Pathogen to commensal? Longitudinal within-host population dynamics, evolution, and adaptation during a chronic >16-year Burkholderia pseudomallei infection

Abstract

Although acute melioidosis is the most common outcome of Burkholderia pseudomallei infection, we have documented a case, P314, where disease severity lessened with time, and the pathogen evolved towards a commensal relationship with the host. In the current study, we used whole-genome sequencing to monitor this long-term symbiotic relationship to better understand B. pseudomallei persistence in P314's sputum despite intensive initial therapeutic regimens. We collected and sequenced 118 B. pseudomallei isolates from P314's airways over a >16-year period, and also sampled the patient's home environment, recovering six closely related B. pseudomallei isolates from the household water system. Using comparative genomics, we identified 126 SNPs in the core genome of the 124 isolates or 162 SNPs/indels when the accessory genome was included. The core SNPs were used to construct a phylogenetic tree, which demonstrated a close relationship between environmental and clinical isolates and detailed within-host evolutionary patterns. The phylogeny had little homoplasy, consistent with a strictly clonal mode of genetic inheritance. Repeated sampling revealed evidence of genetic diversification, but frequent extinctions left only one successful lineage through the first four years and two lineages after that. Overall,

An Evolutionary Arms Race Between Burkholderia pseudomallei and Host Immune System: What Do We Know?

“…Small-scale genetic variations in B. pseudomallei can be introduced by point mutation which substitutes one nucleotide with another or microindel (an insertion or deletion) that impact 1–50 bp. B. pseudomallei substitution rate was reported to be 1.7–4.9 × 10 –7 substitutions per site per year ( Viberg et al, 2017 ; Pearson et al, 2020 ), which is comparable to those detected in other Burkholderia genera ( Lieberman et al, 2014 ). The rates of indels have not been quantified in B. pseudomallei .…”

“…The mutation in both genes may confer to the reduction in LPS modification and production, assisting in the escape from the host immune response. In addition, a partial deletion of D512_20407, wbiA homolog is also identified in MSHR6686 ( Price et al, 2013 ; Pearson et al, 2020 ). However, genomic analysis of the rough serotype that is naturally found in the environment or initial infection has not been done to determine the genetic makeup of this serotype.…”

“…On the other hand, a single nucleotide insertion of the wbiI gene is observed in the LPS biosynthesis gene cluster of a rough serotype in a patient with more than 16-year chronic lung infection associated with melioidosis. This frame-shift mutation of wbiI gene (an essential gene for the O-antigen synthesis) disrupts the epimerase/dehydratase function of this gene and results in the loss of O-antigen moiety, possibly switching the serotype of B. pseudomallei isolates from type A to type R ( Price et al, 2013 ; Pearson et al, 2020 ). Pearson and colleagues also revealed the nucleotide insertion of D512_15771 (wbiH) and D512_06755 gene are observed in B. pseudomallei MSHR6686 of the same patient.…”

“…With rare exceptions ( Abbink et al, 2001 ; Ralph et al, 2004 ; Aziz et al, 2020 ), B. pseudomallei is not known to transmit from person to person; indicating that B. pseudomallei has not evolved virulence mechanisms through consecutive passage in human hosts. Moreover, B. pseudomallei within-host evolution observed in chronic infections are often linked to attenuated virulence ( Price et al, 2013 ; Viberg et al, 2017 ; Pearson et al, 2020 ), which is possibly mediated by host immune evasion. While environment exposure can lead to melioidosis, most patients are elderly or have one or more underlying health risks.…”

Genomic loss in environmental and isogenic morphotype isolates of Burkholderia pseudomallei is associated with intracellular survival and plaque-forming efficiency

“…We mapped the deletion regions of strains K96243 type II and A4 in our study to B . pseudomallei MSHR1435 genome as the reference, and found the deletions located in region 6 associated with T3SS and T6SS in their study [ 57 ]. Furthermore, a large chromosomal deletion has also been discovered in an environmental isolate, B .…”