Pathogenicity & virulence of Histoplasma capsulatum - A multifaceted organism adapted to intracellular environments

Figures & data

Figure 1. Major receptors involved with H. capsulatum recognition by phagocytes. Association of H. capsulatum with phagocytes. (A) TLR2, CR3, CR4, Dectin-1 and Lactosylceramide (LacCer) participate in the recognition of yeasts of H. capsulatum by macrophages. TLR2 and Dectin-1 are involved with activation of NF-kB and production of cytokines IL-6 and TNF-α, respectively. During H. capsulatum adhesion and internalization, CR3 is recruited to lipid microdomains. (b) Dendritic Cells interact with H. capsulatum using plasma membrane receptors VLA-5, CR3, Dectin-1 and Dectin-2. VLA-5 is the main receptor involved in phagocytosis of H. capsulatum yeasts, CR3 is involved with fungal phagocytosis and Dectin 1 and 2 with the activation of NLRP3 inflammasome. Intracellular receptors TLR7 and TLR9 are involved with production of IFN-1. (c) in neutrophils, the major receptors for ic3b-opsonized H. capsulatum are CR1 and CR3 while non-opsonized yeasts are recognized by FcγRIII, NET release is dependent on CD18. the fungal structures involved with each host cell receptor are shown in Table 1.

Table 1. Histoplasma capsulatum virulence factors and regulators.

Surviving in host temperature			Ref
Cysteine and sulphhydryl compounds	Reactivation of mitochondrial respiration by “shunt pathways”		(Maresca [4], Sacco [5])
DRK1	Directly associated with hypha-to-yeast transition process, responsible for yeast growth and expression of other proteins		(Nemecek [6])
Ryp 1, Ryp 2, Ryp 3 and Ryp 4	Key regulators of the yeast-phase transcriptional program		(Inglis [7]; Beyhan [8]; Edwards [9])
Bypassing host barriers			Ref
Surfactant proteins of the Host (Collectins SP-A and SP-D)	Direct antifungal activity	H. capsulatum evades collectins by invading macrophages	(McCormack [10], Carreto-Binaghi [11])
Evading the immune system			Ref
Hsp60	Mediates yeast recognition and internalization by CR3 receptor of macrophages and has potent immunogenic activity		(Gomez [12], Long [13], Guimarães [14], Guimarães [15], Guimarães [16])
α-1,3-glucan	Impairs recognition of β-1,3-glucan by Dectin-1		(Rappleye [17], Garfoot [18], Ray and Rappleye [19])
Eng1	Acts associated with α-1,3-glucan, hydrolysing any exposed β-1,3-glucans in the cell wall, avoiding recognition by Dectin-1		(Garfoot [18,20])
Sod3, CatB and CatP	Promotes ROS resistance		(Holbrook [21], Youseff [22], Holbrook [23])
CBP1	Required for induction of integrated stress response, leading to apoptosis of macrophages		(Isaac [24], English [25], Azimova [26])
Cyclophylin A	Recognized by VLA-5 in DCs leading to yeast internalization		(Gomez [27])
Nutrient Acquisition			Ref
PCK1	Encodes a phosphoenolpyruvate carboxykinase, related to the first step of gluconeogenesis,essential to intracellular growth and virulence		(Shen [28])
Ctr3	Copper transporter required for intracellular proliferation		(Shen [29])

Figure 2. Schematic illustration of a hypothetical model of H. capsulatum cell wall. Cell wall of H. capsulatum consists primarily of polysaccharides, including chitin (dark blue), β1,3 and β1,6 glucans (light blue), a1,3 glucans (yellow), proteins (black coil) and mannoproteins (black coil with mannans in green). Extracellular vesicles (EVs) are shown as bilayered compartments. For didactic purposes, minor components such as lipids are not shown.

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