Malaria-induced bacteremia has been shown to result from intestinal mast cell (MC) activation. The appearance of MCs in the ileum and increased intestinal permeability to enteric bacteria are ...preceded by an early Th2-biased host immune response to infection, characterized by the appearance of IL-4, IL-10, mast cell protease (Mcpt)1 and Mcpt4, and increased circulating basophils and eosinophils. Given the functional similarities of basophils and MCs in the context of allergic inflammation and the capacity of basophils to produce large amounts of IL-4, we sought to define the role of basophils in increased intestinal permeability, in MC influx, and in the development of bacteremia in the context of malaria. Upon infection with nonlethal
17XNL, Basoph8 × ROSA-DTα mice or baso (-) mice that lack basophils exhibited increased intestinal permeability and increased ileal MC numbers, without any increase in bacterial 16S ribosomal DNA copy numbers in the blood, relative to baso (+) mice. Analysis of cytokines, chemokines, and MC-associated factors in the ileum revealed significantly increased TNF-α and IL-13 at day 6 postinfection in baso (-) mice compared with baso (+) mice. Moreover, network analysis of significantly correlated host immune factors revealed profound differences between baso (-) and baso (+) mice following infection in both systemic and ileal responses to parasites and translocated bacteria. Finally, basophil depletion was associated with significantly increased gametocytemia and parasite transmission to
mosquitoes, suggesting that basophils play a previously undescribed role in controlling gametocytemia and, in turn, mammalian host-to-mosquito parasite transmission.
Authors’ Reply Wu, Haojia; Kirita, Yuhei; Donnelly, Erinn L. ...
Journal of the American Society of Nephrology,
4/2019, Letnik:
30, Številka:
4
Journal Article
Authors’ Reply Wu, Haojia; Kirita, Yuhei; Donnelly, Erinn L. ...
Journal of the American Society of Nephrology,
03/2019, Letnik:
30, Številka:
4
Journal Article
Malaria, caused by parasites in the genus Plasmodium and vectored by Anopheles mosquitoes, remains an enormous public health burden throughout much of the world, with 627,000 deaths and 241 million ...cases reported by the World Health Organization in 2020. Bacteremia, the presence of bacteria in the bloodstream, is a potentially life-threatening complication that contributes to morbidity and mortality associated with malaria and occurs across the spectrum of ages and disease severities. Malaria-induced bacteremia has previously been shown in mouse models to result from intestinal mast cell (MC) influx or mastocytosis. However, the upstream drivers of mastocytosis in the ileum following infection remain unclear. Interestingly, basophils, short-lived circulating granulocytes associated with allergic inflammation, have been shown to increase in number preceding the onset of MC influx and increased intestinal permeability. The role of basophils in malaria disease biology is not well understood, but given that they are strongly activated by malaria parasites and early cytokine signals such as IL-18 following infection, and their ability to release cytokines and mediators that can activate MCs, we sought to define a role for these cells in the development of mastocytosis, intestinal permeability and bacteremia during malaria infection. Remarkably, our studies showed these cells to be protective against the development of increased intestinal permeability and MC influx, with no effect on bacterial burdens. The depletion of basophils also altered the intestinal and systemic immune response to both parasites and translocating bacteria, suggesting these cells play a role in fine-tuning the immune response to infection. Additionally, we found that while basophil depletion did not alter overall parasitemia, it did increase the number of gametocytes (sexual stage parasites) in circulation and in turn, the intensity of infection in the mosquito vector. Our subsequent studies demonstrated that the protective effects of basophils on the intestinal barrier are at least partially mediated via IL-18 signaling. The effect of IL-18 signaling via basophils on transmission is complex, as mice lacking the IL-18 receptor on basophils showed no difference in gametocyte numbers but were less likely to infect mosquitoes. Future directions of this work should be directed at uncovering the mechanism(s) by which basophils effect gametocyte numbers and transmission, as this could have implications for malaria control efforts.
Authors' Reply Wu, Haojia; Kirita, Yuhei; Donnelly, Erinn L ...
Journal of the American Society of Nephrology,
04/2019, Letnik:
30, Številka:
4
Journal Article
Authors' Reply Wu, Haojia; Kirita, Yuhei; Donnelly, Erinn L ...
Journal of the American Society of Nephrology,
04/2019, Letnik:
30, Številka:
4
Journal Article
Background Bioavailability of nitric oxide ( NO ) and hydrogen sulfide (H 2 S) is reduced in heart failure ( HF ). Recent studies suggest cross‐talk between NO and H 2 S signaling. We previously ...reported that sodium nitrite (Na NO 2 ) ameliorates myocardial ischemia‐reperfusion injury and HF. Nuclear factor‐erythroid‐2‐related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H 2 S. We examined the Na NO 2 effects on endogenous H 2 S bioavailability and Nrf2 activation in mice subjected to ischemia‐induced chronic heart failure (CHF). Methods and Results Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. Na NO 2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic ( LVEDD ) and systolic dimensions ( LVESD ) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein‐related assays. We found that Na NO 2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia‐induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in Na NO 2 ‐treated mice as compared to vehicle, suggesting a reduction in oxidative stress. Na NO 2 therapy markedly increased expression of Cu,Zn‐superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, Na NO 2 upregulated the activity of Nrf2, as well as H 2 S‐producing enzymes, and ultimately increased H 2 S bioavailability in ischemia‐induced CHF in mice as compared with vehicle. Conclusions Our results demonstrate that Na NO 2 therapy significantly improves LV function via increasing H 2 S bioavailability, Nrf2 activation, and antioxidant defenses.
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