Unraveling the lethal synergism between Trypanosoma cruzi infection and LPS: A role for increased macrophage reactivity

Abstract

Various infections sensitize to lethal shock by promoting hyperactivation of macrophages to LPS stimulation. Although macrophages are thought to be deactivated upon contact with apoptotic cells during Trypanosoma cruzi infection, T. cruzi infection also sensitizes mice to endotoxemia. Herein, we studied the mechanisms of sensitization to endotoxemia in T. cruzi-infected mice in order to solve the paradox. Live (but not fixed) trypomastigotes from various stocks sensitized mice to endotoxemia. Mice deficient in glycolipid recognition (TLR2 -/-and CD1d -/-) were sensitized by infection to challenge with LPS. Infected mice hyperproduced TNF and IL-10 upon LPS challenge. Infected TNF-R1 -/-, macrophage migration inhibitory factor (MIF) -/-and IFN-c -/-mice were lethally sensitized, but infected TNF-R1 -/-mice administered anti-MIF survived shock with LPS. Macrophages from infected mice hyperproduced TNF in response to LPS stimulation and displayed increased expression of TLR4 compared to non-infected controls. Treatment with the PGE 2 synthesis inhibitor acetylsalicylic acid (AAS) in vivo reduced parasitemia and enhanced LPS-stimulated production of TNF by macrophages, but the effect was less in infected mice than in normal mice. Nevertheless, AAS treatment did not increase the susceptibility of infected mice to sublethal shock with LPS. Our results point to independent MIF and TNF/TNF-R1 lethal pathways and suggest a role for hyperactivated macrophages in T. cruzi-sensitized LPS-induced shock.

Aspirin Modulates Innate Inflammatory Response and Inhibits the Entry ofTrypanosoma cruziin Mouse Peritoneal Macrophages

“…Moreover, evidence suggests that administration of NSAIDs may enhance mortality in chagasic patients [12]. Conversely, others have found that inhibition of PG synthesis/release reduces parasitemia and extends survival of mice infected with T. cruzi [14–17]. This was often associated with a decrease in the levels of circulating inflammatory cytokines (such as TNF- α , IFN- γ , and IL-10) [16].…”

CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production

“…However, the present work suggests that GIF is one of the emerging immunoregulatory cytokines. Although the unmodified GIF has been implicated in the activation of innate immunity (10), the sensitivity of GIFdeficient mice to endotoxin shock has been controversial (11,12,14). Our in vitro experiments indicated that expression of GIF is not required for macrophages or dendritic cells to respond to TLR ligands.…”

“…The initial report of the mutant mice demonstrated a reduced rate of endotoxin shock (11). However, the same (14) and other (12) lines of the mutant mice later showed a normal sensitivity to LPS. Thus, the role of GIF in innate immunity needs to be reevaluated.…”

Decoding caspase signaling in host immunity to the protozoan Trypanosoma cruzi

“…Therefore, increased apoptosis during infection might help parasite persistence, by affecting macrophagemediated immunity [16]. Nonetheless, there is evidence of macrophage activation and control of parasite infection in different experimental models of Chagas' disease [21,22].…”