Table 2.

General microbial virulence factors arsenal detected in A. baumannii.

Structures		Virulence Genes	Gene Position	Virulence Factors	Roles	References
Capsule (CPS)		>100 unique capsule loci (KL) with different sizes in length (between 20 and 35 kilobases (kb))	Between the fkpA and lldP genes on the chromosome	Capsular biosynthesis and export	Bacterial pathogenicity, Virulence, Antimicrobial resistance, Persistence, Evasion of host immune system (antiphagocytosis), reduction of interactions between human host and pathogen	[3,64,68,71,74,157]
Efflux pumps	ATP binding cassette (ABC) transporter	A1S-0536	Chromosome	A1S-0536	Resistance to erythromycin	[3,68,79,80]
		A1S-1535		A1S-1535	Resistance to chloramphenicol and gentamicin
		abuO		AbuO	Response to oxidative stress
		macAB-tolC		MacAB-TolC	Potentially resistance to macrolides and tigecycline
	Multidrug and toxic compound extrusion (MATE)	abeM		AbeM	Resistance to fluoroquinolones and disinfectants	[3,6,68,79,80]
	Major facilitator superfamily (MFS)	abaF	Chromosomal genomic islands	AbaF	Resistance to fosfomycin	[3,68,79,80,158]
		abaQ		AbaQ	Resistance to quinolones
		amvA		AmvA	Resistance to erythromycin
		cmlA		CmlA	Resistance to chloramphenicol
		craA		CraA	Resistance to chloramphenicol
		emrAB		EmrAB	Resistance to colistin and adaptation to osmotic stress
		tetA	Plasmids and MGEs	TetA	Resistance to tetracycline and tigecycline
		tetB		TetB	Resistance to minocycline and tetracycline
	Resistance nodulation division (RND)	abeD	Chromosome	AbeD	Resistance to benzalkonium chloride, ceftriaxone, gentamicin, rifampin, tobramycin, killing the host cells	[3,6,65,74,75,76,77]
		acrAB		AcrAB	Resistance to disinfectants, colistin and tobramycin
		adeABC		AdeABC	Resistance to aminoglycosides, chloramphenicol, fluoroquinolones, pentamide, tetracyclines, trimethoprim and osmotic stress
		adeDE		AdeDE	Resistance to chloramphenicol, erythromycin, tetracycline, amikacin, meropenem, ceftazidime, rifampin and ciprofloxacin
		adeFGH		AdeFGH	Resistance to clindamycin, chloramphenicol, fluoroquinolones, tetracycline-tigecycline and trimethoprim, biofilm formation
		adeIJK		AdeIJK	Resistance to erythromycin, β-lactam antibiotics, trimethoprim, tetracycline, fusidic acid, chloramphenicol, novobiocin, lincosamides and rifampin
		adeL		AdeL	Resistance to fluoroquinolones and tetracycline
		adeN		AdeN	Resistance to macrolides, tetracycline, cephalosporins, carbapenem, penems, fluoroquinolones and rifamycin
		adeXYZ		AdeXYZ	Similar to AdeIJK in phenotypic, structural and genetic characteristics (homologs)
		arpAB		ArpAB	Resistance to tobramycin and amikacin
		czcABCD		CzcABCD	Resistance to heavy metals, e.g., copper
	Proteobacterial antimicrobial compound efflux (PACE)	A1S-1503	Chromosome	A1S-1503	Resistance to disinfectants	[3,68,79,80]
		aceI		AceI	Resistance to disinfectants
	Small multidrug resistance (SMR)	abeS	Chromosome	AbeS	Resistance to novobiocin, erythromycin, chloramphenicol, fluoroquinolones and disinfectants	[3,68,79,80]
		qacE		QacE	Resistance to disinfectants
Lipopolysaccharide (LPS)		lpxACD operon; lpxB	Chromosome, plasmids	lipidA biosynthesis, LPS biosynthesis	Bacterial surface-associated motility, Microbe associated molecular pattern (MAMP), Immune system activation through triggering the expression of versatile pro-inflammatory cytokines, e.g., toll-like receptor 4 (TLR4), interleukin 8 (IL-8), Tumor necrosis factor-α (TNF-α) and CCL4, Bacterial susceptibility against colistin	[62,87,94,98,159,160]
