Long-term persistence of crAss-like phage crAss001 is associated with phase variation in Bacteroides intestinalis

Abstract

Background The crAss-like phages are ubiquitous and highly abundant members of the human gut virome that infect commensal bacteria of the order Bacteroidales. Although incapable of lysogeny, these viruses demonstrate long-term persistence in the human gut microbiome, dominating the virome in some individuals. Results Here we show that rapid phase variation of alternate capsular polysaccharides in Bacteroides intestinalis cultures plays an important role in a dynamic equilibrium between phage sensitivity and resistance, allowing phage and bacteria to multiply in parallel. The data also suggests the role of a concomitant phage persistence mechanism associated with delayed lysis of infected cells, similar to carrier state infection. From an ecological and evolutionary standpoint, this type of phage-host interaction is consistent with the Piggyback-the-Winner model, which suggests a preference towards lysogenic or other “benign” forms of phage infection when the host is stably present at high abundance. Conclusion Long-term persistence of bacteriophage and host could result from mutually beneficial mechanisms driving bacterial strain-level diversity and phage survival in complex environments.

Discovery, diversity, and functional associations of crAss-like phages in human gut metagenomes from four Dutch cohorts

“…Despite the 4-year period separating the two time points, we observed a degree of stability both at the level of individual genus-level clusters (the numbers of individuals positive for frequently detected genus-level clusters at both time points were considerably higher than what would be expected if the crAss-like phage composition at the two time points was completely independent) and at the level of the overall composition of the crAss-like fraction of the virome (on average, dissimilarity between samples collected from the same individual at the two time points was lower than the dissimilarity between pairs of samples collected from different individuals at the same time point). These observations are in line with previous reports of temporal stability of crAss-like phages (Edwards et al, 2019;Shkoporov et al, 2019;Siranosian et al, 2020), which may be explained by a relatively peaceful co-existence of phage and host (Guerin et al, 2021;Shkoporov et al, 2018Shkoporov et al, , 2021.…”

“…In this study, both CRISPR-based and co-abundance analyses strongly pointed to Prevotella copri as a host of the crAss-like phages belonging to the genus-level cluster delta27. The fact that the correlation between the relative abundance of the delta27 phages and their potential host is positive suggests that the dynamics in this phage-host pair may be similar to the co-existence in equilibrium reported for several crAss-like phages isolated in cultures of their hosts (Guerin et al, 2021;Hryckowian et al, 2020;Shkoporov et al, 2018Shkoporov et al, , 2021.…”

“…There are three major functional regions that can be distinguished in the crAss-like phage genome: a replication gene module, a transcription gene module, and a capsid gene module Yutin et al, 2018). Transcription of the three modules is initiated early (by a virion-packaged RNA polymerase [RNAP]), in the middle of, and late in the infection, respectively (Drobysheva et al, 2021;Holmfeldt et al, 2013;Shkoporov et al, 2018Shkoporov et al, , 2021. The genomes of various crAss-like phages bear unique features, including reassignment of the stop codons TAG and TGA for amino acids and a high density of introns and inteins (Yutin et al, 2021).…”

“…Numerous crAss-like phages have been predicted to infect bacteria of the phylum Bacteroidetes (Dutilh et al, 2014;Yutin et al, 2021), and accordingly, several crAss-like phages have been isolated in cultures of Bacteroidetes hosts (Guerin et al, 2021;Hryckowian et al, 2020;Shkoporov et al, 2018), enriched in the presence of Bacteroidetes hosts (Fitzgerald et al, 2021), or linked to Bacteroidetes hosts using a chromosome conformation capture approach (Marbouty et al, 2021), although there is also evidence that some crAss-like phages may infect hosts from different phyla (Yutin et al, 2021). Apparently, crAss-like phages may coexist with their hosts relatively peacefully, because the same crAss-like phages were often recurrently detected in metagenomic samples of longitudinal study participants (Edwards et al, 2019;Shkoporov et al, 2019;Siranosian et al, 2020), and four crAss-like phages were shown to persist in the cultures of their hosts for a long time without a significant reduction in the host population (Guerin et al, 2021;Shkoporov et al, 2018Shkoporov et al, , 2021. Interestingly, hosts were shown to develop resistance to crAss-like phage infection via the phase variation mechanism: inversions in the bacterial genome loci responsible for cell surface coating biosynthesis were linked to altered cell surface architecture and a reduced ability of the bacteria to absorb phage (Shkoporov et al, 2021).…”

“…Apparently, crAss-like phages may coexist with their hosts relatively peacefully, because the same crAss-like phages were often recurrently detected in metagenomic samples of longitudinal study participants (Edwards et al, 2019;Shkoporov et al, 2019;Siranosian et al, 2020), and four crAss-like phages were shown to persist in the cultures of their hosts for a long time without a significant reduction in the host population (Guerin et al, 2021;Shkoporov et al, 2018Shkoporov et al, , 2021. Interestingly, hosts were shown to develop resistance to crAss-like phage infection via the phase variation mechanism: inversions in the bacterial genome loci responsible for cell surface coating biosynthesis were linked to altered cell surface architecture and a reduced ability of the bacteria to absorb phage (Shkoporov et al, 2021). The crAss-like phages are globally distributed in the human population, although the abundance of specific crAss-like phage taxa may vary depending on the geographic location (Camarillo-Guerrero et al, 2021;Edwards et al, 2019;Guerin et al, 2018).…”