Using two phases of the CD4 T cell response to blood‐stage murine malaria to understand regulation of systemic immunity and placental pathology in Plasmodium falciparum infection

Abstract

P. falciparum infection and malaria remain a risk for millions of children and pregnant women.Here, we seek to integrate knowledge of mouse and human T helper cell (Th) responses to bloodstage Plasmodium infection to understand their contribution to protection and pathology. Although there is no complete Th subset differentiation, the adaptive response occurs in two phases in nonlethal rodent Plasmodium infection, coordinated by Th cells. In short, cellular immune responses limit the peak of parasitemia during the first phase; in the second phase, humoral immunity from T cell dependent germinal centers is critical for complete clearance of rapidly changing parasite. A strong IFN-γ response kills parasite, but an excess of TNF compared to regulatory cytokines (IL-10, TGF-β) can cause immunopathology. This common pathway for pathology is associated with anemia, cerebral malaria and placental malaria. These two phases can be used to both understand how the host responds to rapidly growing parasite, and how it attempts to control immunopathology and variation. This dual nature of T cell immunity to Plasmodium is discussed, with particular reference to the protective nature of the continuous generation of effector T cells, and the unique contribution of effector memory T cells.

T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria

“…Both Th1 and Tfh cells are required to eliminate parasites in Plasmodium infection. Previous work on the immune response to P. chabaudi shows that IFN-γ controls the height of the peak of parasitemia, whereas Tfh and IL-21 are required for antibodies to eliminate the parasite ( Perez-Mazliah et al., 2015 , 2017 ; Su and Stevenson, 2002 ; Gbedande et al, 2020 ; Meding and Langhorne, 1991 ). We have found that both types of effector functions are combined in one cell type in this infection ( Carpio et al., 2015 ).…”

“…As both Th1/Tfh and GC Tfh express both CXCR5 and CXCR3, it will be important to study the location of each cell type and interactions with B cells in vivo in our next study. Although we have used multiple models of rodent malaria, and the predictions from these models are often predictive of human malaria immunology ( Stephens et al., 2012 ; Gbedande et al, 2020 ), there are likely to be differences of degree in P. falciparum infection. These models have the potential to inform other immune environments including other persistent pathogens and the response to transformed cells in vivo .…”

CircDCLRE1C Regulated Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Regulating miR-214b-3p/STAT3 Pathway in Macrophages

“…Elevated serum TNF-α levels have been reported to be directly correlated with the severity of Plasmodium falciparum malaria [ 49 ]. IFN-γ stimulated the release of pro-inflammatory cytokines involved in the control of infection [ 50 ]. Elevated levels or injection of IFN-γ could lead to parasite clearance and/or increase host survival [ 51 ].…”

Recent Advances in Understanding the Inflammatory Response in Malaria: A Review of the Dual Role of Cytokines

“…TNF-α. TNF-α plays a pivotal role in increasing phagocytic uptake of parasites, being involved in parasite control [41]. In endemic areas, P. falciparum-specific CD4+ T cells coproducing IFN-γ and TNF-α were detected in patients who underwent P. falciparum infection [42].…”

“…Consecutively, elevated serum TNF-α levels have been reported to directly correlate with the severity of P. falciparum malaria. Moreover, recent research states the role of TNF in lethal malaria forms [41]. A systematic review that included 34 studies showed that elevated levels of TNF-α could be associated with cerebral malaria caused by P. falciparum, but the results are inconsistent.…”