Polyphosphate and associated enzymes as global regulators of stress response and virulence in Campylobacter jejuni

Table 1 Comprehensive summary of Campylobacter infections in humans

Type	Clinical form/presentation	Risk factors	Target site	Symptoms	Species associated
(A) Intestinal	Periodontal diseases	Oral bleeding, increased vascular permeability[70], and pregnancy[71]?	Oral cavity	Bleeding, tenderness, and tooth loss	C. rectus[70], C. gracilis, C. showae[72] and C. concisus[73]
	Esophageal diseases	Mucosal damage due to stomach contents regurgitation[1]	Esophagus	Heart burn, regurgitation, bloating, bad breath, nausea, and abdominal pain	C. concisus[74]
	(gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma)
	Self-limited gastroenteritis, most common form	All factors as described in review	Jejunum and ileum	Diarrhea, fever, and abdominal pain	C. jejuni and C. coli[1,75]
	Post-infectious functional gastrointestinal disorder, irritable bowel syndrome, and functional dyspepsia	Infection with C. jejuni and other species[1]		Diarrhea, constipation or both, and abdominal pain	C. jejuni, C. coli and C. consisus[76]
	Inflammatory bowel disease, Crohn’s diseases (CD), and ulcerative colitis (UC)	Gut dysbiosis[77]	CD-any part of intestine UC- colon	Diarrhea, fever and fatigue, abdominal pain, weight loss, and reduced appetite	C. concisus, C. showae, C. hominis, C. rectus, and C. ureolyticus[78]
	Colorectal cancer	Gut dysbiosis[79]	Colon	Diarrhea, constipation, abdominal pain, weight loss, and rectal bleeding	C. showae[80]
	Cholecystitis	Gall stones[1]	Gall bladder	Pain and tenderness in right abdomen, nausea, vomiting, and fever	C. jejuni[81]
(B) Extra-intestinal	Guillain-Barre syndrome	C. jejuni infection[82]	Nervous system	Progressive symmetric weakness in limbs, below or lack of reflex (hyporeflexia)	C. jejuni[1,82]
	Miller Fisher syndrome	C. jejuni[83]	Nervous system	Oculo-motor weakness	C. jejuni[83]
	Reactive arthritis	Infection with enteric bacterial pathogens, including Campylobacter[84]	Joints, eyes, and genitourinary tract	Pain and stiffness of joints, swollen toes, eye inflammation, and urinary problems	C. jejuni and C. coli[1,84]
	Cardiovascular complications	Immuno-compromised condition, and bacteremia[1]	Cardiovascular system	Chest pain leading to arrhythmia, dilated cardiomyopathy, and sudden death due to congestive heart failure	C. jejuni and C. fetus[85,86]
	Meningitis	Immuno-compromised condition[1,87]	Meninges of brain and spinal cord	Headache with nausea or vomiting, seizures, sensitive to light, and loss of appetite	C. jejuni and C. fetus[88,89]
	Abscesses of breast, brain, vertebra, and liver	Secondary bacterial infection	Breast, brain, vertebra, and liver	Varies with target organ	C. rectus[90], C. curvus, C. gracilis and C. showae[91]
	Reproductive complication	Bowel infection, and periodontal disease[92]	Uterus, and placenta	Preterm birth, low birth weight, and intra-uterine growth restriction	C. jejuni, C. coli, C. fetus and C. upsaliensis[92]

Campylobacter infection types, clinical presentations, risk factors, target organ or tissues involved, symptoms and associated Campylobacter species are described.

Table 2 Phenotypes associated with enzymes of poly P and ppGpp metabolism

Phenotype	PPK1	PPK2	PPX1	PPX2	PPX1-PPX2	PhoAcj	SpoT
Poly P metabolism
Poly P synthesis/accumulation	↑	-	-	-	-	↑	↑
Poly P-dependent GTP synthesis	-	↑	NT	NT	NT	NT	NT
Poly P degradation	-	-	↑	↑	↑	NT	NT
Maintenance of ATP:GTP ratio	NT	↑	NT	NT	NT	NT	NT
ppGpp metabolism
ppGpp synthesis	NT	-	↑	-	↑	NT	↑
Stress survival
Stationary phase survival and growth	-	-	-	-	-	-	↑
Survival under low CO2	NT	NT	NT	NT	NT	NT	↑
Osmotic shock survival	↑	↑	↑	↑	↑	↑	NT
Low nutrient stress survival	↑	↑	↑	↑	↑	↑	NT
Aerobic stress survival	-	↑	NT	NT	NT	NT	↑
VBNC formation	↑	↑	NT	NT	NT	NT	NT
Natural transformation	↑	NT	NT	NT	NT	NT	NT
Antimicrobial resistance	↑	↑	NT	NT	NT	↓	R
Virulence-related
Motility	-	-	↑	↑	↑	NT	NT
Biofilm formation	↓	↓	↑	↑	↑	↓	NT
Resistance to complement-mediated killing	NT	NT	↑	↑	↑	NT	NT
Adherence	NT	-	NT	NT	NT	NT	↑
Invasion	-	↑	↑	↑	↑	↑	↑
Intraepithelial survival	↑	↑	↑	↑	↑	↑	↑
Chicken colonization	↑	↑	NT	NT	NT	↑	NT

NT: Not tested; R: Tested only for Rifampicin resistance; -: Phenotype absent; ↑: Phenotype is positively regulated i.e., deletion of the gene reduces the phenotype when compared to wildtype; ↓: Phenotype is negatively regulated i.e., deletion of the gene enhances the phenotype when compared to wildtype.

Table 3 Summary of chicken colonization phenotypes of ppk1 and ppk2 mutants

Study	Organ/feces	Inoculation dose (CFU/chick)	Wildtype (CFU/g)	ppk1 mutant (No. of chicks colonized)	ppk2 mutant (No. of chicks colonized)
Candon et al[24] 2007	Ceca	1.5 × 105	1.8 × 108	0/10 chicks	NS
		1.5 × 106	1.8 × 108	8/10 chicks	NS
		1.5 × 107	1.8 × 108	10/10 chicks at an average of 1.8 × 108 CFU/g	NS
Gangaiah et al[25] 2009 and 2010	Ceca	1.0 × 103	1.0 × 106	0/5 chicks	0/5 chicks
		1.0 × 104	1.0 × 108	0/5 chicks	0/5 chicks
		1.0 × 105	8.0 × 108	5/5 chicks at an average of 2.0 × 104 CFU/g	5/5 chicks at an average of 9.0 × 103 CFU/g
	Bursa	1.0 × 103	1.0 × 104	0/5 chicks	0/5 chicks
		1.0 × 104	1.0 × 105	0/5 chicks	0/5 chicks
		1.0 × 105	1.5 × 105	5/5 chicks at an average of 1.0 × 102 CFU/g	5/5 chicks at an average of 8.0 × 102 CFU/g
	Feces	1.0 × 103	1.0 × 105	0/5 chicks	0/5 chicks
		1.0 × 104	1.0 × 107	0/5 chicks	0/5 chicks
		1.0 × 105	3.0 × 107	5/5 chicks at an average of 1.5 × 103 CFU/g	5/5 chicks at an average of 8.0 × 103 CFU/g

NS: Not studied.