Pathogenicity and virulence of Mycobacterium tuberculosis

Figures & data

Figure 1. Overview of Mtb infection. Mtb enters the human body through the airway where it engages the innate immune system within the alveolar space. Macrophages and dendritic cells ingest the bacteria, recruiting new cells and activating adaptive immunity. Together, the innate and adaptive immune systems collaborate to eradicate the bacteria or restrict its active replication within a granuloma. Active tuberculosis occurs either after primary infection or after reactivation due to immunodeficiency, leading to symptomatic disease and transmission to a new host to start a new infection cycle.

Table 1. Non-protein virulence factors of Mtb.

Molecule	Abbreviation	Category	Function	References
Phthiocerol Dimycocerosates	PDIMs	Lipid	Masks PAMPs, induces membrane rupture	[78]
Mycolic acid	MA	Lipid	TLR2 inhibitor, induces MCP-1	[79–81]
1-tuberculosinyladenosine	1-TbAd	Lipid	Lysosomal escape, inhibits acidification	[82–84]
Phenolic glycolipid	PGL	Glycolipid	Inhibits cytokine activity	[85–88]
Sulfolipid-1	SL-1	Glycolipid	Cough induction	[63,89]
Trehalose dimycolic acid	TDM	Glycolipid	Granuloma formation, induces TNF-α, IL-6, MCP-1 cytokines	[90–95]
Trehalose monomycolic acid	TMM	Glycolipid	Induces TNF-α, IL-6, MCP-1, other cytokines	[96–98]
Lipomannan	LM	Glycolipid	TLR2/TLR4 agonist, induces IL-12 production	[99,100]
Mannosylated Lipoarabinomannan	ManLAM	Glycolipid	Phagocytosis & phagosome maturation arrest	[101–104]
Phosphatidyl inositol mannosides	PIMs	Glycolipid	TLR2 & C-type lectin agonist	[105–109]
Diacyl trehalose, pentaacyl trehalose	DAT, PAT	Glycolipid	Inhibits IL-12 production, induces IL-10 & TNF-α, inhibits NO production	[110–113]
Arabinomannan	AM	Glycan	Similar to LAM	[114–118]
Mannan		Glycan	Similar to LM	[114–118]
α-glucan		Glycan	Induces IL-10 production, inhibits CD1 expression, induces phagocytosis	[119–121]
Deoxyribonucleic acid	DNA	Nucleic acid	Induces IFN-β, triggers autophagy	[122–125]
Ribonucleic acid	RNA	Nucleic acid	Induces IFN-β	[126]
Metabolites		Small molecule metabolites	Metabolites impact Mtb pathogenesis	[127–133]

Figure 2. Non-protein virulence factors of Mtb. Schematic of Mtb lipids, glycolipids, glycans, and nucleic acids that contribute to virulence. TDM: trehalose dimycolate, SL-1: sulfolipid-1, PGL: phenolic glycolipid, MA: mycolic acid, PAT: pentaacyl trehalose, PDIM: phthiocerol dimycocerosates, ManLAM: mannosylated lipoarabinomannan.

Figure 3. Protein virulence factors of Mtb. Schematic representation of Mtb interactions within infected macrophages highlighting (i) toll-like receptors, (ii) phagosome arrest and escape, (iii) autophagy subversion, (iv) cell death modulation, and (v) cytokine production. Each box contains representative Mtb virulence factors that engage host cell biologic processes detailed in the text.

Table 2. Protein virulence factors of Mtb.

