Inducible nitric oxide synthase controls experimental <i>Strongyloides</i> infection

Rodrigues, Raphael Silva; Gonçalves, Ana Lúcia Ribeiro; Silva, Neide Maria; Cardoso, Cristina Ribeiro de Barros; Araújo, Natália Rodrigues; Coutinho, Loyane Bertagnolli; Alves, Ronaldo; Ueta, Marlene Tiduko; Costa-Cruz, Júlia Maria

doi:10.1111/pim.12576

Cited by 7 publications

(4 citation statements)

References 46 publications

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“…However, neither pharmaceutical inhibition of nitric oxide synthesis nor iNOS knockout in mice abrogated resistance to circulating L. sigmodontis [55]. More recently, iNOS −/− mice infected with Strongyloides venezuelensis showed increased susceptibility to infection [56]. These results illustrate that mechanisms of protection or susceptibility defined in one model system cannot be simply assigned to all helminth-host interactions: rather particular differences can be critical in favoring initial inflammatory responses that have a major role in inducing protection during helminth infections.…”

Section: Discussionmentioning

confidence: 99%

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

et al. 2019

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Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1−/− and STAT6−/−) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1−/− mice; in contrast, STAT6−/− mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing.

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Section: Discussionmentioning

confidence: 99%

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

et al. 2019

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“…Apart from schistosomes, the important role of NO was suggested also in the control of other helminths such as Trichinella spiralis [21][22][23], Brugia malayi [24,25], Strongyloides venezuelensis [26,27] and Taenia crassiceps [28]. However, particular effector mechanisms of NO/ RNS antiparasitic actions remain rather unexplored.…”

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confidence: 99%

Nitric oxide debilitates the neuropathogenic schistosome Trichobilharzia regenti in mice, partly by inhibiting its vital peptidases

et al. 2020

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Background: Avian schistosomes, the causative agents of human cercarial dermatitis (or swimmer's itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity. Methods: Inducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected by T. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluated in vivo. The vulnerability of T. regenti schistosomula to NO and peroxynitrite was assessed in vitro by viability assays and electron microscopy. Additionally, the effect of NO on the activity of T. regenti peptidases was tested using a fluorogenic substrate. Results: iNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord. In vitro, NO did not impair the parasites, but inhibited the activity of T. regenti cathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viability in vitro, but rather did not participate in parasite clearance in vivo. Conclusions: Reactive nitrogen species, specifically NO, do not directly kill T. regenti in mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.

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“…ROS are released from both the host immune effector cells and through degradation of haemoglobin. Induced nitric oxide synthase provides protection against Strongyloides venezuelensis infection in mice, as inducible nitric oxide synthase (iNOS) knock out (KO) resulted in mice being more susceptible to infection (Rodrigues et al ., 2018 ). Previous studies have found that NO can contribute to either parasite clearance or to susceptibility by exacerbating inflammation that worsens disease manifestation, or facilitates parasite killing (Diliani and Dondji, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Comparative transcriptomics from intestinal cells of permissive and non-permissive hosts during Ancylostoma ceylanicum infection reveals unique signatures of protection and host specificity

et al. 2023

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Soil-transmitted nematodes (STNs) place a tremendous burden on health and economics worldwide with an estimate of at least 1.5 billion people, or 24% of the population, being infected with at least 1 STN globally. Children and pregnant women carry the heavier pathological burden, and disease caused by the blood-feeding worm in the intestine can result in anaemia and delays in physical and intellectual development. These parasites are capable of infecting and reproducing in various host species, but what determines host specificity remains unanswered. Identifying the molecular determinants of host specificity would provide a crucial breakthrough towards understanding the biology of parasitism and could provide attractive targets for intervention. To investigate specificity mechanisms, members of the hookworm genus Ancylostoma provide a powerful system as they range from strict specialists to generalists. Using transcriptomics, differentially expressed genes (DEGs) in permissive (hamster) and non-permissive (mouse) hosts at different early time points during infection with A. ceylanicum were examined. Analysis of the data has identified unique immune responses in mice, as well as potential permissive signals in hamsters. Specifically, immune pathways associated with resistance to infection are upregulated in the non-permissive host, providing a possible protection mechanism that is absent in the permissive host. Furthermore, unique signatures of host specificity that may inform the parasite that it has invaded a permissive host were identified. These data provide novel insight into the tissue-specific gene expression differences between permissive and non-permissive hosts in response to hookworm infection.

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Inducible nitric oxide synthase controls experimental Strongyloides infection

Cited by 7 publications

References 46 publications

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection

Nitric oxide debilitates the neuropathogenic schistosome Trichobilharzia regenti in mice, partly by inhibiting its vital peptidases

Comparative transcriptomics from intestinal cells of permissive and non-permissive hosts during Ancylostoma ceylanicum infection reveals unique signatures of protection and host specificity

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