Neutrophils Increase or Reduce Parasite Burden in Trypanosoma cruzi-Infected Macrophages, Depending on Host Strain: Role of Neutrophil Elastase

Abstract

Neutrophils are involved in the initial steps of most responses to pathogens and are essential components of the innate immune response. Due to the ability to produce and release various soluble mediators, neutrophils may participate in the regulation of the inflammatory response. Little is known about the role of neutrophils during protozoan infections including infection by Trypanosoma cruzi. In the present study we investigated the importance of inflammatory neutrophils on macrophage activation and T. cruzi replication in vitro, in cells obtained from BALB/c mice and C57Bl/6 mice. Co-cultures of BALB/c apoptotic or live neutrophils with infected peritoneal macrophages resulted in increased replication of the parasites and in the production of TGF-β and PGE2. The treatment with anti-TGF-β neutralizing antibody and COX inhibitor blocked the parasite replication in vitro. On the other hand, co-cultures of T. cruzi infected macrophages with live neutrophils isolated from C57BL/6 mice resulted in decreased number of trypomastigotes in culture and increased production of TNF-α and NO. The addition of anti-TNF-α neutralizing antibody or elastase inhibitor resulted in the abolishment of macrophage microbicidal effect and increased parasite replication. Addition of elastase to infected macrophages reduced the replication of the parasites, and on the other hand, addition of a selective inhibitor of iNOS increased parasite growth, suggesting the role of NO in this system. Our findings reveal that neutrophils may regulate T. cruzi experimental infection and determine susceptibility and resistance to infection.

B-1 cells modulate the murine macrophage response toLeishmania majorinfection

“…These two drugs are recognized as potent inhibitors of PGE 2 production[19,20]. Our data demonstrate that the blockade of PGE 2 production affected the parasite burden inside the macrophages (Figure 6).…”

“…The cytokine TGF-β, which is another important mediator involved in the modulation of macrophages infected with intracellular parasites[19-20], was not detected in the present study model (data not shown).…”

The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

“…Therefore, inhibition of NE, to decrease airway inflammation and to prevent infections in cystic fibrosis, is currently under investigation. However, in healthy subjects the inhibition of NE favours bacterial, fungal and parasite infections [23,24]. A study conducted in HIV-positive patients, undergoing highly active antiretroviral therapy, containing a protease inhibitor (saquinavir, ritonavir, lopinavir, amprenavir or nelfinavir), showed a significant decrease in neutrophil function [25], which may suggest protease inhibitors might not only affect viral proteases but might also impair the function of neutrophil serine proteases.…”

Implication of Apoptosis for the Pathogenesis of Trypanosoma cruzi Infection

“…Many studies in this area describe the existence of different strategies developed by the parasite to modulate the immune response of the vertebrate host in its favor (4, 8–12). …”