Group	Protein	Rv number	Category	Function	Refs
Modulation of TLR2 signaling	LpqH	Rv3763	Lipoprotein	TLR2 agonist, induces T cell proliferation	[204,205]
	PE_PGRS33	Rv1818c	PE/PPE family member	Participates in Mtb cell entrance via TLR2, induces TNF-α release, induces apoptosis, induces mitochondrial fusion	[206–208]
	LprG	Rv1411c	Lipoprotein	TLR2 agonist, translocates glycolipids to cell surface, induces mitochondrial fission	[209,210]
	PstS1 phoS1	Rv0934	Lipoprotein	TLR2 and TLR4 agonist	[211]
	CFP 32	Rv0577	Putative glyoxylase	TLR2 agonist	[212–214]
	LpqT	Rv1016c	Lipoprotein	TLR2 agonist, inhibits MHC II	[215–217]
	PE-PGRS61	Rv3653	PE/PPE family member	TLR2 agonist	[218,219]
	PPE34	Rv1917c	PE/PPE family member	TLR2 agonist, induces DCs maturation	[220]
	PPE26	Rv1789	PE/PPE family member	TLR2 agonist, induces TNF-α, IL-6, and IL-12 p40 secretion, induces necrosis	[221,222]
	PPE57	Rv3425	PE/PPE family member	TLR2 agonist	[223]
	PPE60	Rv3478	PE/PPE family member	TLR2 agonist, induces DCs maturation, induces pyroptosis	[224,225]
	PE-PGRS11	Rv0754	PE/PPE family member	Interacts with TLR2, induces DCs maturation, required for oxidative stress	[226,227]
	PE-PGRS17	Rv0978c	PE/PPE family member	Interacts with TLR2, induces DCs maturation	[226]
Modulation of cytokine production	Mce2E LprL	Rv0593	Lipoprotein	Suppresses host immune response, epithelial cell proliferation	[228]
	Mce3E LprM	Rv1970	Lipoprotein	Down-regulates TNF and IL-6 expression	[229]
	Mce4E LprN	Rv3495c	Lipoprotein	Induces T-cell proliferation and increases production of TNF-α and IFN-γ cytokines	[230,231]
	RpfB	Rv1009	-	Induces T-cell proliferation, is required to Mtb reactivation,	[232,233]
	LpqS	Rv0847	Lipoprotein	Induces TNF-α, IL-12, and IL-6 secretion	[234]
	EspL	Rv3880c	ESX1 secretion system	Induces IL-1β, IFN-β, ISG15, and IL-6 production, stabilizes EspE, EspF and EspH	[235]
	-	Rv1987	RD2 gene	Induces TH2 immune response	[236,237]
	PE27	Rv2769c	PE/PPE family member	Induces Th1 response polarization	[238]
	Cas6	Rv2824c	Crispr/cas	Induces apoptosis, Upregulates IL-6, IL-1β and TNF-α	[239,240]
	Hip1 CaeA	Rv2224c	Protease	Reduces proinflammatory response, hampers DCs maturation, and inhibits antigen presentation and T cell responses	[241–243]
Phagosome arrest & autophagy subversion	SapM	Rv3310	Acid phosphatase	Suppresses phagosome maturation and autophagy flux	[244–247]
	ESAT-6 EsxA	Rv3875	ESX-1 secretion system	Diverse roles including phagosome rupture and translocation to the cytosol	[248,249]
	PE_PGRS30	Rv1651c	PE/PPE family member	Inhibits phagosome-lysosome fusion, reduces IL-12, TNF-α, and IL-6, required for lung tissue colonization	[250,251]
	SecA2	Rv1821	Secretion system	Protein export system that participates in the phagosome and autophagosome maturation arrest	[247,252]
	PtpA MptpA	Rv2234	Hydrolase, Protein phosphatase	Inhibits phagosome-lysosome fusion, phagosome acidification, suppresses innate immune response	[253–255]
	PknG	Rv0410c	Protein Kinase	Inhibits phagosome-lysosome fusion, inhibits autophagy flux, suppresses innate immune response, latent Mtb reactivation	[256–258]
	MPT63	Rv1926c	-	Forms membrane pores	[259,260]
	PE_PGRS62	Rv3812	PE/PPE family member	Inhibits phagosome-lysosome maturation, induces ER stress-mediated apoptosis	[261,262]
	TlyA	Rv1694	RNA methyl-transferase	Inhibits phagosome maturation, increases IL-12 secretion, reduces IL-1β and IL-10 secretion	[263,264]
	LpdC	Rv0462	Oxidoreductase	Inhibits phagosome maturation, induces DCs maturation	[265,266]
	Ndk	Rv2445c	Kinase, Transferase	Inhibits phagosome maturation	[267]
	-	Rv3091	Patatin-like phospholipase	Phagosome escape	[268]
	EsxH	Rv0288	ESX-1 secretion system	Inhibits phagosome maturation	[269]
	EIS	Rv2416c	Acyltransferase	Inhibits autophagy, suppress TNF-α and IL-6 secretion and ROS generation	[270–272]
	EspB	Rv3881c	ESX-1 secretion system	Inhibits autophagy	[273]
Cell death modulation	HbhA	Rv0475	Cell wall protein	Induces apoptosis, essential for the infection of lung epithelial cells and extrapulmonary infection	[274–277]
	EspC	Rv3615c	ESX-1 secretion system	Induces ER stress-mediated apoptosis	[278]
	NuoG	Rv3151	Translocase	Inhibits apoptosis	[279,280]
	-	Rv3654c	Secreted protein	Inhibits apoptosis	[281]
	-	Rv3655c	Secreted protein	Inhibits apoptosis	[281]
	PknE	Rv1743	Protein Kinase	Inhibits apoptosis, induces TNF-α and IL-6 secretion	[282,283]
	-	Rv3033	-	Inhibits intrinsic apoptosis	[284]
	CpnT	Rv3903c	Hydrolase Porin	Induces necrotic cell death	[285,286]
	PE25 PPE41	Rv2431c/Rv2430c	PE/PPE family member	Induces necrosis, induces DCs maturation	[287]
	PE11 LipX	Rv1169c	PE/PPE family member	Induces necrotic cell death, reduces IL-6 production, alters cell wall lipid composition	[288–290]
	Zmp1	Rv0198c	Metallo-protease	Induces necroptosis, inhibits phagosome-lysosome fusion, induces TNF-α, IL-6, IL-1β, MCP-1, MIP-1β, and IL-8 secretion	[291,292]
	-	Rv3364c	-	Inhibits pyroptosis	[293]
	PknF	Rv1746	Protein kinase	Inhibits pyroptosis	[294]
Other functions	LprI	Rv1541c	Lipoprotein	Lysozyme inhibitor	[295]
	CFP-10 EsxB	Rv3874	ESX-1 secretion system	EsxA chaperone, activates neutrophils	[296,297]
	Acr1	Rv2031c	Latency-associated protein	Inhibits maturation and differentiation of dendritic cells and macrophages	[298,299]
	-	Rv0431	Glycoprotein	Regulates vesiculogensis	[300–302]
	GroEL2	Rv0440	Chaperonin	Modulates DC responses	[303]
	-	Rv3194c	Serine protease	Degrades components of complement	[304]
	MPT64	Rv1980c	-	Up-regulates bcl-2, modulates ER stress	[305,306]
	PknH	Rv1266c	Protein kinase	Regulates LAM and AG	[307–309]
	RipA	Rv1477	Hydrolase Protease	Endopeptidase, activates TLR4	[310]
	PPE38	Rv2352c	PE/PPE family member	Coordinates ESX-5 effector secretion, regulates NF-kB activity	[311,312]

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