Hematologists understand the critical role that inflammatory cell oxidants play in killing microbes since their neutropenic patients, or those with chronic granulomatous disease, are often overwhelmed by infection. Many of the oxidants are catalyzed by iron, yet iron is also an excellent nutrient for microbes. Patients with iron overload have a propensity for opportunistic infections such as Yersinia or mucormycosis. Murray suggested that hyperferremia associated with refeeding individuals in Central Africa led to rapid multiplication of parasites leading to attacks of malaria.1 In Chagas disease, caused by Trypanasoma cruzi (T. cruzi), the acute phase is characterized by intense parasitism, a mononuclear and polymorphonuclear cell inflammatory response that surrounds the ruptured infected cells, and myocarditis complicated by myocyte necrosis and edema. The exuberant reactive oxygen species from these inflammatory cells causes free iron and heme to be released from the myoglobinrich myocytes. T. cruzi have potent antioxidant defenses that confer resistance to oxidative cytotoxicity. Thus, the inflammatory response damages the heart but does not kill the bug. Paiva and colleagues in Brazil address this paradox experimentally and showed that oxidative stress contributes to parasite persistence in host tissues and suggest that the process may be exploited as a target for novel therapies.
Nuclear factor erythroid-derived 2 (NRF2) induces the expression of various genes including those that encode for antioxidant molecules that play a role in the regulation of oxidative stress. Activation of NRF2 by cobalt protoporphyrin (CoPP) induced heme oxygenase-1 (HO-1) in mice infected with T. cruzi and significantly reduced parasitemia. Inhibiting HO-1 with tin protoporphyrin had the opposite effect. Thus, contrary to the usual circumstance, oxidative stress worsens parasitism while anti-oxidant cellular responses inhibit T. cruzi growth. CoPP reduced macrophage T. cruzi parasitism in vivo and in vitro indirectly through effects on macrophage physiology, not through direct parasite toxicity. This effect was not due to CoPP-inducing macrophage apoptosis nor was it mediated by nitric oxide, tumor necrosis factor, or type 1 interferon. Infection promotes a macrophage respiratory burst and added H2O2 enhanced parasitism, while antioxidants including super oxide dismutase, catalase, bilirubin, biliverdin, N-acetyl cysteine, resveratrol, and apocynin inhibited T. cruzi growth. Moreover, upon infection, gp91phox (Nox1)-deficient macrophages and mice had reduced reactive oxygen species production and diminished parasitism. Cellular iron is mobilized by oxidative stress and fuels T. cruzi growth. Anti-oxidants induce ferroportin and H-ferritin expression, both of which decrease free iron in macrophages. Iron chelation by deferoxamine or increased expression of ferritin reduced macrophage parasitism. In contrast, added FeSO4 to mice increased parasitemia and reversed the protective effect of CoPP.
In Brief
This paradoxical effect of diminishing an inflammatory response while promoting an anti-microbial response by limiting access to cellular iron is in concert with new views of the innate immune response to pathogens.2,3 The immune system can identify and eliminate the invading infectious agent; however, the host protects its vital organs by reducing the negative impact of infections (i.e., oxidative stress) on host health. The capacity to tolerate T. cruzi presence is a distinct host defense strategy, consistent with the notion of “disease tolerance.” Murray’s observations of the toxic effects of refeeding starved, malaria-infected patients fit this paradigm. During starvation, patients were relatively asymptomatic, but upon refeeding (and, presumably, restoration of iron stores) symptoms of malaria developed. The findings by Paiva showing inhibition of growth of T. cruzi starved of iron through macrophage sequestration of Fe3+ in ferritin and exported via ferroportin support Murray’s interpretation. Finally, the work of Claude Bernard and Walter Bradford Cannon on homeostasis reminds us that a balance between oxidative stress and antioxidant effects is necessary for stability in living organisms.
References
Competing Interests
Dr. Vercellotti indicated no relevant conflicts of interest.
