The spleen: “epicenter” in malaria infection and immunity

Ghosh, Debopam; Stumhofer, Jason S.

doi:10.1002/jlb.4ri1020-713r

Cited by 34 publications

(35 citation statements)

References 190 publications

(499 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One route to tolerance may be to reduce systemic inflammation -this correlates with clinical immunity in endemic regions (11) but whether it also coincides with immunity to severe disease is not known. In human challenge studies the immune response detected in whole blood at the peak of infection is largely driven by activated monocytes and neutrophils, which are in transit from the bone marrow (site of activation) (21) to the spleen (target organ) (22). To capture this acute phase response we used whole blood RNAsequencing and DESeq2 to identify differentially expressed genes at diagnosis (relative to baseline) in first, second and third infection.…”

Section: Re-challenge Triggers a Hardwired Emergency Myeloid Responsementioning

confidence: 99%

“…This emergency myeloid response has been extensively described in naive hosts infected with P. falciparum (13,23,24) and P. vivax (Bach et al, under review, preprint available at doi.org/10.1101/2021.03. 22.21252810) but it was surprising to see no obvious change upon re-challenge. Nevertheless, by analysing each infection independently it was possible that we were missing important quantitative differences and we therefore performed direct pairwise comparisons between first, second and third infection.…”

Section: Re-challenge Triggers a Hardwired Emergency Myeloid Responsementioning

confidence: 99%

See 1 more Smart Citation

Cytotoxic T cells are silenced to induce disease tolerance in human malaria

Sandoval

Bach

Nahrendorf

et al. 2021

Preprint

View full text Add to dashboard Cite

Immunity to severe malaria is acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance in human malaria remains unknown. We developed a re-challenge model of falciparum malaria in which healthy naive adult volunteers were infected three times over a 12-month period to track the development of disease tolerance in real-time. We found that parasitaemia triggered a hardwired emergency myeloid response that led to systemic inflammation, pyrexia and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, CD4+ T cell activation was quickly modified to reduce the number and diversity of effector cells upon re-challenge. Crucially, this did not silence critical helper T cell functions but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerised hosts were thus able to prevent collateral tissue damage and injury. Host control of T cell activation can therefore be established after a single infection and in the absence of anti-parasite immunity. And furthermore, this rapid host adaptation can protect vital organs to minimise the harm caused by systemic inflammation and sequestration.

show abstract

Section: Re-challenge Triggers a Hardwired Emergency Myeloid Responsementioning

confidence: 99%

Section: Re-challenge Triggers a Hardwired Emergency Myeloid Responsementioning

confidence: 99%

Cytotoxic T cells are silenced to induce disease tolerance in human malaria

Sandoval

Bach

Nahrendorf

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Next, we analyzed the T cell response in the spleen of mice, since these cells are responsible for the immune reaction during malaria infection [ 41 ]. Vaccinated or unvaccinated mice were examined both before and 8 days after PbA challenge.…”

Section: Resultsmentioning

confidence: 99%

Live Vaccination with Blood-Stage Plasmodium yoelii 17XNL Prevents the Development of Experimental Cerebral Malaria

et al. 2022

View full text Add to dashboard Cite

In our work, we aim to develop a malaria vaccine with cross-strain (-species) protection. C57BL/6 mice infected with the P. berghei ANKA strain (PbA) develop experimental cerebral malaria (ECM). In contrast, ECM development is inhibited in infected mice depleted of T cells. The clinical applications of immune-cell depletion are limited due to the benefits of host defense against infectious diseases. Therefore, in the present study we attempted to develop a new method for preventing ECM without immune cell depletion. We demonstrated that mice inoculated with a heterologous live-vaccine of P. yoelii 17XNL were able to prevent both ECM and lung pathology and survived longer than control mice when challenged with PbA. Live vaccination protected blood–organ barriers from PbA infection. Meanwhile, live vaccination conferred sterile protection against homologous challenge with the P. yoelii 17XL virulent strain for the long-term. Analysis of the immune response induced by live vaccination showed that cross-reactive antibodies against PbA antigens were generated. IL-10, which has an immunosuppressive effect, was strongly induced in mice challenged with PbA, unlike the pro-inflammatory cytokine IFNγ. These results suggest that the protective effect of heterologous live vaccination against ECM development results from IL-10-mediated host protection.

show abstract

“…In a long-term follow-up study, patients whose spleen had been surgically removed had an increased risk of developing bacterial infections ( 124 ). In malaria, the spleen is important in controlling the blood stage infection, clearance of parasitized red blood cells, induction of memory lymphocytes and replenishment of healthy red blood cells ( 125 , 126 ). Splenectomized patients infected with malaria experienced enhanced parasitic burden, severe disease symptoms, and higher mortality rate ( 126 ).…”

Section: Slos In Diseasementioning

confidence: 99%

Secondary Lymphoid Organs in Mesenchymal Stromal Cell Therapy: More Than Just a Filter

et al. 2022

View full text Add to dashboard Cite

Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in inflammatory models of human disease. However, clinical translation has fallen short of expectations, with many trials failing to meet primary endpoints. Failure to fully understand their mechanisms of action is a key factor contributing to the lack of successful commercialisation. Indeed, it remains unclear how the long-ranging immunomodulatory effects of MSCs can be attributed to their secretome, when MSCs undergo apoptosis in the lung shortly after intravenous infusion. Their apoptotic fate suggests that efficacy is not based solely on their viable properties, but also on the immune response to dying MSCs. The secondary lymphoid organs (SLOs) orchestrate immune responses and play a key role in immune regulation. In this review, we will discuss how apoptotic cells can modify immune responses and highlight the importance of MSC-immune cell interactions in SLOs for therapeutic outcomes.

show abstract

The spleen: “epicenter” in malaria infection and immunity

Cited by 34 publications

References 190 publications

Cytotoxic T cells are silenced to induce disease tolerance in human malaria

Cytotoxic T cells are silenced to induce disease tolerance in human malaria

Live Vaccination with Blood-Stage Plasmodium yoelii 17XNL Prevents the Development of Experimental Cerebral Malaria

Secondary Lymphoid Organs in Mesenchymal Stromal Cell Therapy: More Than Just a Filter

Contact Info

Product

Resources

About