Reactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase.

Abstract

SummaryNitric oxide (NO) generated by the inducible isoform of NO synthase (iNOS) is required for the resolution of acute cutaneous leishmaniasis in resistant C57BL/6 mice. As is the case in several other infections, the clinically cured host organism still harbors small amounts of live Leishmania major parasites. Here, we demonstrate lifelong expression of iNOS at the site of the original skin lesion and in the draining lymph node of long-term-infected C57BL/6 mice. iNOS activity in the lymph node was dependent on CD4 +, but not on CD8 + T cells. By double labeling techniques, iNOS and L. major were each found in macrophages (F4/80 +, BM-8 +, and/ or MOMA-2 +) and dendritic cells (NLDC-145+), but not in granulocytes or endothelial cells. In situ triple labeling of lymph node sections revealed that "-'30-40% of the L. major foci were associated with iNOS-positive macrophages or dendritic cells. The majority of the L. major foci (60-70%), however, was located in areas that were negative for both iNOS and the macrophage and dendritic cell markers. In L. major-infected C57BL/6 mice, which had cured their cutaneous lesions, administration of t-Nt-iminoethyl-lysine 0.-NIL), a potent inhibitor of iNOS, led to a 104-10S-fold increase of the parasite burden in the cutaneous and lymphoid tissue and caused clinical recrudescence of the disease. Persistent expression ofiNOS and resumption of parasite replication after application oft-NIL was also observed in resistant C3H/HeN and CBA/J mice. We conclude that iNOS activity is crucial for the control of Leishmania persisting in immunocompetent hosts after resolution of the primary infection. Failure to maintain iNOS activity might be the mechanism underlying endogenous reactivation of latent infections with NO-sensitive microbes during phases ofimmunosuppression.

Control of Leishmania major in the absence of Tyk2 kinase

“…Promastigotes of the L. major strain (MHOM/IL/81/FE/BNI) were grown from amastigotes isolated from skin lesions of BALB/c mice and propagated in vitro [36].…”

“…l PBS. Footpad swelling was measured with a metric caliper and related to the uninfected footpad as the % increase of footpad thickness [36]. The number of parasites in the tissue was determined by limiting dilution analysis using two-or fivefold serial dilutions of the tissue suspensions with 12 individual wells per dilution step and applying Poisson statistics and the £ 2 minimization method [36].…”

“…M cryostat skin, lymph node or spleen sections by immunoperoxidase staining and hematoxylin counterstaining as described [6,36].…”

The role of nitric oxide and lipid peroxidation in patients withPlasmodium vivaxmalaria

“…NO diffuses freely across membranes to mediate its effects. NO plays a vital role in the supression of the acute parasitemia in experimental Leisbmania major infections as well as in the prevention of reactivation of chronic low grade infection (Wei et al, 1995;Stenger et al, 1996). NO is a bioreactive free radical and an important signalling molecule that acts in many tissues to regu late a diverse range of physiological processes (Beckman & Koppenol, 1998).…”

Susceptibility of peritoneal macrophage from different species of neotropical primates to Ex vivo Leishmania (L.) infantum chagasi-infection

“…12,28,36 . However, for this activity the TNF-α and IL-12 production is necessary, which will then provide the macrophage activation and the subsequent NO response 6,40 .…”