Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria

Rocha, Bruno Coelho; Marques, Pedro Elias; Leoratti, Fabiana Maria de Souza; Junqueira, Caroline; Pereira, Dhélio Batista; Antonelli, Lis Ribeiro do Valle; Menezes, Gustavo B.; Golenbock, Douglas T.; Gazzinelli, Ricardo T.

doi:10.1016/j.celrep.2015.11.055

Cited by 114 publications

(125 citation statements)

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“…Many different cell types produce Type I IFNs. Transcription of Type I IFNs has been shown for pDCs and to a lesser extent cDCs3536, and neutrophils have an Interferon transcriptional signature during P. vivax infection37. Most of these cells are not located within the brain; however with disruption of the BBB it is possible that cytokines such as IFNs access the brain parenchyma and thus microglia by this route.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

Capuccini

Lin

Talavera-López

et al. 2016

Sci Rep

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Cerebral malaria is a pathology involving inflammation in the brain. There are many immune cell types activated during this process, but there is little information on the response of microglia, in this severe complication. We examined microglia by genome wide transcriptomic analysis in a model of experimental cerebral malaria (ECM), in which C57BL/6 mice are infected with Plasmodium berghei ANKA. Thousands of transcripts were differentially expressed in microglia at two different time points during infection. Proliferation of microglia was a dominant feature before the onset of ECM, and supporting this, we observed an increase in numbers of these cells in the brain. When cerebral malaria symptoms were manifest, genes involved in immune responses and chemokine production were upregulated, which were possibly driven by Type I Interferon. Consistent with this hypothesis, in vitro culture of a microglial cell line with Interferon-β, but not infected red blood cells, resulted in production of several of the chemokines shown to be upregulated in the gene expression analysis. It appears that these responses are associated with ECM, as microglia from mice infected with a mutant P. berghei parasite (ΔDPAP3), which does not cause ECM, did not show the same level of activation or proliferation.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

Capuccini

Lin

Talavera-López

et al. 2016

Sci Rep

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“…Furthermore, IFN-I-signalling was reported to induce Bcl6, CXCR5 and PD1 expression in naïve CD4 + T cells following TCR stimulation in vitro [37]. IFN-I-related immune responses have also been observed in PBMC from malaria patients [38,39,40]. Although their functional relevance in humans remains to be established, we recently showed in ex vivo cultures of PBMC from P .…”

Section: Introductionmentioning

confidence: 99%

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

et al. 2016

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Parasite-specific antibodies protect against blood-stage Plasmodium infection. However, in malaria-endemic regions, it takes many months for naturally-exposed individuals to develop robust humoral immunity. Explanations for this have focused on antigenic variation by Plasmodium, but have considered less whether host production of parasite-specific antibody is sub-optimal. In particular, it is unclear whether host immune factors might limit antibody responses. Here, we explored the effect of Type I Interferon signalling via IFNAR1 on CD4+ T-cell and B-cell responses in two non-lethal murine models of malaria, P. chabaudi chabaudi AS (PcAS) and P. yoelii 17XNL (Py17XNL) infection. Firstly, we demonstrated that CD4+ T-cells and ICOS-signalling were crucial for generating germinal centre (GC) B-cells, plasmablasts and parasite-specific antibodies, and likewise that T follicular helper (Tfh) cell responses relied on B cells. Next, we found that IFNAR1-signalling impeded the resolution of non-lethal blood-stage infection, which was associated with impaired production of parasite-specific IgM and several IgG sub-classes. Consistent with this, GC B-cell formation, Ig-class switching, plasmablast and Tfh differentiation were all impaired by IFNAR1-signalling. IFNAR1-signalling proceeded via conventional dendritic cells, and acted early by limiting activation, proliferation and ICOS expression by CD4+ T-cells, by restricting the localization of activated CD4+ T-cells adjacent to and within B-cell areas of the spleen, and by simultaneously suppressing Th1 and Tfh responses. Finally, IFNAR1-deficiency accelerated humoral immune responses and parasite control by boosting ICOS-signalling. Thus, we provide evidence of a host innate cytokine response that impedes the onset of humoral immunity during experimental malaria.

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“…Transcriptomic analysis carried out in mice with blood-stage infection with P. berghei revealed that IFN regulatory factors were upregulated during the acute phase (41). Induction of a typical type I IFN signature was also observed in hepatocytes from mice infected with P. berghei and P. chabaudi sporozoites, where genes such as Mda, Irf3, Irf7 , and Stat1 were upregulated (42–44). Similar results were observed in humans.…”

Section: Protozoan Parasites and Ifn-imentioning

confidence: 90%

“…Similar results were observed in humans. Patients infected with P. vivax and P. falciparum showed a predominantly IFN-I transcriptional signature during the mild and the severe phase of infection (44, 45). …”

Section: Protozoan Parasites and Ifn-imentioning

confidence: 99%

Protozoan Parasites and Type I IFNs

Silva‐Barrios¹,

Stäger²

2017

Front. Immunol.

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For many years, the role of interferon (IFN)-I has been characterized primarily in the context of viral infections. However, regulatory functions mediated by IFN-I have also been described against bacterial infections and in tumor immunology. Only recently, the interest in understanding the immune functions mediated by IFN-I has dramatically increased in the field of protozoan infections. In this review, we discuss the discrete role of IFN-I in the immune response against major protozoan infections: Plasmodium, Leishmania, Trypanosoma, and Toxoplasma.

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Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria

Cited by 114 publications

References 50 publications

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Protozoan Parasites and Type I IFNs

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