How the Knowledge of Interactions between Meningococcus and the Human Immune System Has Been Used to Prepare Effective Neisseria meningitidis Vaccines

Table 2

An overview of the most important genes and gene products of Neisseria meningitidis involved in immunoescape mechanisms.

N. meningitidis molecule	Immunological role	Reference
aniA	A nitrite reductase: it protects Neisseria from nitrosative stress during both colonization and invasion	[90, 100–102]
App	It is phase-variable	[103]
ausI/MspA	An autotransporter and a serine protease; it is phase-variable	[45, 46]
Biofilm (and molecules involved in the biofilm synthesis, such as autA or hrpA, or optimizing pathogen survival in biofilm, such as the alpha-peptide of IgA1 protease, adhC, estD)	Biofilm protects from macrophages; adhC is involved in S-nitrosoglutathione metabolism and in glutathione-dependent detoxification system; EstD is involved also in Neisseria colonization	[104–108]
Blebs (with OMPs and LPS/LOS) and SOMVs	They protect from neutrophils-mediated killing and NETs; they divert the immune response away from the pathogen	[78]
Capsule and molecules involved in the capsule synthesis such as kpsC, kpsS	It activates TLR2 pathway, it increases serum resistance, and it inhibits the classical pathway of complement	[109–111]
Cas9 and the CRISPR-Cas system	CRISPR-Cas9-mediated repression of bacterial lipoprotein expression facilitates evasion of TLR2 by the pathogen; it is involved in gene expression and regulation	[112, 113]
cbpA	It mediates zinc piracy and protects from nutritional immunity	[93]
Cps	As a gene, it is involved in the capsule biosynthesis; as RNA, it acts as a thermosensor; Cps gene amplification protects the pathogen	[99, 114]
CrgA	It is involved in the regulation of pili and capsule expression; it plays a major role in the infectious cycle of Neisseria	[114–116]
Css	As a gene, it is involved in the capsule biosynthesis; as RNA, it acts as a thermosensor	[99]
ctrA, ctrD	As genes, they are involved in the capsule export; as RNAs, they act as thermosensors; IS1301 in the IGR between sia and ctr operons mediates resistance to Abs	[99, 117, 118]
cycP	It is involved in denitrification metabolism and protects Neisseria from nitrosative stress	[90, 119, 120]
dam	It is involved in phase variation and modulation	[42]
dcaC	It is phase-variable	[40]
dinB	A DNA polymerase IV belonging to the SOS regulon: it is involved in phase variation and modulation	[42]
DNA mismatch repair genes (fpg, mutL, mutS, mutY, recA, recN, uvrD)	They are phase-variables; they protect against oxidative stress	[42, 48, 51, 121]
drg	It is involved in phase variation and modulation	[42]
farA, farB, farR	They remove antimicrobial peptides, proteases, lysozyme, and acids from the bacterial cytosol and protect the pathogen	[122, 123]
fbpA, fbpB	They are involved in phase variation and modulation	[51]
Feta	It is involved in phase variation and modulation	[124–126]
fHbp (formerly known as GNA1870)	It is involved in phase variation and modulation; it protects Neisseria from complement-mediated killing, binding fH	[90, 127]
frpA, frpB, frpC	They are phase-variable; they can act as a molecular decoy	[124, 125, 128]
funZ	It is a site of bacteriophage insertion; it is phase-variable	[49]
fur	It is involved in phase variation and modulation; it tunes the gene expression of virulence genes	[102, 129]
ggt	It regulates pathogen growth	[130]
Ght	It is involved in the capsule biosynthesis and in the resistance mechanisms of the pathogen	[131, 132]
gltT	It favours meningococcal internalization into human endothelial and epithelial cells; it regulates pathogen growth	[133, 134]
H.8	AAEAP motifs are target for generation of blocking Abs	[135–138]
Haemoglobin-linked iron receptors (hpuA, hpuB, hmbR)	They are involved in phase variation and modulation	[43, 139–141]
Hfq	A RNA chaperone: it is involved in stress response and virulence and is a pleiotropic regulator of protein expression	[142]
hsdS	It is phase-variable	[49]