Lipooligosaccharide (LOS)		Outer core (OC) loci (OCL)	Between ilvE and aspS genes on the chromosome	lipid-carbohydrate surface structure	Antimicrobial peptides resistance, Bacterial adhesion, Bacterial resistance against human host opsonophagocytotic activities, bacterial cell motility, Induction of expression of several pro-inflammatory cytokines	[3,96]
Outer membrane proteins (OMPs)		carO	Chromosome, plasmids	CarO	Resistance to Carbapenems, uptake of glycine, imipenem, and ornithine, contribution to bacterial adhesion, invasion and dissemination	[3,68,77,119,125,161]
		occAB1–AB5		OccAB1–AB5	Substrates translocation, metal ions acquisition, e.g., iron (Fe2+) and magnesium (Mg2+), antibiotics (β-lactams) and amino acids uptake, participation in nutritional immunity and stress survival caused by the host (host–pathogen interactions)
		omp33–36		Omp33–36	Resistance to carbapenems, activation of caspase enzymes of 3 and 9 and apoptosis within the host cells, cytotoxicity, bacterial adhesion and invasion into the host’s epithelial cells
		ompA		OmpA	Resistance to β-lactams and colistin, iron siderophores (e.g., acenitobactin) acquisition, cytotoxicity, bacterial adhesion through fibronectin (irreversible attachment), invasion and persistence, induction of reactive oxygen species (ROS) and apoptosis within the host cells, it has been recognized in up to 81% of isolated strains of A. baumannii
		ompW		OmpW	Bacterial adhesion and invasion into pulmonary epithelial cell lines, cytotoxicity, iron acquisition
Pili	Chaperon-usher type I pili	csuA/BABCDE	Plasmid/chromosome	Formation of chaperone-usher Csu fimbriae; CsuA/B (Shaft of the pili (Major subunit)), CsuA (Minor subunit), CsuB (Minor subunit), CsuC (Chaperon), CsuD (Usher), CsuE (Adhesin tip)	Biofilm formation on abiotic surfaces, irreversible attachment; recognized in up to 100% of the isolated strains belonging to A. baumannii	[68,77,162,163]
	Type IV pili	pilApgyA, pilBCD, pilTU	Plasmid/chromosome	Formation of type IV pili; PilA (Major subunit), PgyA (O-glycosylase), PilB (putative traffic ATPase), PilC (putative inner membrane platform protein), PilD (putative prepilin peptidase), PilT (putative retraction ATPase), PilU (putative retraction ATPase)	Biofilm formation, host-cell adhesion, twitching motility, HGT, microcolony formation	[77,139,164]
	Curli fiber	csgBAC csgDEFG		Amyloid protein (composed of major subunits of csgA)	Adherence, matrix formation, biofilm maturation; recognized in up to 70% of the isolated strains belonging to A. baumannii	[77,165]
	Type I fimbriae	fimBEAICDFGH	Chromosome	FimH (adhesin)	Bacterial cell adhesion (irreversible attachment), recognized in up to 50% of the isolated strains belonging to A. baumannii	[77,165]
	P fimbriae	papIBAHCDJKEFG	PAIs/chromosome	PapG (adhesin)	Biofilm formation (homologous to Escherichia coli); recognized in up to 80% of the isolated strains belonging to A. baumannii	[77,165]
Metal ion uptake systems	Phospholipase	plc1, plc2	Plasmid/chromosome	Phospholipase C	Red blood cell lytic and hemoglobin releasing enzyme, iron uptake and lipolytic activity	[3,68]
		pld1, pld2, pld3		Phospholipase D	iron uptake and lipolytic activity	[3]
