Suppression of humoral immunity and lymphocyte responsiveness during experimental trypanosoma cruzi infections

C3H/He and C57B1/6 mice were inoculated with 500 Trypanosoma cruzi trypomastigotes (Strain Y). During the acute phase infected mice presented parasitemia and enlargement of lymph nodes and spleens and intracellular parasites were observed in the heart. Examinations of cells derived from spleen and lymph nodes showed increased numbers of IgM and IgG-bearing cells. During the peak of splenomegaly, about day 17 post-infections, splenic lymphocytes showed a marked decrease in responsiveness to T and B-cell mitogens, parasite antigens and plaque forming cells (PFC) to sheep red blood cells (SRBC). Unfractionated or plastic adherent splenic cells from mice, obtained during the acute phase were able to suppress the response to mitogens by lymphocytes from uninfected mice. During the chronic phase. Disappearance of parasitemia and intracellular parasites in the hearts as well as a decrease in spleen size, was observed. These changes preceded the complete recovery of responsiveness to mitogens and T. cruzi antigens by C57B1/6 splenic lymphocytes. However, this recovery was only partial in the C3H/He mice, known to be more sensitive to T. cruzi infection. Partial recovery of humoral immune response also occurred in both strains of mice during the chronic phase

Trypanosoma cruzi: enhanced alpha-macroglobulin levels correlate with the resistance of BALB/cj mice to acute infection.

Trypanosoma cruzi proteinases are very likely involved in host-cell invasion. Physiological plasma-proteinase inhibitors from the macroglobulin (MG) family, among them alpha-2-macroglobulin (A2M), are found in tissues and in the plasma of mammals. By complexing to all classes of proteinases, MGs inhibit their action on high-molecular-weight substrates. In vitro studies have shown that A2M impairs T. cruzi proteases and, consequently, the parasite's ability to invade host cells and enhances the phagocytic and microbicidal actions of resident macrophages against T. cruzi. To test the hypothesis of a putative "protective" effect for MG, we quantified it in BALB/cj mice during the course of an experimental T. cruzi infection, comparing a posteriori the levels in mice that died with those in animals that survived, which were considered as being susceptible and resistant to the infection, respectively. The results showed that surviving mice showed an increase in plasma concentrations of MG during the first few weeks after the infection, whereas the levels in mice that died during the acute phase did not differ significantly from those in non-infected mice. These findings and the previous in vitro data indicate a role for physiological proteinase inhibitors, particularly alpha-macroglobulins, in resistance to T. cruzi infection, whereby a balance between parasite proteases and host protease inhibitors may be crucial. MG may thus participate in the complex network of reactions involved in the early acute phase of the disease and contribute by conferring to the host an ability to survive the infection.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides

Sampling of California nearshore sediments resulted in the isolation of a Gram-negative bacterium, <i>Photobacterium halotolerans</i>, capable of producing unusual biosynthetic products. Liquid culture in artificial seawater-based media provided cyclic depsipeptides including four known compounds, kailuins B–E (<b>2</b>–<b>5</b>), and two new analogues, kailuins G and H (<b>7</b> and <b>8</b>). The structures of the new and known compounds were confirmed through extensive spectroscopic and Marfey’s analyses. During the course of these studies, a correction was made to the previously reported double-bond geometry of kailuin D (<b>4</b>). Additionally, through the application of a combination of derivatization with Mosher’s reagent and extensive ¹³C NMR shift analysis, the previously unassigned chiral center at position C-3 of the β-acyloxy group of all compounds was determined. To evaluate bioactivity and structure–activity relationships, the kailuin core (<b>13</b>) and kailuin lactam (<b>14</b>) were prepared by chiral synthesis using an Fmoc solid-phase peptide strategy followed by solution-phase cyclization. All isolated compounds and synthetic cores were assayed for solid tumor cell cytotoxicity and showed only minimal activity, contrary to other published reports. Additional phenotypic screenings were done on <b>4</b> and <b>5</b>, with little evidence of activity