|
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] |
|