Serum-Mediated Activation of Macrophages Reflects TcVac2 Vaccine Efficacy against Chagas Disease

Gupta, Shivali; Silva, Trevor S.; Osizugbo, Jessica E.; Tucker, Laura; Spratt, Heidi; Garg, Nisha

doi:10.1128/iai.01186-13

Cited by 19 publications

(21 citation statements)

References 45 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have previously shown that incubation of mφs with sera of chagasic mice elicited a proinflammatory phenotype (CD64 hi CD80 hi) and functional response (increased TNFα/IFNγ production) [25]. In this study, circulatory MPs from chagasic patients and experimentally infected mice produced a similar proinflammatory activation of mφs (Figs.…”

Section: Discussionsupporting

confidence: 63%

“…Flow cytometry analysis showed that IFNγ-treated (proinflammatory) mφs were primarily CD80 + /CD64 + , and IL4- and IL10-treated (immunoregulatory) mφs were CD163 + /CD206 + . The IL-10-treated THP-1 mφs exhibited CD16 hi /CD200 hi profile and IL4-treated mφs exhibited CD16 lo /CD200 lo profile [25]. THP-1 mφs incubated with MPs isolated from the plasma of chagasic patients exhibited no significant change in cell viability and/or cell proliferation (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Gene Expression Profiling and Functional Characterization of Macrophages in Response to Circulatory Microparticles Produced during Trypanosoma cruzi Infection and Chagas Disease

Chowdhury

Koo²,

Gupta

et al. 2016

J Innate Immun

Self Cite

View full text Add to dashboard Cite

Background: Chronic inflammation and oxidative stress are hallmarks of chagasic cardiomyopathy (CCM). In this study, we determined if microparticles (MPs) generated during Trypanosoma cruzi (Tc) infection carry the host's signature of the inflammatory/oxidative state and provide information regarding the progression of clinical disease. Methods: MPs were harvested from supernatants of human peripheral blood mononuclear cells in vitro incubated with Tc (control: LPS treated), plasma of seropositive humans with a clinically asymptomatic (CA) or symptomatic (CS) disease state (vs. normal/healthy [NH] controls), and plasma of mice immunized with a protective vaccine before challenge infection (control: unvaccinated/infected). Macrophages (mφs) were incubated with MPs, and we probed the gene expression profile using the inflammatory signaling cascade and cytokine/chemokine arrays, phenotypic markers of mφ activation by flow cytometry, cytokine profile by means of an ELISA and Bioplex assay, and oxidative/nitrosative stress and mitotoxicity by means of colorimetric and fluorometric assays. Results:Tc- and LPS-induced MPs stimulated proliferation, inflammatory gene expression profile, and nitric oxide (∙NO) release in human THP-1 mφs. LPS-MPs were more immunostimulatory than Tc-MPs. Endothelial cells, T lymphocytes, and mφs were the major source of MPs shed in the plasma of chagasic humans and experimentally infected mice. The CS and CA (vs. NH) MPs elicited >2-fold increase in NO and mitochondrial oxidative stress in THP-1 mφs; however, CS (vs. CA) MPs elicited a more pronounced and disease-state-specific inflammatory gene expression profile (IKBKB, NR3C1, and TIRAP vs. CCR4, EGR2, and CCL3), cytokine release (IL-2 + IFN-γ > GCSF), and surface markers of mφ activation (CD14 and CD16). The circulatory MPs of nonvaccinated/infected mice induced 7.5-fold and 40% increases in ∙NO and IFN-γ production, respectively, while these responses were abolished when RAW264.7 mφs were incubated with circulatory MPs of vaccinated/infected mice. Conclusion: Circulating MPs reflect in vivo levels of an oxidative, nitrosative, and inflammatory state, and have potential utility in evaluating disease severity and the efficacy of vaccines and drug therapies against CCM.

show abstract

Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling and Functional Characterization of Macrophages in Response to Circulatory Microparticles Produced during Trypanosoma cruzi Infection and Chagas Disease

Chowdhury

Koo²,

Gupta

et al. 2016

J Innate Immun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Acute infection results in increased levels of infiltrating inflammatory cells (Nagajyothi et al 2014). Because we and others previously showed that inflammatory cells infiltrate the hearts during T. cruzi infection (Nagajyothi et al 2014; Nagajyothi et al 2012; Gupta et al 2014; Cunha-Neto et al 1998), we measured the levels of inflammatory cells in mouse livers. We found that the livers of HFD fed infected mice contained fewer inflammatory cells (50%) compared to RD fed infected mice (Fig 3 and Supplemental fig 3), suggesting that HFD prevents the infiltration of inflammatory cells into the liver during acute infection.…”

