Taxonomy-aware, sequence similarity ranking reliably predicts phage–host relationships

BACKGROUND: Characterizing phage–host interactions is critical to understanding the ecological role of both partners and effective isolation of phage therapeuticals. Unfortunately, experimental methods for studying these interactions are markedly slow, low-throughput, and unsuitable for phages or hosts difficult to maintain in laboratory conditions. Therefore, a number of in silico methods emerged to predict prokaryotic hosts based on viral sequences. One of the leading approaches is the application of the BLAST tool that searches for local similarities between viral and microbial genomes. However, this prediction method has three major limitations: (i) top-scoring sequences do not always point to the actual host; (ii) mosaic virus genomes may match to many, typically related, bacteria; and (iii) viral and host sequences may diverge beyond the point where their relationship can be detected by a BLAST alignment. RESULTS: We created an extension to BLAST, named Phirbo, that improves host prediction quality beyond what is obtainable from standard BLAST searches. The tool harnesses information concerning sequence similarity and bacteria relatedness to predict phage–host interactions. Phirbo was evaluated on three benchmark sets of known virus–host pairs, and it improved precision and recall by 11–40 percentage points over currently available, state-of-the-art, alignment-based, alignment-free, and machine-learning host prediction tools. Moreover, the discriminatory power of Phirbo for the recognition of virus–host relationships surpassed the results of other tools by at least 10 percentage points (area under the curve = 0.95), yielding a mean host prediction accuracy of 57% and 68% at the genus and family levels, respectively, and drops by 12 percentage points when using only a fraction of viral genome sequences (3 kb). Finally, we provide insights into a repertoire of protein and ncRNA genes that are shared between phages and hosts and may be prone to horizontal transfer during infection. CONCLUSIONS: Our results suggest that Phirbo is a simple and effective tool for predicting phage–host relationships. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01146-6.