Mechanisms of Splenic Control of Murine Malaria: Tissue Culture Studies of the Erythropoietic Interplay of Spleen, Bone Marrow, and Blood in Lethal (Strain 17XL) Plasmodium Yoelii Malaria in BALB/c Mice

Weiss, Leon; Johnson, Joseph R.; Weidanz, William P.

doi:10.4269/ajtmh.1989.41.135

Cited by 38 publications

(29 citation statements)

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“…In contrast to the human studies cited, a decrease in mouse bone marrow cellularity of between 40% to 75% of normal levels is seen at peak parasitemia or death, whichever is reached first, [62][63][64][65] with reductions in cellularity proportional to the severity of infection. 54,63,66 However, despite these discrepancies with the reported pathology in human infection, reports of only a minimal reduction in the total number of BFU-Es, and at best only a modest increase in CFU-Es in mice, [63][64][65][66] suggest that the bone marrow is unable to compensate for RBC loss in both humans and mice through increased erythropoiesis during the acute phase of infection. At present there are no studies reporting the production of dyserythropoietic erythroblasts during mouse malaria infection, most probably because there are few chronic infection models.…”

Section: Erythropoietic Suppression and Dyserythropoiesismentioning

confidence: 81%

“…In mice, massive splenomegaly is observed with cellularity increasing 20-fold at peak parasitemia compared with that of naive animals. 64,81 This rise is reflected in greater erythroid progenitor populations with up to an 8-fold increase of BFU-E and 100-fold increase of CFU-E total numbers in the spleen. 65,66 Interestingly, there is a strong correlation between the severity of disease and the observed increases in splenic erythropoiesis.…”

Section: Org Frommentioning

confidence: 99%

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Malarial anemia: of mice and men

Lamikanra

Brown²,

Potocnik³

et al. 2007

Blood

229

215

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Severe malaria is manifest by a variety of clinical syndromes dependent on properties of both the host and the parasite. In young infants, severe malarial anemia (SMA) is the most common syndrome of severe disease and contributes substantially to the considerable mortality and morbidity from malaria. There is now growing evidence, from both human and mouse studies of malaria, to show that anemia is due not only to increased hemolysis of infected and clearance of uninfected red blood cells (RBCs) but also to an inability of the infected host to produce an adequate erythroid response. In this review, we will summarize the recent clinical and experimental studies of malaria to highlight similarities and differences in human and mouse pathology that result in anemia and so inform the use of mouse models in the study of severe malarial anemia in humans. Malaria in humansThe vast majority of morbidity and mortality from malaria is caused by infection with Plasmodium falciparum, although P vivax, P ovale, and P malariae also are responsible for human infections. The total burden of disease has recently been estimated to 515 million episodes annually and malaria is responsible for 18% of all childhood deaths in sub-Saharan Africa, equivalent to 800 000 deaths each year. 1,2 The study of malarial anemia has somewhat belatedly excited academic and professional interest. Severe malarial anemia (SMA) certainly merits concern as a major public health problem because of the very large numbers of children affected, and it is likely that these numbers may increase as drug resistance spreads. Concerns have also been raised by data from recent vaccine studies, which suggest that monkeys immunized with erythrocytic-stage antigens, and that have acquired protection from acute infection, may succumb to severe anemia during a subacute or chronic phase of infection. 3,4 Moreover, there is increasing awareness of the difficulty of satisfactory treatment by blood transfusion outside specialist centers in many endemic areas as a result of the limited availability of a rapid and safe supply of blood. 1,5 SMA is seen most frequently in areas of very high malaria transmission and most commonly in young children and pregnant women. 6 The prevalence of anemia, defined as a hematocrit (Hct) level higher than 0.33, in malaria-endemic areas of Africa, varies between 31% and 91% in children, and between 60% and 80% in pregnant women. 7,8 Given the high degree of morbidity that is associated with SMA in children, this term will be used to refer to severe anemia in this group, unless stated otherwise.It is very difficult to determine the number of cases of severe anemia attributable to malaria as the WHO definition of SMA (a hemoglobin [Hb] concentration of Ͻ 50 g/L [5 g/dL], or a Hct Ͻ 0.15, in the presence of a parasitemia Ͼ 10 000 parasites per microliter [L], and a normocytic blood film) may exclude the considerable proportion of children admitted with severe anemia that has a blood smear negative for malaria parasites but that responds to an...

