Fig 9. Model for modulation of phage infection by multiple susceptibility factors in A. baumannii.

Vulnerability factors that act to enhance Loki infection are shown in blue; defense factors that antagonize Loki infection are shown in red. Additional candidate defense factors, including the methyltransferase AamA or transcription factor DksA, were identified through screening but require confirmation and are not shown. (A) Loki infection of WT bacteria. Loki adsorbs in two steps: (1) interaction with the primary adsorption receptor, capsular polysaccharide of type K3, and (2) interaction with an LOS-associated secondary site. This site may be the conserved LOS inner core, or LOS-proximal capsule residues, and access is antagonized by the LOS outer core. BfmRS controls Loki infection by positively regulating both the capsule receptor (via transcriptional activation of capsule biosynthesis) and intracellular phage replication (by unknown mechanisms). Lon protease provides defense by negatively regulating intracellular phage replication, by unknown mechanisms. (B) Loki resistance arises from capsule receptor down-regulation (BfmRS deficiency), structural alteration (via mutation of hotspot gene gtr6), or complete loss (mutation of a core biosynthesis gene, e.g. itrA or wzx), blocking phage adsorption. BfmRS deficiency may also reduce phage intracellular replication. (C) By contrast, Loki hypersusceptibility arises from hyperactivity of vulnerability factors or loss of defense factors. Hyperactivation of BfmRS, defined by increased BfmR∼P (yellow halo), results from bfmS, dsbA, or rnaA mutations and may also be triggered by external stresses related to oxidative protein folding. BfmRS hyperactivity increases capsule receptor levels, enhancing phage adsorption, while also stimulating phage intracellular multiplication. Loss of LOS OC sugars increases binding of Loki to surface sites without altering its intracellular multiplication. Loss of Lon increases phage multiplication without increasing adsorption.