IgA protease	It cleaves secretory IgA, hinders Ab binding and function, and may play role in biofilm formation; it cleaves lysosomal LAMP1 in epithelial cells; moreover, it is phase-variable	[122, 142, 143]
katA	It confers resistance to RNS, including peroxynitrite (PN), protects against ROS, and detoxifies H2O2	[90, 102, 122, 144]
Laz	A lipid-modified azurin: it protects against hydrogen peroxide and copper toxicity; it promotes Neisseria growth and survival	[135, 138, 145]
lbpA, lbpB	They are involved in iron acquisition and metabolism; they are phase-variable; moreover, the release of LbpB enables Neisseria to escape from complement-mediated killing	[90, 122, 146]
lctP	Its inactivation results in C3-mediated cell lysis	[102, 147, 148]
lgtA, lgtB, lgtC, lgtD, lgtE, lgtG	They are involved in LOS biosynthesis and are phase-variable; for example, lgtA or lgtC phase variation mediates LPS immunotype switch from L3 to L8/L1	[60]
LOS/LPS	It protects from macrophages; strains of the same species produce different LOS glycoforms	[122]
lptA	It adds a phosphoethanolamine group to lipid A and confers resistance to defensins and cathelicidins	[90, 149]
Lst	LOS sialylation (by the enzyme Lst) prevents complement deposition and phagocytosis by neutrophils	[122, 150]
mesJ	It is phase-variable	[49]
Msf	It binds to vitronectin; it increases serum resistance	[151]
Mip	It tunes gene expression	[102, 152, 153]
misR, misS	They are phase-variable; they are involved in capsule regulation and modification	[114, 154]
mltA (formerly known as GNA33)	It tunes gene expression	[155]
mntA, mntB, mntC	They protect against oxidative stress	[122, 156]
modA, modB	They are phase-variable	[34]
msrA, msrB	They are involved in the methionine sulfoxide reduction and they repair oxidized proteins	[122, 157]
mtrC, mtrD, mtrE	They protect against cationic antimicrobial peptides and toxic hydrophobic molecules	[122, 158, 159]
nadA and its regulator nadR	It binds to Hsp90, recruits ARF6 and Rab11, and activates human monocytes and macrophages, triggering IFN-gamma and R-848 dependent pathways; it interacts with beta1 integrins; it is phase-variable	[39, 160–165]
nalP	An autotransporter protease: it cleaves C3, facilitates degradation of C3b, and enhances Neisserial survival in human serum; it stabilizes the biofilm; moreover, it is involved in the processing of other proteases, such as the proteases which release LbpB, whose release enables Neisseria to escape from complement-mediated killing; NalP processes also App and IgA1 protease; it has an important role in the virulence of the pathogen	[24, 102, 166]
Nhba (formerly known as GNA2132)	It tunes gene expression	[167]
nhhA	It activates TLR4-dependent and independent pathways; it triggers apoptosis in macrophages; it increases serum resistance and protects from phagocytosis and complement attack; it is essential for colonization	[168, 169]
nifS	It is phase-variable	[49]
nirK	It protects Neisseria from nitrosative stress during colonization and invasion	[170, 171]
norB	It favours the pathogen growth, enabling utilization and consumption of NO during microaerobic respiration, enhances pathogen survival, protects Neisseria from nitrosative stress during colonization and invasion, decreases and downregulates the production of NO-regulated cytokines, such as TNF-alpha, IL-12, IL-10, CCL5 (RANTES), and CXCL8 (IL-8), and prevents host cell S-nitrosothiol formation	[100, 119, 120, 170, 172]
nspA	It binds to factor H and inhibits AP	[122, 173–175]
nsrR	It is involved in denitrification metabolism and protects Neisseria against nitrosative stress	[176, 177]
oatW, oatY	They tune gene expression	[178]
Opa	It interacts with CEACAM, promoting endothelial cell attachment and upregulating endoglin (CD105) and cooperation with β1 integrins; it elicits innate host defences and actively suppresses adaptive immune responses that would eliminate the pathogen	[179–184]
Opc	It binds to vitronectin, it inhibits AP, and it increases serum resistance; it elicits innate host defences and actively suppresses adaptive immune responses that would eliminate the pathogen	[179–182, 184]
