Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype

Guha, Rajan; Mathioudaki, Anna; Doumbo, Safiatou; Doumtabé, Didier; Skinner, Jeff; Arora, Gunjan; Siddiqui, Shafiuddin; Li, Shanping; Kayentao, Kassoum; Ongoïba, Aïssata; Zaugg, Judith B.; Traoré, Boubacar; Crompton, Peter D.

doi:10.1371/journal.ppat.1009430

Cited by 52 publications

(58 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since our in vitro system used PBMCs from malaria-naive individuals, it modeled the first infection with malaria, similar to the child patients with malaria in this study. These findings correlate well with another study of patients with malaria in Mali, where the authors found that monocytes from children with no or limited malaria infection history had a more inflammatory response to malaria in in vitro stimulation, whereas monocytes from adults with a history of recurrent malaria infections over their lifespan exhibited a tolerant response ( 34 ).…”

Section: Discussionsupporting

confidence: 89%

Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum

Crabtree¹,

Caffrey²,

Silva³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

Plasmodium falciparum ( P. falciparum ) induces trained innate immune responses in vitro, where initial stimulation of adherent PBMCs with P. falciparum –infected RBCs (iRBCs) results in hyperresponsiveness to subsequent ligation of TLR2. This response correlates with the presence of T and B lymphocytes in adherent PBMCs, suggesting that innate immune training is partially due to adaptive immunity. We found that T cell–depleted PBMCs and purified monocytes alone did not elicit hyperproduction of IL-6 and TNF-α under training conditions. Analysis of P. falciparum– trained PBMCs showed that DCs did not develop under control conditions, and IL-6 and TNF-α were primarily produced by monocytes and DCs. Transwell experiments isolating purified monocytes from either PBMCs or purified CD4 + T cells, but allowing diffusion of secreted proteins, enabled monocytes trained with iRBCs to hyperproduce IL-6 and TNF-α after TLR restimulation. Purified monocytes stimulated with IFN-γ hyperproduced IL-6 and TNF-α, whereas blockade of IFN-γ in P. falciparum –trained PBMCs inhibited trained responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from patients with malaria showed persistently open chromatin at genes that appeared to be trained in vitro. Together, these findings indicate that the trained immune response of monocytes to P. falciparum is not completely cell intrinsic but depends on soluble signals from lymphocytes.

show abstract

Section: Discussionsupporting

confidence: 89%

Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum

Crabtree¹,

Caffrey²,

Silva³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…Secondly, although recent parasitemia was not associated with COVID-19 serostatus or reported symptoms, it is possible that lifetime cumulative malaria exposure could affect COVID-19 severity rather than the recent exposures assessed in this study. While P. falciparum infection of malaria-naïve adults and children may result in a short-lived response ( 23 , 24 ), a sustained skewing of monocytes towards a regulatory phenotype appears to require multiple exposures over the course of several years ( 4 ). As a result, malaria-induced trained immunity or cross tolerance sufficient to affect COVID-19 may require incremental and cumulative malaria exposure.…”

Section: Discussionmentioning

confidence: 99%

Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa

Woodford

Sagara²,

Diawara³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Malaria has been hypothesized as a factor that may have reduced the severity of the COVID-19 pandemic in sub-Saharan Africa. To evaluate the effect of recent malaria on COVID-19 we assessed a subgroup of individuals participating in a longitudinal cohort COVID-19 serosurvey that were also undergoing intensive malaria monitoring as part of antimalarial vaccine trials during the 2020 transmission season in Mali. These communities experienced a high incidence of primarily asymptomatic or mild COVID-19 during 2020 and 2021. In 1314 individuals, 711 were parasitemic during the 2020 malaria transmission season; 442 were symptomatic with clinical malaria and 269 had asymptomatic infection. Presence of parasitemia was not associated with new COVID-19 seroconversion (29.7% (211/711) vs. 30.0% (181/603), p=0.9038) or with rates of reported symptomatic seroconversion during the malaria transmission season. In the subsequent dry season, prior parasitemia was not associated with new COVID-19 seroconversion (30.2% (133/441) vs. 31.2% (108/346), p=0.7499), with symptomatic seroconversion, or with reversion from seropositive to seronegative (prior parasitemia: 36.2% (64/177) vs. no parasitemia: 30.1% (37/119), p=0.3842). After excluding participants with asymptomatic infection, clinical malaria was also not associated with COVID-19 serostatus or symptomatic seroconversion when compared to participants with no parasitemia during the monitoring period. In communities with intense seasonal malaria and a high incidence of asymptomatic or mild COVID-19, we did not demonstrate a relationship between recent malaria and subsequent response to COVID-19. Lifetime exposure, rather than recent infection, may be responsible for any effect of malaria on COVID-19 severity.

show abstract

“…This may induce tolerance in the host in the long term, and the host becomes tolerant not only to parasite antigens but also to unrelated antigens. Recently, two groups [Guha et al., human field data ( 63 ), and Nahrendorf et al., mouse model data ( 64 )] have shown that monocytes from malaria-exposed individuals differentiate into anti-inflammatory M2-type macrophages. Although their views differed on the locations where monocytes changed to the M2 phenotype, both groups agreed that these changes occurred through epigenetic modifications (a decrease in H3K4me3) at the inflammatory cytokine gene loci.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium berghei-Released Factor, PbTIP, Modulates the Host Innate Immune Responses

et al. 2021

View full text Add to dashboard Cite

The Plasmodium parasite has to cross various immunological barriers for successful infection. Parasites have evolved mechanisms to evade host immune responses, which hugely contributes to the successful infection and transmission by parasites. One way in which a parasite evades immune surveillance is by expressing molecular mimics of the host molecules in order to manipulate the host responses. In this study, we report a Plasmodium berghei hypothetical protein, PbTIP (PbANKA_124360.0), which is a Plasmodium homolog of the human T-cell immunomodulatory protein (TIP). The latter possesses immunomodulatory activities and suppressed the host immune responses in a mouse acute graft-versus-host disease (GvHD) model. The Plasmodium berghei protein, PbTIP, is expressed on the merozoite surface and exported to the host erythrocyte surface upon infection. It is shed in the blood circulation by the activity of an uncharacterized membrane protease(s). The shed PbTIP could be detected in the host serum during infection. Our results demonstrate that the shed PbTIP exhibits binding on the surface of macrophages and reduces their inflammatory cytokine response while upregulating the anti-inflammatory cytokines such as TGF-β and IL-10. Such manipulated immune responses are observed in the later stage of malaria infection. PbTIP induced Th2-type gene transcript changes in macrophages, hinting toward its potential to regulate the host immune responses against the parasite. Therefore, this study highlights the role of a Plasmodium-released protein, PbTIP, in immune evasion using macrophages, which may represent the critical strategy of the parasite to successfully survive and thrive in its host. This study also indicates the human malaria parasite TIP as a potential diagnostic molecule that could be exploited in lateral flow-based immunochromatographic tests for malaria disease diagnosis.

show abstract

Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype

Cited by 52 publications

References 49 publications

Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum

Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum

Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa

Plasmodium berghei-Released Factor, PbTIP, Modulates the Host Innate Immune Responses

Contact Info

Product

Resources

About