Hemotrophic Mycoplasmas Induce Programmed Cell Death in Red Blood Cells

Felder, Kathrin M.; Hoelzle, Katharina; Ritzmann, M.; Kilchling, Tim; Schiele, Daniela; Heinritzi, K.; Groebel, Katrin; Hoelzle, Ludwig E.

doi:10.1159/000329957

Cited by 84 publications

(59 citation statements)

References 30 publications

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“…Guimaraes et al (23) hypothesized that the extensive scavenging of M. suis for glucose, inosine, hypoxanthine, amino acids, ribose, and NADH/ NADPH from the host cell increases the oxidative stress and consequently reduces the life span of red blood cells, which aggravates anemia. This hypothesis is in accordance with our previous findings of increased rates of programmed cell death in M. suisinfected red blood cells, i.e., eryptosis (20).…”

Section: Resultssupporting

confidence: 94%

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Insights into the Gene Expression Profile of Uncultivable Hemotrophic Mycoplasma suis during Acute Infection, Obtained Using Proteome Analysis

et al. 2012

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f Hemotrophic mycoplasmas, bacteria without cell walls whose niche is the erythrocytes of their hosts, have never been cultivated in vitro. Therefore, knowledge of their pathogenesis is fundamental. Mycoplasma suis infects pigs, causing either acute fatal hemolytic anemia or chronic low-grade anemia, growth retardation, and immune suppression. Recently, the complete genomes of two hemotrophic mycoplasma species, M. suis and M. haemofelis, were sequenced, offering new strategies for the analysis of their pathogenesis. In this study we implemented a proteomic approach to identify M. suis proteins during acute infection by using tandem mass spectrometry. Twenty-two percent of the predicted proteins encoded in M. suis strain KI_3806 were identified. These included nearly all encoded proteins of glycolysis and nucleotide metabolism. The proteins for lipid metabolism, however, were underrepresented. A high proportion of the detected proteins are involved in information storage and processing (72.6%). In addition, several proteins of different functionalities, i.e., posttranslational modification, membrane genesis, signal transduction, intracellular trafficking, inorganic ion transport, and defense mechanisms, were identified. In its reduced genome, M. suis harbors 65.3% (strain Illinois) and 65.9% (strain KI_3806) of the genes encode hypothetical proteins. Of these, only 6.3% were identified at the proteome level. All proteins identified in this study are present in both M. suis strains and are encoded in more highly conserved regions of the genome sequence. In conclusion, our proteome approach is a further step toward the elucidation of the pathogenesis and life cycle of M. suis as well as the establishment of an in vitro cultivation system. Mycoplasma suis belongs to the hemotrophic mycoplasmas (hemoplasmas) that parasitize the red blood cells of a wide range of domestic and wild animals (32). The resulting disease is known as infectious anemia of pigs (IAP) or, historically, as porcine eperythrozoonosis. Acute IAP is characterized by fever, hemolytic anemia, severe hypoglycemia, and sepsis, with high numbers of M. suis cells in the blood (up to 10 12 /ml) (22, 32). Antibiotic treatment saves the animals from death, but M. suis is not eliminated (latent infection of carrier animals). Chronic lowgrade M. suis infections vary from asymptomatic infections to a range of clinical conditions, including anemia and mild icterus in newborns, growth retardation in feeder pigs, and poor reproductive performance in sows (27,28,32). Moreover, the increased incidence of respiratory and enteric infections found among infected feeder pigs has been associated with the immunosuppressive effect of M. suis infections (88).Hemotrophic mycoplasmas are not cultivable in vitro. Until recently, the lack of in vitro-derived bacteria has hampered wholegenome sequencing and proteome studies. To identify proteins, cross-species comparisons were necessary. However, the identifications were not confident due to uncertain protein assignments (unpu...

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Section: Resultssupporting

confidence: 94%

“…Animal experiments were performed as described earlier (20,22). All animal experiments were conducted with the approval of the Veterinary Office of Zurich, Switzerland, according to national and international guidelines.…”

Section: Ethics Statementmentioning

confidence: 99%

Insights into the Gene Expression Profile of Uncultivable Hemotrophic Mycoplasma suis during Acute Infection, Obtained Using Proteome Analysis

et al. 2012

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“…To this end, total RNA was isolated using the Trifast Reagent (Peqlab). Reverse transcription of 2 g RNA was performed using oligo(dT) [12][13][14][15][16][17][18] 2% agarose gel electrophoresis. All PCRs were performed in duplicate, and mRNA fold changes were calculated by the 2 Ϫ⌬⌬CT method using GAPDH as internal reference.…”

