Cytotoxic T Cell-Derived Granzyme B Is Increased in Severe Plasmodium Falciparum Malaria

Kaminski, Lea-Christina; Riehn, Mathias; Abel, Annemieke; Steeg, Christiane; Yar, Denis Dekugmen; Addai‐Mensah, Otchere; Aminkiah, Francis; Dabo, Ellis O; Jacobs, Thomas; Mackroth, Maria Sophia

doi:10.3389/fimmu.2019.02917

Cited by 27 publications

(29 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, IL-4 has been reported to suppress the upregulation of granzyme B in T cells, thereby reducing induced cell death ( Riou et al, 2006 ). Additionally, decreasing levels of granzyme B has been associated with a Th2 response ( Devadas et al, 2006 ), whereas, increasing levels in malaria have been observed in children with severe and uncomplicated infections ( Kaminski et al, 2019 ). Here the lower levels of granzyme B observed in children with malaria infection and the upregulation of IL-4 support the immunoregulatory activity of IL-4 on granzyme B.…”

Section: Discussionmentioning

confidence: 99%

Asymptomatic Malaria Infection Is Maintained by a Balanced Pro- and Anti-inflammatory Response

et al. 2020

View full text Add to dashboard Cite

Background Pro- and anti-inflammatory cytokines are important mediators of immunity and are associated with malaria disease outcomes. However, their role in the establishment of asymptomatic infections, which may precede the development of clinical symptoms, is not as well-understood. Methods We determined the association of pro and anti-inflammatory cytokines and other immune effector molecules with the development of asymptomatic malaria. We measured and compared the plasma levels of pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin (IL)-6, IL-12p70, IL-17A, and granzyme B, the anti-inflammatory cytokine IL-4 and the regulatory cytokine IL-10 from children with asymptomatic malaria infections (either microscopic or submicroscopic) and uninfected controls using Luminex. Results We show that individuals with microscopic asymptomatic malaria had significantly increased levels of TNF-α and IL-6 compared to uninfected controls. Children with either microscopic or submicroscopic asymptomatic malaria exhibited higher levels of IFN-γ, IL-17A, and IL-4 compared to uninfected controls. The levels of most of the pro and anti-inflammatory cytokines were comparable between children with microscopic and submicroscopic infections. The ratio of IFN-γ/IL-10, TNF-α/IL-10, IL-6/IL-10 as well as IFN-γ/IL-4 and IL-6/IL-4 did not differ significantly between the groups. Additionally, using a principal component analysis, the cytokines measured could not distinguish amongst the three study populations. This may imply that neither microscopic nor submicroscopic asymptomatic infections were polarized toward a pro-inflammatory or anti-inflammatory response. Conclusion The data show that asymptomatic malaria infections result in increased plasma levels of both pro and anti-inflammatory cytokines relative to uninfected persons. The balance between pro- and anti-inflammatory cytokines are, however, largely maintained and this may in part, explain the lack of clinical symptoms. This is consistent with the generally accepted observation that clinical symptoms develop as a result of immunopathology involving dysregulation of inflammatory mediator balance in favor of pro-inflammatory mediators.

show abstract

Section: Discussionmentioning

confidence: 99%

Asymptomatic Malaria Infection Is Maintained by a Balanced Pro- and Anti-inflammatory Response

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The ability of CTLs and NK cells to kill infected cells is essential for the control of several infectious diseases, although in some cases cytotoxicity is not protective and provokes a destructive inflammatory response [ 67 , 68 ]. This is the case in cutaneous leishmaniasis, where excessive cytolysis leads to inflammasome activation and subsequent production of the proinflammatory cytokine IL-1β [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature

et al. 2021

View full text Add to dashboard Cite

Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional analysis of patient lesions identified an interferon stimulated gene (ISG) signature. To determine whether localized L. braziliensis infection triggers a systemic immune response that may influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients and healthy controls. Functional enrichment analysis identified an ISG signature as the dominant transcriptional response in the blood of patients. This ISG signature was associated with an increase in monocyte- and macrophage-specific marker genes in the blood and elevated serum levels IFN-γ. A cytotoxicity signature, which is a dominant feature in the lesions, was also observed in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis–another localized infection–but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria. Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests a mechanism to limit systemic spread of the parasite, as well as enhance parasite control by pre-activating cells prior to lesion entry.

show abstract

“…Previous studies of T cells in malaria have shown that the upregulation of co-inhibitory molecules such as LAG-3 and TIM-3 in response to acute infection can have both beneficial and detrimental effects (29)(30)(31)(32). It is still highly debated whether T cell exhaustion can occur during early malaria infection or other acute viral infections since the expression of inhibitory receptors is also induced through T cell activation and differentiation (17,24,27,63). Legat et al showed that stimulating human CD8 + T cells induced a strong and rapid upregulation of inhibitory receptors after 24 h while cytokine production was not necessarily affected (17).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Cytotoxic T Cell-Derived Granzyme B Is Increased in Severe Plasmodium Falciparum Malaria

Cited by 27 publications

References 33 publications

Asymptomatic Malaria Infection Is Maintained by a Balanced Pro- and Anti-inflammatory Response

Asymptomatic Malaria Infection Is Maintained by a Balanced Pro- and Anti-inflammatory Response

Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature

Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

Contact Info

Product

Resources

About