Mapping the Lectin-Like Activity of Tumor Necrosis Factor

Abstract

Tumor necrosis factor (TNF), but not lymphotoxin (LT), is directly trypanolytic for salivarian trypanosomes. This activity was not blocked by soluble 55-kilodalton and 75-kilodalton TNF receptors, but was potently inhibited by N,N'-diacetylchitobiose, an oligosaccharide that binds TNF. Comparative sequence analysis of TNF and LT localized the trypanocidal region, and synthetic peptides were trypanolytic. TNF molecules in which the trypanocidal region was mutated or deleted retained tumoricidal activity. Thus, trypanosome-TNF interactions occur via a TNF domain, probably with lectin-like affinity, which is functionally and spatially distinct from the mammalian TNF receptor binding sites.

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

“…In mammals, TNF-␣ has been shown to directly bind to the variant specific glycoprotein present in the flagellar pocket of some African trypanosomes and to cause direct lysis (31)(32)(33)(34). An invertebrate functional analog of mammalian TNF-␣, named coelomic cytolytic factor (CCF-1), has been described in the earthworm Eisenia foetida foetida (78).…”

“…We investigated whether the lectin-like activity ascribed to mammalian TNF-␣, and known to act through its TIP domain (31,32), would be conserved in the homologous carp TNF-␣ molecule. The ability of carp TNF-␣1 and TNF-␣2 to kill the bloodstream form of T. brucei (AnTat 1.1 clone) was investigated in a trypanolytic assay.…”

“…The lectin domain is located at the top of the pyramid-shaped TNF-␣ molecule, also referred to as TIP domain, and is spatially and functionally distinct from the receptor binding region. TNF-␣ binds through its lectin-like domain to mannose moieties present in the flagellar pocket of some African trypanosomes and can cause direct parasite lysis (31)(32)(33)(34). The lectin-like activity of TNF-␣, a yet unexamined receptor-independent function of fish TNF-␣, was investigated in a trypanolytic assay in vitro.…”

Biological Variation Among African Trypanosomes: I. Clonal Expression of Virulence Is Not Linked to the Variant Surface Glycoprotein or the Variant Surface Glycoprotein Gene Telomeric Expression Site

“…Because the VSG molecule plays a critical role in antigenic variation and because of the ability of the trypanosome to evade host immune responses during infection, we previously asked whether there was an association between expressed VSG molecules and virulence levels in the T. brucei rhodesiense LouTat 1 serodeme. Our preliminary observations, as well as unrelated studies by others (Musoke and Barbet, 1977;Mathias et al, 1990;Lucas et al, 1994;Magez et al, 1997Magez et al, , 1998, suggested that the VSG molecule could play a direct role in the relative expression of trypanosome virulence expression for a host. This suggestion was derived from our observation that all daughter cell trypanosome populations that expressed elevated virulence in an infected host were derived from a less-virulent trypanosome parent cell population that expressed a surface coat distinct from each of the virulent populations (Inverso and Mansfield, 1983).…”

“…Therefore, we initially hypothesized that trypanosome virulence may be determined directly by the VSG molecule itself. Such an hypothesis has an experimental basis because VSG molecules and their substituents have been shown to express or induce biological activities independent of their status as variant antigens (Musoke and Barbet, 1977;Mathias et al, 1990;Lucas et al, 1994;Magez et al, 1997Magez et al, , 1998Coller et al, 2003;Leppert et al, 2007;Lopez et al, 2008). Alternatively, we proposed that the expression of virulence may be linked to the ES utilized by VSG genes.…”