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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Distinct STING-IRF3 activation determines IL-35+ Breg differentiation in rodent malaria
Anni Feng1, Qilong Li1, Ning Jiang1
1Research Unit for Pathogenic Mechanisms of Zoonotic Parasites of Chinese Academy of Medical Sciences, Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, China.
Abstract:
Augmented regulatory B cell (Breg) responses are commonly observed in malaria; however, the specific parasite components and Breg subtypes involved remain unclear. In this study, we investigated C57BL/6 mice infected with Plasmodium berghei ANKA, which induces cerebral malaria pathology, in comparison to P. yoelii YM, which does not. We found that distinct Breg types differentiated in response to these infections, driven by hemozoin-mediated Toll-like receptor 9 activation. Interleukin-35-positive (IL-35+) Breg expansion occurred in P. yoelii YM-infected mice but not in those infected with P. berghei ANKA. We demonstrated that stimulator of interferon genes (STING)-mediated interferon regulatory factor 3 (IRF3) phosphorylation suppressed IL-35+ Breg differentiation, potentially contributing to experimental cerebral malaria (ECM). In contrast, P. yoelii YM infection activated IRF3 in a STING-independent manner, promoting IL-35+ Breg expansion. These findings highlight IL-35+ Bregs as key modulators in malarial immunopathology.
Insights
Regulatory B cell (Breg) responses in malaria are complex. This study reveals that Interleukin-35-positive (IL-35+) Breg expansion is crucial for malaria outcomes, influenced by parasite components and STING-IRF3 signaling.
Area of Science:
- Immunology
- Parasitology
- Cell Biology
Background:
- Augmented regulatory B cell (Breg) responses are characteristic of malaria infections.
- The precise parasite components and Breg subtypes driving these responses remain incompletely understood.
- Understanding Breg involvement is critical for deciphering malarial immunopathology.
Purpose of the Study:
- To investigate the distinct Breg subtypes and parasite-driven mechanisms involved in experimental cerebral malaria (ECM) versus non-cerebral malaria.
- To elucidate the role of STING-IRF3 signaling in regulating Breg differentiation during Plasmodium infections.
Main Methods:
- Comparative analysis of C57BL/6 mice infected with Plasmodium berghei ANKA (inducing ECM) and Plasmodium yoelii YM (non-cerebral).
- Investigation of hemozoin-mediated Toll-like receptor 9 activation.
- Assessment of stimulator of interferon genes (STING)-mediated interferon regulatory factor 3 (IRF3) phosphorylation.
- Flow cytometry and molecular analysis to quantify Breg populations and signaling pathways.
Main Results:
- Distinct Breg subtypes differentiated based on the Plasmodium species, driven by hemozoin-TLR9 activation.
- Interleukin-35-positive (IL-35+) Breg expansion was observed in P. yoelii YM infection but suppressed in P. berghei ANKA infection.
- STING-IRF3 signaling suppressed IL-35+ Breg differentiation in P. berghei ANKA infection, potentially contributing to ECM.
- P. yoelii YM infection promoted IL-35+ Breg expansion via STING-independent IRF3 activation.
Conclusions:
- IL-35+ Bregs are key modulators of malarial immunopathology, with their expansion differentially regulated by parasite components.
- STING-IRF3 pathway plays a critical role in suppressing IL-35+ Breg differentiation during severe malaria.
- These findings offer insights into the differential immune responses to various Plasmodium infections.