Section: Methodsmentioning

confidence: 99%

Sphingomyelinase-induced adhesion of eryptotic erythrocytes to endothelial cells

Abed

Towhid

Mia

et al. 2012

American Journal of Physiology-Cell Physiology

141

101

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Eryptosis, the suicidal erythrocyte death, leads to cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptotic erythrocytes adhere to the vascular wall by binding of phosphatidylserine to the CXC chemokine ligand 16 (CXCL16). Stimulators of eryptosis include increased cytosolic Ca 2ϩ activity, energy depletion, and activation of ceramide-producing sphingomyelinase. The present study explored whether sphingomyelinase triggers erythrocyte adhesion to endothelial cells. To this end, human erythrocytes were exposed for 6 h to bacterial sphingomyelinase (1-10 mU/ml) and phosphatidylserine exposure was estimated from fluorescent annexin-V-binding, cell volume from forward scatter in FACS-analysis, erythrocyte adhesion to human umbilical vein endothelial cells (HUVEC) from trapping of labeled erythrocytes in a flow chamber under flow conditions at arterial shear rates, and CXCL16 protein abundance utilizing Western blotting and FACS analysis of fluorescent antibody binding. As a result, sphingomyelinase (Ն1 mU/ml) triggered cell shrinkage, phosphatidylserine exposure and erythrocyte adhesion to HUVEC, effects blunted by Ca 2ϩ removal. Adhesion was significantly blunted by phosphatidylserine-coating annexin-V (5 l/ml), following addition of neutralizing antibodies against endothelial CXCL16 (4 g/ml) and following silencing of the CXCL16 gene with small interfering RNA. Pretreatment of HUVEC with sphingomyelinase upregulated CXCL16 protein abundance. Six hours pretreatment of HUVEC with sphingomyelinase (10 mU/ml) or C6-ceramide (50 M) augmented erythrocyte adhesion following a 30-min treatment with Ca 2ϩ ionophore ionomycin (1 M) or following energy depletion by 48-h glucose removal. Thus exposure to sphingomyelinase or C6-ceramide triggers eryptosis followed by phosphatidylserine-and CXCL16-sensitive adhesion of eryptotic erythrocytes to HUVEC.

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“…Accelerated suicidal erythrocyte death may contribute to the anemia of several clinical disorders and eryptosis may be triggered by a wide variety of xenobiotics [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. …”

Section: Introductionmentioning

confidence: 99%

The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

Ahmed

Langer

Abed

et al. 2013

Kidney Blood Press Res

150

123

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Background: Anemia is a major complication of end stage renal disease. The anemia is mainly the result of impaired formation of erythrocytes due to lack of erythropoietin and iron deficiency. Compelling evidence, however, points to the contribution of accelerated erythrocyte death, which decreases the life span of circulating erythrocytes. Erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i). Erythrocytes could be sensitized to cytosolic Ca²⁺ by ceramide. In end stage renal disease, eryptosis may possibly be stimulated by uremic toxins. The present study explored, whether the uremic toxin acrolein could trigger eryptosis. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, [Ca²⁺]_i from Fluo3-fluorescence, and ceramide from fluorescent antibodies. Results: A 48 h exposure to acrolein (30 － 50 µM) did not significantly modify [Ca²⁺]_i but significantly decreased forward scatter and increased annexin-V-binding. Acrolein further triggered slight, but significant hemolysis and increased ceramide formation in erythrocytes. Acrolein (50 µM) induced annexin-V-binding was significantly blunted in the nominal absence of extracellular Ca²⁺. Acrolein augmented the annexin-V-binding following treatment with Ca²⁺ ionophore ionomycin (1 µM). Conclusion: Acrolein stimulates suicidal erythrocyte death or eryptosis, an effect at least in part due to stimulation of ceramide formation with subsequent sensitisation of the erythrocytes to cytosolic Ca²⁺.

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Hemotrophic Mycoplasmas Induce Programmed Cell Death in Red Blood Cells

Cited by 84 publications

References 30 publications

Insights into the Gene Expression Profile of Uncultivable Hemotrophic Mycoplasma suis during Acute Infection, Obtained Using Proteome Analysis

Insights into the Gene Expression Profile of Uncultivable Hemotrophic Mycoplasma suis during Acute Infection, Obtained Using Proteome Analysis

Sphingomyelinase-induced adhesion of eryptotic erythrocytes to endothelial cells

The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

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