	Acinetobactin (including three gene clusters of A1S-2392-A1S_2372)	basAB, basCD, basFG, basHIJ	Plasmid/chromosome	BasA–J	Biosynthesis of acinetobactin for iron uptake, persistence of the infection within the epithelial cell and apoptosis	[3,68,147,148,153,166]
		barA, barB		BarAB	Members of siderophore efflux system of the ABC superfamily, which secrete the produced acinetobactin via bas gene clusters
		bauABECD, bauF		BauA–F	Receptor for complexes of ferric-acinetobactin to translocate these complexes into the bacterial cell of A. baumannii, persistence of the infection within the epithelial cell and apoptosis
	Baumanoferrin (including one gene cluster of A1S_1647-A1S-2372)	bfnABCDEFGHIJKL		BfnA–L	Biosynthesis, translocation and the uptake of iron
	Fimsbactins (including two gene clusters of A1S-2582-A1S_2562)	fbsABCDEFGHIJKLMNOPQ		FbsA–Q	Biosynthesis, translocation and the uptake of iron
	mum operon	mumRTLUHC		MumR–C	MumR contributes to oxidative stress resistance and regulating of Mn homeostasis; MumT participates in Mn chelating, it also acts as Mn and urea transporter
	Fur	fur		Fur	Transcriptional regulator of iron metabolism
	Zinc uptake system	zigA		ZigA	Zinc homeostasis,
		znuBC, znuA, znuD, znuD2		ZnuB (inner membrane channel), ZnuC (ATPase), ZnuA (periplasmic binding protein), ZnuD (outer membrane channel), ZnuD2 (outer membrane channel)	Zinc acquisition, homologous to ZnuABC system in E. coli, pathogenesis
		zur		Zur	Transcriptional regulator of zinc metabolism
Two-component systems (TCSs)	A1S_2811	A1S_2811	Plasmid/chromosome	A1S_2811	Hybrid sensor kinase, involved in motility (via flagella or pili), contribution to biofilm formation, regulation of quorum sensing	[155]
	AdeRS	adeRS		AdeR, AdeS	Involved in antibiotic susceptibility in A. baumannii, contribution to controlling the expression of ~600 genes (involved in, e.g., biofilm formation, multidrug-efflux activity (such as AdeABC) and virulence), directly or indirectly.	[76,155]
	BaeSR	baeSR		BaeS, BaeR	There is a homology between this TCS in A. baumannii and E. coli, triggered by sucrose, regulation of overlapping regulons relating to other present TCSs in A. baumannii, BaeSR may occur cross-talk with the other members of TCSs; it regulates the expression of AdeABC, ADEIJK, MacAB-TolC drug efflux pumps, Susceptible to tannic acid, contributes to bacterial antibiotic resistance	[76,155]
	BfmRS	bfmRS		BfmR, BfmS	This TCS (recognized in up to 92% of isolated strains of A. baumannii) is a type of sensor kinase that regulates the expression of csu operon (pili) in A. baumannii, contribution to biofilm formation (irreversible attachment), regulation on capsule production through controlling the exopolysaccharide biosynthesis (expression of K locus), regulation of bacterial TCSs and virulence in A. baumannii, BfmS phosphorylates the BfmR	[76,77,155]
	GacSA	gacSA	Transposon/chromosome	GacS, GacA	Regulation of ~680 genes in association with motility, pili formation, biofilm formation, bacterial resistance towards human serum, immune evasion, catabolism of aromatic compounds (paa operon, which has homology to E. coli), bacterial pathogenesis	[76,155]
	PmrAB	pmrAB	Plasmid/chromosome	PmrA, PmrB	Lipid A modification, contribution to colistin and polymyxin B resistance (via gene mutations)	[155]
