Immune system pathogenesis is prevented by the neutralization of the systemictrans-sialidase fromTrypanosoma cruziduring severe infections

Abstract

During the acute phase of Trypanosoma cruzi infection, strong haematological and immune system alterations are observed. The parasite expresses trans-sialidase, a virulence factor responsible for the sialylation of its surface glycoconjugates. This enzyme is also shed to the bloodstream where it is associated with immune system alterations triggered during the infection. During experimental and human infections, the host elicits antibodies able to neutralize the enzyme activity that would be responsible for restricting systemic trans-sialidase to the early steps of the infection, when major immune alterations are induced. The actual relevance of these antibodies was tested by passive transference of monoclonal neutralizing antibodies in acute infection models displaying extreme sensitivity to the infection. Mice were inoculated with virulent parasite strains that induce high parasitaemia, early mortality and strong immune tissue abnormalities. The trans-sialidase-neutralizing antibodies were able to preserve B cell areas both in ganglia and spleen as well as the thymus architecture even in these extreme models. Although no differences between control and treated mice regarding animal survival were found, a major role for the humoral response in controlling the damage of the immune system induced by a systemically distributed virulence factor was defined in an infection with a eukaryotic pathogen.

Trypanosoma cruzitrans-Sialidase Prevents Elicitation of Th1 Cell Response via Interleukin 10 and Downregulates Th1 Effector Cells

“…and 5 g of OVA subcutaneously on day ϩ7 postinoculation (p.i.). A group of animals received 3 g of purified anti-TS monoclonal antibody (neutralizing titer of over 1:15,000) (17,18) by i.p. passive transfer every 2 days (four doses total), starting 1 day before the splenocyte transfer.…”

“…However, TS is also shed and found in the bloodstream, and its systemic distribution induces modified host cell sialylation patterns (14,15). These are associated with several abnormalities during early infection stages, including depletion of thymocytes (16), absence of germinal centers in secondary organs (17), and thrombocytopenia and erythropenia (18,19), all of which can be prevented by the passive transfer of anti-TS neutralizing antibodies to infected mice (17,18,20). TS also inhibits human lymphocyte proliferation involving IL-2 signaling (21).…”

Continuous nonradioactive method for screening trypanosomal trans-sialidase activity and its inhibitors

“…The activity as neuraminidase of the TcTS is low in the presence of an appropriate acceptor (Agusti et al 2004). Transfer of SA to compound 1 was almost completely inhibited ( Figure 1C) by previous incubation of the enzyme with a neutralizing antibody (Risso et al 2007). …”

“…Production and purification of TcTS-neutralizing antibodies Monoclonal antibodies were obtained by growing the IgG 2a -secreting 13G9-34 hybridoma (Risso et al 2007). Human antibodies were obtained from serum samples pooled from eight chronically T. cruzi-infected patients.…”

“…Sialylated mucins are in turn involved in the invasion of mammalian host cells and in the protection against lysis by serum factors (Tomlinson et al 1994;PereiraChioccola et al 2000). The TcTS is anchored to the membrane by glycosylphosphatidylinositol (Agusti et al 1997(Agusti et al , 1998 and is shed to the medium, then it can be detected in the blood during the acute phase of the infection Buscaglia et al 1999;Alvarez et al 2004) and may produce several abnormalities in the immune system (Leguizamón et al 1999;Mucci et al 2002Mucci et al , 2005Mucci et al , 2006Risso et al 2007). Animals that survive infection and chronic Chagas disease patients both elicit TcTS-neutralizing antibodies that inhibit the enzymatic activity and have been used on the detection of T. cruzi infections , Leguizamón, Campetella, Russomando et al 1994Blejer et al 2008).…”