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Section: Erythropoietic Suppression and Dyserythropoiesismentioning

confidence: 81%

Section: Org Frommentioning

confidence: 99%

Malarial anemia: of mice and men

Lamikanra

Brown²,

Potocnik³

et al. 2007

Blood

229

215

View full text Add to dashboard Cite

show abstract

“…NTS bacteremia in both adults and children is also associated with other conditions resulting in anemia, such as sickle cell disease (36,37). Hemolytic anemia is also a hallmark of pediatric malaria and occurs in part due to the clearance of damaged or parasitized erythrocytes from the circulation by the spleen (8,38,58). Previous experimental studies by Kaye and colleagues have shown that antibody-induced hemolysis prior to infection of mice with S. Typhimurium leads to a more rapidly fatal disease (19,20).…”

mentioning

confidence: 99%

Both Hemolytic Anemia and Malaria Parasite-Specific Factors Increase Susceptibility to NontyphoidalSalmonella entericaSerovar Typhimurium Infection in Mice

Roux¹,

Butler²,

Chau³

et al. 2010

Infect Immun

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Severe pediatric malaria is an important risk factor for developing disseminated infections with nontyphoidal Salmonella serotypes (NTS). While recent animal studies on this subject are lacking, early work suggests that an increased risk for developing systemic NTS infection during malaria is caused by hemolytic anemia, which leads to reduced macrophage microbicidal activity. Here we established a model for oral Salmonella enterica serotype Typhimurium challenge in mice infected with Plasmodium yoelii nigeriensis. Initial characterization of this model showed that 5 days after coinoculation, P. yoelii nigeriensis infection increased the recovery of S. Typhimurium from liver and spleen by approximately 1,000-fold. The increased bacterial burden could be only partially recapitulated by antibody-mediated hemolysis, which increased the recovery of S. Typhimurium from liver and spleen by 10-fold. These data suggested that both hemolysis and P. yoelii nigeriensis-specific factors contributed to the increased susceptibility to S. Typhimurium. The mechanism by which hemolysis impaired resistance to S. Typhimurium was further investigated. In vitro, S. Typhimurium was recovered 24 h after infection of hemophagocytic macrophages in 2-fold-higher numbers than after infection of mock-treated macrophages, making it unlikely that reduced macrophage microbicidal activity was solely responsible for hemolysis-induced immunosuppression during malaria. Infection with P. yoelii nigeriensis, but not antibodymediated hemolysis, reduced serum levels of interleukin-12p70 (IL-12p70) in response to S. Typhimurium challenge. Collectively, studies establishing a mouse model for this coinfection suggest that multiple distinct malaria-induced immune defects contribute to increased susceptibility to S. Typhimurium.

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“…Previous histologic studies have shown that the spleens of animals infected with 17XNL parasites erect a cellular barrier that functions to isolate newly produced reticulocytes away from ongoing infection. In contrast, a competent blood-spleen barrier fails to develop in animals infected with the lethal 17XL strain, resulting in phagocytosis of parasitized erythrocytes and late-stage erythroblasts (30)(31)(32). The spleen plays critical roles in establishing immune responses to infection, particularly the suppression of B-cell proliferative responses in animals infected with nonlethal forms of P. yoelii (29).…”

mentioning

confidence: 99%

Genome-Wide Expression Profiling in Malaria Infection Reveals Transcriptional Changes Associated with Lethal and Nonlethal Outcomes

Schaecher¹,

Kumar

Yadava³

et al. 2005

Infect Immun

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High-density oligonucleotide microarrays are widely used to study gene expression in cells exposed to a variety of pathogens. This study addressed the global genome-wide transcriptional activation of genes in hosts infected in vivo, which result in radically different clinical outcomes. We present an analysis of the gene expression profiles that identified a set of host biomarkers which distinguish between lethal and nonlethal blood stage Plasmodium yoelii malaria infections. Multiple biological replicates sampled during the course of infection were used to establish statistically valid sets of differentially expressed genes. These genes that correlated with the intensity of infection were used to identify pathways of cellular processes related to metabolic perturbations, erythropoiesis, and B-cell immune responses and other innate and cellular immune responses. The transcriptional apparatus that controls gene expression in erythropoiesis was also differentially expressed and regulated the expression of target genes involved in the host's response to malaria anemia. The biological systems approach provides unprecedented opportunities to explore the pathophysiology of hostpathogen interactions in experimental malaria infection and to decipher functionally complex networks of gene and protein interactions.

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Mechanisms of Splenic Control of Murine Malaria: Tissue Culture Studies of the Erythropoietic Interplay of Spleen, Bone Marrow, and Blood in Lethal (Strain 17XL) Plasmodium Yoelii Malaria in BALB/c Mice

Cited by 38 publications

References 0 publications

Malarial anemia: of mice and men

Malarial anemia: of mice and men

Both Hemolytic Anemia and Malaria Parasite-Specific Factors Increase Susceptibility to NontyphoidalSalmonella entericaSerovar Typhimurium Infection in Mice

Genome-Wide Expression Profiling in Malaria Infection Reveals Transcriptional Changes Associated with Lethal and Nonlethal Outcomes

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