Mechanism of splenic cell death and host mortality in a Plasmodium yoelii malaria model

Abstract

Malaria is a fatal disease that displays a spectrum of symptoms and severity, which are determined by complex host-parasite interactions. It has been difficult to study the effects of parasite strains on disease severity in human infections, but the mechanisms leading to specific disease phenotypes can be investigated using strains of rodent malaria parasites that cause different disease symptoms in inbred mice. Using a unique mouse malaria model, here we investigated the mechanisms of splenic cell death and their relationship to control of parasitemia and host mortality. C57BL/6 mice infected with Plasmodium yoelii nigeriensis N67C display high levels of pro-inflammatory cytokines and chemokines (IL-6, IFN-γ, TNF-α, CXCL1, and CCL2) and extensive splenic damage with dramatic reduction of splenic cell populations. These disease phenotypes were rescued in RAG2−/−, IFN-γ−/−, or T cell depleted mice, suggesting IFN-γ and T cell mediated disease mechanisms. Additionally, apoptosis was one of the major pathways involved in splenic cell death, which coincides with the peaks of pro-inflammatory cytokines. Our results demonstrate the critical roles of T cells and IFN-γ in mediating splenic cell apoptosis, parasitemia control, and host lethality and thus may provide important insights for preventing/reducing morbidity associated with severe malaria in humans.

Plasmodium yoelii Erythrocyte-Binding-like Protein Modulates Host Cell Membrane Structure, Immunity, and Disease Severity

“…Parasitemia was monitored by microscopic examination of Giemsa-stained thin tail blood smears. Additional methods can be found in the supplemental materials (51)(52)(53).…”

Detection of host pathways universally inhibited after Plasmodium yoelii infection for immune intervention

“…For example, Plasmodium y. nigeriensis N67 (N67) triggers an early IFN-I response leading to suppression of parasitemia day 7 post infection ( p.i ), whereas its isogenic parasite P. y. nigeriensis N67C stimulates a strong inflammatory response resulting in host death by day 7 p.i . 12 , 14 , 15 . Infection of mice with P. y. yoelii 17XL (or YM) results in host death within 7 days due to high parasitemia, whereas mice infected with its isogenic strain P. y. yoelii 17XNL recover from infection 13 , 16 – 18 .…”

Host-Malaria Parasite Interactions and Impacts on Mutual Evolution

“…A replacement of Cys to Arg (at position 731 or C731R) at the second Cys position in region 6 of PyEBL was found to be the major determinant for the difference in virulence and parasite growth; however, this mutation cannot explain the entire parasite growth phenotype (Otsuki et al, 2009). A second example is the isogenic parasites of P. y. nigeriensis N67 (N67) and P. y. nigeriensis N67C (N67C) that also have very different disease phenotypes in C57BL/6 mice, including parasitemia, tissue pathology, and host mortality (Wu et al, 2014;Lacerda-Queiroz et al, 2017). Parasitemia in C57BL/6 infected with N67 (1 × 10 6 iRBCs) increases to ∼40-50% day 5 pi, declines to below 10% on day 7 pi, and increases to ∼60% at day 15 pi (Wu et al, 2014).…”

“…The N67 infected mice die at ∼day 20 pi. Mice infected with N67C have ∼50% parasitemia day 6 pi and begin to die day 7 pi with declining parasitemia (Lacerda-Queiroz et al, 2017). Similarly, a substitution of Cys to Tyr (C741Y) in the protein trafficking domain of PyEBL between N67 and N67C parasites was found to influence disease phenotypes and host mortality (Peng et al, 2020).…”