oxyR	It regulates catalase expression and is involved in the protection from oxidative stress	[185, 186]
P36	It is involved in Neisserial adhesion.	[187]
pacA, pacB	They are involved in the composition and regulation of peptidoglycan membrane	[188]
pglA, pglB, pglG, pglH	They are phase-variable	[60–62]
Pili	They alter the expression levels of human genes known to regulate apoptosis, cell proliferation, inflammatory response, adhesion, and genes for signaling pathway proteins such as TGF-beta/Smad, Wnt/beta-catenin, and Notch/Jagged	[189]
pilC1	It interacts with mucosal surface and mediates the crossing of the BBB	[41, 169]
PilE, pilS	They are involved in nonreciprocal recombination-based antigenic variation	[76]
PilE, pilV	They bind to CD147 for vascular colonization; they mediate also Neisseria internalization	[190, 191]
pilP, pilQ	They are involved in pilus biogenesis and outer membrane stabilization	[51, 192]
porA	It binds to fH, C3b, C4b, and C4bp (more strongly under hypotonic conditions); it increases serum resistance; it is involved in phase variation	[122, 139, 173]
porB	It inhibits factor H-dependent AP; it interacts with TLR1 and TLR2 and activates IκB, MAPK/MAPKK, and PTK pathways, leading to CD86 upregulation, to IL-6, IL-12, and TNF secretion in B cells and DCs, and to IgB secretion in B cells	[122, 173]
pptA	It is phase-variable	[47]
Ppx	It is an exopolyphosphatase whose mutation protects Neisseria from complement-mediated killing; it interacts with the AP of the complement activation	[64]
rmpM	It is involved in phase variation and modulation	[193, 194]
Sialic acid synthase (neuB, siaA, siaB, siaC, synC)	They are phase-variable	[102]
sodB, sodC	They protect from phagocytosis by human monocytes/macrophages	[102]
tbpA, tbpB (also known as tbp1, tbp2)	They are involved in nutritional immunity	[121]
TdfF	It is involved in intracellular iron acquisition and is found only in genomes of pathogen strains	[28]
Temperature sensors (such as RNA thermosensors located in the 5′ UTRs of genes necessary for capsule biosynthesis, the expression of fHbp, and sialylation of LOS/LPS)	Activated by coinfecting pathogens, they recruit mechanisms of resistance and immunity escape	[99]
tonB	It is involved in nutritional immunity, supplying energy to the pathogen	[93]
Uncharacterized proteins (NGO1686, NMB0741, NMB1436, NMB1437, NMB1438, and NMB1828)	They protect from nonoxidative factors, but their mechanisms are still not understood; NMB1436, NMB1437, and NMB1438 are putatively involved in iron metabolism	[122, 195]
Uncharacterized factor (NMA1233)	It is involved in phase variation and modulation	[26, 51]
xseB	It is involved in phase variation	[26]
znuD	It protects from neutrophils and nutritional immunity	[92]

Ab: antibody; AP: Alternative Pathway; ARF6: ADP-ribosylation factor 6; App: adhesion and penetration protein; BBB: blood-brain barrier; cbp: calprotectin binding protein; CEACAMs: carcinoembryonic antigen-related cell adhesion molecules; CRISPR: clustered regularly interspaced short palindromic repeats; ctr: capsule transport apparatus; dam: DNA adenine methyltransferase; drg: dam replacing gene; fur: ferric uptake regulator; ggt: gamma-glutamyl aminopeptidase; hsp: heat-shock protein; IgA: immunoglobulin A; lbp: lactoferrin binding protein; lct: lactate permease; LOS: lipooligosaccharide; Mip: macrophage infectivity potentiator; mltA: membrane-bound lytic transglycosylase A; IGR: intergenic region; Msf: meningococcal surface fibril; Msr: methionine sulfoxide reductase; NadA: Neisseria adhesion A; NhhA: Neisseria hia homologue A; oat: O-acetyltransferase; OMV: outer membrane vesicle; opa: opacity-associated protein a; opc: opacity-associated protein c; pac: peptidoglycan O-acyltransferase; pil: pilin; por: porin; RNA: ribonucleic acid; RNS: reactive nitrogen species; Sod: superoxide dismutase; SOMVs: spontaneously released OMVs; Tbp: transferrin-binding protein; TLR: toll-like receptor; UTRs: untranslated regions; uvr: ultraviolet resistant.