Section: Discussionmentioning

confidence: 99%

Diet regulates liver autophagy differentially in murine acute Trypanosoma cruzi infection

et al. 2016

View full text Add to dashboard Cite

Chagas disease is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi, which affects about 10 million people in its endemic regions of Latin America. After the initial acute stage of infection, 60-80% of infected individuals remain asymptomatic for several years to a lifetime; however, the rest develop the debilitating symptomatic stage, which affects the nervous system, digestive system and heart. The challenges of Chagas disease have become global due to immigration. Despite well documented dietary changes accompanying immigration, as well as a transition to a western style diet in the Chagas endemic regions, the role of host metabolism in the pathogenesis of Chagas disease remains underexplored. We have previously used a mouse model to show that host diet is a key factor regulating cardiomyopathy in Chagas disease. In this study we investigated the effect of a high fat diet on liver morphology and physiology, lipid metabolism, immune signaling, energy homeostasis, and stress responses in the murine model of acute T. cruzi infection. Our results indicate that in T. cruzi infected mice diet differentially regulates several liver processes, including autophagy, a stress response mechanism, with corresponding implications for human Chagas disease patients.

show abstract

“…The proinflammatory markers TNF-␣, ROS, and ·NO are indicators of ms that have been activated for innate immune defense (22). Indeed, murine and human ms incubated with LPS/ IFN-␥ exhibited a Ͼ1,000-fold increase in TNF-␣ production at 3 h (Fig.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Promote Oxidative Metabolism To Drive Nitric Oxide Generation in Response to Trypanosoma cruzi

et al. 2016

Self Cite

View full text Add to dashboard Cite

dTrypanosoma cruzi is the causative agent of chronic chagasic cardiomyopathy. Why macrophages (ms), the early responders to infection, fail to achieve parasite clearance is not known. Mouse (RAW 264.7) and human (THP-1 and primary) ms were infected for 3 h and 18 h with T. cruzi TcI isolates, SylvioX10/4 (SYL, virulent) and TCC (nonpathogenic), which represent m stimulation and infection states, respectively. Ms incubated with lipopolysaccharide and gamma interferon (LPS/IFN-␥) and with interleukin-4 (IL-4) were used as controls. We monitored the cytokine profile (using enzyme-linked immunosorbent assay [ELISA]), reactive oxygen species (ROS; fluorescent probes), nitric oxide (·NO; Griess assay), and metabolic state using a customdesigned mitoxosome array and Seahorse XF24 Analyzer. LPS/IFN-␥ treatment of ms elicited a potent increase in production of tumor necrosis alpha (TNF-␣) at 3 h and of ROS and ·NO by 18 h. Upon SYL infection, murine ms elicited an inflammatory cytokine profile (TNF-␣ > > TGF-␤ ؉ IL-10) and low levels of ·NO and ROS production. LPS/IFN-␥ treatment resulted in the inhibition of oxidative metabolism at the gene expression and functional levels and a switch to the glycolytic pathway in ms, while IL-4-treated ms utilized oxidative metabolism to meet energy demands. SYL infection resulted in an intermediate functional metabolic state with increased mitoxosome gene expression and glycolysis, and IFN-␥ addition shut down the oxidative metabolism in SYL-infected ms. Further, TCC-and SYL-stimulated ms exhibited similar levels of cell proliferation and production of TNF-␣ and ROS, while TCC-stimulated ms exhibited up to 2-fold-higher levels of oxidative metabolism and ·NO production than SYL-infected ms. Inhibiting ATP-coupled O 2 consumption suppressed the ·NO generation in SYL-infected ms. Mitochondrial oxygen consumption constitutes a mechanism for stimulating ·NO production in ms during T. cruzi infection. Enhancing the oxidative metabolism provides an opportunity for increased ·NO production and pathogen clearance by ms to limit disease progression. Chagas cardiomyopathy is a neglected debilitating disease caused by the blood-borne parasite Trypanosoma cruzi. T. cruzi isolates are classified within six genetic groups (TcI to TcVI) which give insight into the evolution of the parasite (1). The virulent T. cruzi strain SylvioX10/4 (SYL) (2) and the nonpathogenic T. cruzi isolate (TCC) (3) are both of the TcI lineage which is considered to be the most common cause of disease in the Southern zone countries of South America, Central America, and Mexico. In mice and rats, SYL elicits acute parasitemia and persistent inflammatory infiltrate and injury in the myocardium and skeletal muscle during the chronic disease phase (4), while infection with the TCC isolate results in no detectable parasitemia or tissue injury (5).Macrophages (ms) serve as the first responders to T. cruzi infection, and their inflammatory activation exerts cytotoxic effects via NADPH oxidase (NOX)-mediated superoxide (O 2 · Ϫ ) ...

show abstract

Serum-Mediated Activation of Macrophages Reflects TcVac2 Vaccine Efficacy against Chagas Disease

Cited by 19 publications

References 45 publications

Gene Expression Profiling and Functional Characterization of Macrophages in Response to Circulatory Microparticles Produced during <b><i>Trypanosoma cruzi</i></b> Infection and Chagas Disease

Gene Expression Profiling and Functional Characterization of Macrophages in Response to Circulatory Microparticles Produced during <b><i>Trypanosoma cruzi</i></b> Infection and Chagas Disease

Diet regulates liver autophagy differentially in murine acute Trypanosoma cruzi infection

Macrophages Promote Oxidative Metabolism To Drive Nitric Oxide Generation in Response to Trypanosoma cruzi

Contact Info

Product

Resources

About