From Gene to Protein—How Bacterial Virulence Factors Manipulate Host Gene Expression During Infection

Abstract

Bacteria evolved many strategies to survive and persist within host cells. Secretion of bacterial effectors enables bacteria not only to enter the host cell but also to manipulate host gene expression to circumvent clearance by the host immune response. Some effectors were also shown to evade the nucleus to manipulate epigenetic processes as well as transcription and mRNA procession and are therefore classified as nucleomodulins. Others were shown to interfere downstream with gene expression at the level of mRNA stability, favoring either mRNA stabilization or mRNA degradation, translation or protein stability, including mechanisms of protein activation and degradation. Finally, manipulation of innate immune signaling and nutrient supply creates a replicative niche that enables bacterial intracellular persistence and survival. In this review, we want to highlight the divergent strategies applied by intracellular bacteria to evade host immune responses through subversion of host gene expression via bacterial effectors. Since these virulence proteins mimic host cell enzymes or own novel enzymatic functions, characterizing their properties could help to understand the complex interactions between host and pathogen during infections. Additionally, these insights could propose potential targets for medical therapy.

Bacterial nucleomodulins: A coevolutionary adaptation to the eukaryotic command center

“…tsutsugamushi (previously Rickettsia tsutsugamushi ) [ 64 , 65 ] secretes one of the largest repertoires of ankyrin (Ank) protein paralogs through a type I secretion system (T1SS). Of this repertoire, 2 Ank groups are reported to be involved in modulating host cell ubiquitination pathways in the nucleus [ 3 , 66 – 68 ]. Ank1 (specifically the 1A, 1B, 1E, 1F, 1U4, 1U5, and 1U9 paralogs) and Ank6 are 2 groups of O .…”

“…Ank1 (specifically the 1A, 1B, 1E, 1F, 1U4, 1U5, and 1U9 paralogs) and Ank6 are 2 groups of O . tsutsugamushi Ank proteins found to localize in the nuclei of HeLa cells and primary macrophages [ 3 , 66 – 68 ]. While these potential nucleomodulins are found within host cell nuclei, the mechanisms behind their nuclear translocation have yet to be determined.…”

“…This domain interacts with CULLIN-1 and SKP1 core components of the SKP1-CULLIN1-F-box protein (SCF) E3 ubiquitin ligase complex [ 3 , 62 , 66 , 67 ]. The Ank domain of Ank1 is suggested to bind cell-specific target substrates in the nucleus, while the F-box binds and recruits SKP1 to promote substrate degradation [ 3 , 66 – 68 ]. By interacting with host ubiquitin ligase complexes, the multiple paralogs of Ank1 localizing to the nucleus are suggested to modulate diverse host cell functions during O .…”

Microbial Virulence Factors

“…Various bacterial species have evolved various strategies to invade, survive, and multiply intracellularly in host cells. The paper of Denzer et al presents an updated review of the mechanisms used by bacteria to invade the host cell, to manipulate their biochemical and gene expression machinery, and to multiply and escape from the host cell [13]. The authors present a thorough review of mechanisms used by intracellular pathogens, including the highjack of host immune defenses to enter into the host cell.…”

“…The authors present a thorough review of mechanisms used by intracellular pathogens, including the highjack of host immune defenses to enter into the host cell. Central attention is given to the various mechanism used to manipulate gene expression, including histone modification, control of host DNA methylation patterns, sabotage of host long non-coding RNAs, interfering with the host RNA transcription and translation, as well as with host protein stability [13]. The importance of the detailed molecular knowledge of pathogenesis mechanisms to the development of strategies to combat bacterial infections is highlighted [13].…”