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Uterine section of an infected SLE mouse (A) or infected WT mouse (D) showing massive decidual necrosis at day 8 post-conception at low-magnification (1.25×). High-magnification views (4× and 10×) of uteri from an infected SLE (B–C) and infected WT mouse (E–F). Uterine section of an uninfected SLE (G) or uninfected WT mouse (J) showing normal morphology of an 8 day old fetus at low-magnification (1.25×). High-magnification views (4× and 10×) of uteri from a non-infected SLE (H–I) or uninfected WT mouse (K–L). Uteri from all mice were analyzed by a pathologist (n = 72).
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Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be me...
Citations
... Infection with Plasmodium chabaudi chabaudi Landau, 1965 of mice is a model of human malaria. This rodent malaria has many features in common with human disease (Cox et al. 1987, Gilks et al. 1990, Mackinnon et al. 2002 and has been used extensively in laboratory research on malaria (Barclay et al. 2012, Schneider et al. 2012, Spence et al. 2012, Cameron et al. 2013, Waisberg et al. 2013. Infection with P. c. chabaudi AS is typically self-resolving in C57BL/6 mice; however, it is lethal in A/J mice (Langhorne et al. 2002). ...
Bacillus Calmette-Guérin (BCG) is an attenuated Mycobacterium tuberculosis vaccine. We performed a series of co-infection experiments with BCG-Plasmodium chabaudi chabaudi Landau, 1965 AS using C57BL/6 mice to analyse whether BCG can affect the development of protective immunity to infection with Plasmodium spp. and the mechanism of this protection. We divided mice into four groups: BCG-inoculation 4 weeks prior to P. c. chabaudi AS infection (B-4w-Pc); simultaneous BCG-inoculation and P. c. chabaudi AS infection (Pc+B); BCG-inoculation 3 days post P. c. chabaudi AS (Pc-3-B) infection; and mono-P. c. chabaudi AS infection as control (Pc). The parasitemia level in the B-4w-Pc group was noticeably higher than control group at 6-19 days post infection (dpi). Compared with the control group, the proportion of CD4(+)CD69(+) T cells was significantly reduced 5, 8 and 12 dpi, but the proportion of CD4(+)CD25(+)Foxp3(+) Tregs was significantly increased in the B-4w-Pc group on 5 and 8 dpi. The B-4w-Pc group also demonstrated reduced levels of IFN-γ and TNF-α on 5 and 8 dpi and significantly elevated level of IL-10 on 12 dpi. There were significantly fewer mDCs (CD11c(+)CD11b(+)) and pDCs (CD11c(+)B220(+)) in the B-4w-Pc group than the control group at all the time points post infection and the expression of MHC II was noticeably reduced on day 8 pi. Our findings confirmed that BCG inoculation prior to Plasmodium infection resulted in excessive activation and proliferation of Tregs and upregulation of anti-inflammatory mediators, which inhibited establishment of a Th1-dominant immune response during the early stages of Plasmodium infection by inhibiting dendritive cells response. BCG inoculation prior to P. c. chabaudi AS infection may contribute to overgrowth of parasites as well as mortality in mice.
... Hemoglobin levels were measured every other day using an Hp201+ (HemoCue, Ä ngelholm, Sweden) using blood from the tail tip. All mice were evaluated daily for the presence of clinical signs of severe malaria using simple scoring adapted from the SNAP scoring system [26,75,76]. Animals were scored by evaluating five categories: interactions, cage grasp, visual placing, gait/posture/appearance, and capacity to hold their body weight on a baton [75]. ...
The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood.
We undertook testing Tempol-a superoxide dismutase (SOD) mimetic and pleiotropic intracellular antioxidant-in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol inhibited LPS-induced production of TNF-α, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants-such as α-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ) and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (gp91(phox-/-)) or mice treated with inhibitors of SOD (diethyldithiocarbamate) or NADPH oxidase (diphenyleneiodonium) did not show protection or exacerbation for CM.
Results with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic targeting of intracellular ROS in CM is discussed.
Malaria is an infectious disease that afflicts nearly 500 million people each year in parts of the world that are least equipped to cope with its devastation, including sub-Saharan Africa. This chapter reviews the acquisition of immunity to uncomplicated malaria and to severe disease. It presents the most striking features of the acquisition of immunity to uncomplicated disease are the years of exposure to parasites that is required to achieve protection. The chapter notes that all young children are susceptible to P. falciparum infections and to uncomplicated disease but that only a minority of children appears susceptible to severe disease. It suggests that important resistance genes may be those that are associated with susceptibility to autoimmune disease and that pathogens of interest may be virus in the herpes family. The chapter concludes that the effort to control inflammation during malaria, while essential to survival, may be deleterious to the acquisition of adaptive malaria immunity.
