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<field name="uid">doi:10.1371/journal.pntd.0001492</field>
<field name="doi">10.1371/journal.pntd.0001492</field>
<field name="data_source">PLoS Open Access XML</field>
<field name="authors">Helton C. Santiago, Claudia Z. Gonzalez Lombana, Juan P. Macedo, Lara Utsch, Wagner L. Tafuri, Maria José Campagnole-Santos, Rosana O. Alves, José C. F. Alves-Filho, Alvaro J. Romanha, Fernando Queiroz Cunha, Mauro M. Teixeira, Rafael Radi, Leda Q. Vieira</field>
<field name="title">NADPH Phagocyte Oxidase Knockout Mice Control Trypanosoma cruzi Proliferation, but Develop Circulatory Collapse and Succumb to Infection</field>
<field name="journal">PLoS Neglected Tropical Diseases</field>
<field name="year">2012</field>
<field name="volume">6</field>
<field name="number">2</field>
<field name="pages">e1492</field>
<field name="license">Creative Commons Attribution (CC BY)</field>
<field name="license_url">http://creativecommons.org/licenses/by/3.0/</field>
<field name="fulltext">
Abstract

•NO is considered to be a key macrophage-derived cytotoxic effector during
Trypanosoma cruzi infection. On the other hand, the microbicidal properties of
reactive oxygen species (ROS) are well recognized, but little importance has
been attributed to them during in vivo infection with T. cruzi. In order to
investigate the role of ROS in T. cruzi infection, mice deficient in NADPH
phagocyte oxidase (gp91phox−/− or phox KO) were infected with Y strain of T.
cruzi and the course of infection was followed. phox KO mice had similar
parasitemia, similar tissue parasitism and similar levels of IFN-γ and TNF in
serum and spleen cell culture supernatants, when compared to wild-type
controls. However, all phox KO mice succumbed to infection between day 15 and
21 after inoculation with the parasite, while 60% of wild-type mice were alive
50 days after infection. Further investigation demonstrated increased serum
levels of nitrite and nitrate (NOx) at day 15 of infection in phox KO animals,
associated with a drop in blood pressure. Treatment with a NOS2 inhibitor
corrected the blood pressure, implicating NOS2 in this phenomenon. We
postulate that superoxide reacts with •NO in vivo, preventing blood pressure
drops in wild type mice. Hence, whilst superoxide from phagocytes did not play
a critical role in parasite control in the phox KO animals, its production
would have an important protective effect against blood pressure decline
during infection with T. cruzi.

Author Summary

When pathogens enter their hosts, they are fought by several resistance
strategies, including capture by phagocytes and the production of pathogen-
toxic molecules. Nitric oxide, a free radical, has been extensively studied as
one of these toxic molecules that successfully mediates intracellular parasite
killing, including Trypanosoma cruzi, the protozoan parasite that causes
Chagas&apos; disease. On the other hand, reactive oxygen species also mediate
resistance to several pathogens, mainly bacterial. In this study, we addressed
the role of reactive oxygen species in the resistance to T. cruzi using gene-
deficient mice, a species which phagocytes lack the ability to produce
(phox−/− mice). We found that phagocyte-derived reactive oxygen species are
not critical to mediate resistance to parasite in the knock-out animals.
However, phox−/− mice presented higher mortality and lower blood pressure due
to infection with T. cruzi than non-deficient mice. The blood pressure was
restored to normal by an inhibitor of nitric oxide synthesis by phagocytes. We
hypothesize that superoxide (one of the oxygen reactive species) controls
blood pressure during infection with T. cruzi, by reacting with nitric oxide
and preventing its action on blood vessels.

Introduction

For a long time, reactive oxygen species (ROS) were considered the main anti-
microbial radical produced by the immune system, playing a role against
bacterial, fungal and protozoa infections. After the discovery of nitric oxide
(•NO), •NO found to play a major role in host defense, especially against
protozoa</field></doc>
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