated virulence mechanisms of pathogenic bacteria.

Use of Host-like Peptide Motifs in Viral Proteins Is a Prevalent Strategy in Host-Virus Interactions

“…In structured domain mimicry, it is generally assumed that domains that are found in pathogen’s proteins and have high sequence similarity in a large portion of the domain, are likely to have been acquired by HGT, whereas mimics of short structural segments (such as repeats) or mimics with small sequence similarity or lack of structural similarity are likely to have arisen in a convergent manner (Doxey and McConkey, 2013; Elde and Malik, 2009) (Fig 4A). Since ELMs are short and easy to evolve, it was suggested that they belong to the latter category (Davey et al, 2011).…”

Novel function discovery through sequence and structural data mining

“…One example application of motif predictions in function discovery is the identification of hostlike proteins in pathogenic organisms, or so-called 'mimicry' [52][53][54]. This feature of many pathogen proteins has been exploited by computational methods to predict novel virulence factors [52,55]. For example, Doxey and McConkey [52] predicted widespread mimicry of human extracellular matrix proteins across a diverse range of human pathogenic bacteria based on detected similarities between motifs in collagen and leucine-rich repeat proteins.…”

“…Because they are short and have a propensity to arise independently, they can also capture convergent evolution of function in unrelated proteins but are statistically difficult to predict without additional (e.g., structural) information. One example application of motif predictions in function discovery is the identification of hostlike proteins in pathogenic organisms, or so-called 'mimicry' [52][53][54]. This feature of many pathogen proteins has been exploited by computational methods to predict novel virulence factors [52,55].…”

“…This feature of many pathogen proteins has been exploited by computational methods to predict novel virulence factors [52,55]. For example, Doxey and McConkey [52] predicted widespread mimicry of human extracellular matrix proteins across a diverse range of human pathogenic bacteria based on detected similarities between motifs in collagen and leucine-rich repeat proteins. The predicted mimics represent new candidate virulence factors.…”

“…Functional associations may be inferred using a wide variety of techniques including detected protein enrichment in certain species or environments [52,63 ], genotype-phenotype correlations [82,83], networks analysis [84], and analysis of neighbouring gene or domain functions (genomic context or domain context) [85,86]. In addition, databases such as STRING provide predicted interactions based on gene fusions, gene neighbourhoods, coexpression, and gene co-occurrence [87] (Figure 1).…”