Infection Vs. Reinfection: The Immunomodulation of Erythropoiesis

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jun 19

PMID 38892340

Authors

Ana Catarina Pego

Illyane Sofia Lima

Ana Catarina Martins

Ines Sa-Pereira

Gracelino Martins

Raffaella Gozzelino

Affiliations

Soon will be listed here.

Abstract

Severe malarial anemia (SMA) increases the morbidity and mortality of , the causative agent of malaria. SMA is mainly developed by children and pregnant women in response to the infection. It is characterized by ineffective erythropoiesis caused by impaired erythropoietin (EPO) signaling. To gain new insights into the pathogenesis of SMA, we investigated the relationship between the immune system and erythropoiesis, conducting comparative analyses in a mouse model of malaria. Red blood cell (RBC) production was evaluated in infected and reinfected animals to mimic endemic occurrences. Higher levels of circulating EPO were observed in response to (re)infection. Despite no major differences in bone marrow erythropoiesis, compensatory mechanisms of splenic RBC production were significantly reduced in reinfected mice. Concomitantly, a pronounced immune response activation was observed in erythropoietic organs of reinfected animals in relation to single-infected mice. Aged mice were also used to mimic the occurrence of malaria in the elderly. The increase in symptom severity was correlated with the enhanced activation of the immune system, which significantly impaired erythropoiesis. Immunocompromised mice further support the existence of an immune-shaping regulation of RBC production. Overall, our data reveal the strict correlation between erythropoiesis and immune cells, which ultimately dictates the severity of SMA.

References

Weiss G, Traore B, Kayentao K, Ongoiba A, Doumbo S, Doumtabe D . The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathog. 2010; 6(5):e1000912. PMC: 2873912. DOI: 10.1371/journal.ppat.1000912. View

Chen K, Liu J, Heck S, Chasis J, An X, Mohandas N . Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci U S A. 2009; 106(41):17413-8. PMC: 2762680. DOI: 10.1073/pnas.0909296106. View

Greenwood B . The epidemiology of malaria. Ann Trop Med Parasitol. 1998; 91(7):763-9. DOI: 10.1080/00034989760518. View

Burgmann H, Looareesuwan S, Kapiotis S, Viravan C, Vanijanonta S, Hollenstein U . Serum levels of erythropoietin in acute Plasmodium falciparum malaria. Am J Trop Med Hyg. 1996; 54(3):280-3. DOI: 10.4269/ajtmh.1996.54.280. View

Gozzelino R, Andrade B, Larsen R, Luz N, VAnoaica L, Seixas E . Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe. 2012; 12(5):693-704. DOI: 10.1016/j.chom.2012.10.011. View

Huebers H, Finch C . The physiology of transferrin and transferrin receptors. Physiol Rev. 1987; 67(2):520-82. DOI: 10.1152/physrev.1987.67.2.520. View

Saha A, Chauhan S, Bagchi T . Effect of recombinant malarial antigen on monocyte functionality. Trans R Soc Trop Med Hyg. 2016; 110(8):480-6. DOI: 10.1093/trstmh/trw049. View

Moxon C, Gibbins M, McGuinness D, Milner Jr D, Marti M . New Insights into Malaria Pathogenesis. Annu Rev Pathol. 2019; 15:315-343. DOI: 10.1146/annurev-pathmechdis-012419-032640. View

Perkins D, Were T, Davenport G, Kempaiah P, Hittner J, Ongecha J . Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sci. 2011; 7(9):1427-42. PMC: 3221949. DOI: 10.7150/ijbs.7.1427. View

10.

Phillips M, Burrows J, Manyando C, Hooft van Huijsduijnen R, Van Voorhis W, Wells T . Malaria. Nat Rev Dis Primers. 2017; 3:17050. DOI: 10.1038/nrdp.2017.50. View

11.

Evans K, Hansen D, van Rooijen N, Buckingham L, Schofield L . Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes. Blood. 2005; 107(3):1192-9. PMC: 1895912. DOI: 10.1182/blood-2005-08-3460. View

12.

Taylor A, Watson J, Chu C, Puaprasert K, Duanguppama J, Day N . Resolving the cause of recurrent Plasmodium vivax malaria probabilistically. Nat Commun. 2019; 10(1):5595. PMC: 6898227. DOI: 10.1038/s41467-019-13412-x. View

13.

Ghosh D, Stumhofer J . The spleen: "epicenter" in malaria infection and immunity. J Leukoc Biol. 2021; 110(4):753-769. PMC: 8518401. DOI: 10.1002/JLB.4RI1020-713R. View

14.

Haldar K, Mohandas N . Malaria, erythrocytic infection, and anemia. Hematology Am Soc Hematol Educ Program. 2009; :87-93. PMC: 2933134. DOI: 10.1182/asheducation-2009.1.87. View

15.

Pathak V, Ghosh K . Erythropoiesis in Malaria Infections and Factors Modifying the Erythropoietic Response. Anemia. 2016; 2016:9310905. PMC: 4789361. DOI: 10.1155/2016/9310905. View

16.

Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R . Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci U S A. 2009; 106(37):15837-42. PMC: 2728109. DOI: 10.1073/pnas.0903419106. View

17.

Weiss G, Ganz T, Goodnough L . Anemia of inflammation. Blood. 2018; 133(1):40-50. PMC: 6536698. DOI: 10.1182/blood-2018-06-856500. View

18.

Stephens R, Albano F, Quin S, Pascal B, Harrison V, Stockinger B . Malaria-specific transgenic CD4(+) T cells protect immunodeficient mice from lethal infection and demonstrate requirement for a protective threshold of antibody production for parasite clearance. Blood. 2005; 106(5):1676-84. DOI: 10.1182/blood-2004-10-4047. View

19.

Horie K, Sasanuma H, Kudo T, Fujita S, Miyauchi M, Miyao T . Down-regulation of GATA1-dependent erythrocyte-related genes in the spleens of mice exposed to a space travel. Sci Rep. 2019; 9(1):7654. PMC: 6529412. DOI: 10.1038/s41598-019-44067-9. View

20.

Skorokhod O, Caione L, Marrocco T, Migliardi G, Barrera V, Arese P . Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal. Blood. 2010; 116(20):4328-37. DOI: 10.1182/blood-2010-03-272781. View