Secretion system	T1SS	tolC-hlyB-hlyD gene cluster (homologous to E. coli)	Chromosome	TolC (a trimeric outer membrane protein interacting with HlyD), HlyB (an ATP-binding cassette transporter that provides the required energy), HylD (a periplasmic adaptor)	T1SS has cross-talk with T2SS and T6SS, Contribution to virulence, secretion of putative effectors, e.g., RTX-serralysin-like toxin and Bap and other effectors such as glycosidases, proteases, phosphatases and invasins which are involved in bacterial attachment, invasion, biofilm formation and pathogenesis	[68,86,167]
	T2SS	gspC-M, pilD	gsp genes dispersed into five clusters within the bacterial genome	GspC (a subunit of the inner membrane (IM) platform), GspD (an outer membrane (OM) complex), GspE (cytoplasmic ATPase), GspF (a subunit of the inner membrane (IM) platform), GspG-K (subunits of the periplasmic pseudopilus (GspG is known as major pseudopilin, while the others are recognized as minor pseudopilins)), GspL (a subunit of the inner membrane (IM) platform), GspM (a subunit of the inner membrane (IM) platform), PilD contributes to processes of cleavage and methylation	Secretion of enzymes and toxins such as CpaA protease, intimin-invasin lipoprotein of InvL and lipases of LipA, LipAN and LipH, pathogenesis, antibiotic resistance (e.g., resistance against ciprofloxacin)
	T4SS (type F)	traA-I, traK-N, traU-W, trbC, finO	Plasmid	TraA (constitutes the extracellular section of the pilus), TraB (constitutes the IM platform of the T4SS), TraC (the cytoplasmic subunit of the T4SS), TraD (the cytoplasmic subunit of the T4SS), TraE, TraF (constitutes the IM platform of the T4SS), TraG (constitutes the IM platform of the T4SS), TraH (constitutes the OM core complex of the T4SS), TraI (contributes to nick), TraK (constitutes the OM core complex of the T4SS), TraL, TraM (participates in translocation initiation), TraN (constitutes the OM core complex of the T4SS), TraU (constitutes the IM platform of the T4SS), TraV (constitutes the OM core complex of the T4SS), TraW (constitutes the IM platform of the T4SS), TrbC (constitutes the IM platform of the T4SS), FinO (regulator)	T4SS is involved in DNA exchanges, e.g., HGT features such as transformation, conjugation which may lead to translocation of virulence genes, drug-resistance genes among bacterial cells, contribution to bacterial pathogenesis, colonization and proliferation within the eukaryotic host cells	[3,68,86]
	T5bSS	cdiA, cdiB, abfhaB, abfhaC	Chromosome	CdiA (toxin), CdiB (OM transporter)	Lethal proteins	[3,68,86]
				AbFhaB, AbFhaC	Adhesion (via fibronectin) to host cell, virulence, bacterial survival, biofilm formation
	T5cSS The most popular T5SS in A. baumannii	ata	Chromosome	Ata	Autotransporter, biofilm formation, attachment to laminin and different types of collagens including I, III, IV and V, bacterial survival, bacterial invasion to host cells, induction of apoptosis (programmed cell death) process within the host cells	[3,68,86,112]
	T6SS	asaA-tssBC-hcp(tssD)-tssEFG-asaB-tssM-tagFN-asaC-tssHAKL-asaDE vgrG-paar	Plasmid/chromosome	TssA–M forms the core, and TagD–L constructs the accessory proteins of the T6SS structure TssL–M and TssJ form the membrane complex of the T6SS within the periplasmic space; TssE–G, TssK, VgrG and PAAR construct the cytoplasmic baseplate; TssA–C and Hcp (TssD) form the tail tube or sheath complex of the bacterial T6SS in A. baumannii	Bacterial virulence factor, pathogenicity factor in eukaryotic host cells, bacterial invasion and adhesion, antibiotic resistance	[86,168,169]