Triggering receptor expressed on myeloid cells 1 (<scp>TREM</scp>‐1) and cytokine gene variants in complicated and uncomplicated malaria

Adukpo, Selorme; Gyan, Ben; Ofori, Michael F.; Dodoo, Daniel; Velavan, Thirumalaisamy P.; Meyer, Christian G.

doi:10.1111/tmi.12787

Cited by 21 publications

(25 citation statements)

References 50 publications

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“…However, our analyses provided hints that certain pathways may be shared, including TREM-1 activation, as well as "alternative activation" pathways similar to M2 alternatively activated macrophages in mice. In malaria, TREM-1 has been described to have a role in severe disease outcomes (79). We have also identified cytokines like OSM and TNFSF14 (LIGHT) that seem to be expressed in human primary DC activation states that lack expression of typical inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 79%

Atypical activation of dendritic cells by Plasmodium falciparum

Götz

Tang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by , the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1β, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with-infected erythrocytes activated antigen-specific naïve CD4 T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to exhibited a transcriptional program distinct from a classical LPS response, pointing to unique -induced activation pathways that may explain the uncharacteristic immune response to malaria.

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Section: Discussionmentioning

confidence: 79%

Atypical activation of dendritic cells by Plasmodium falciparum

Götz

Tang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Another plausible explanation could be attributed to the host genetic factors, as donor-to-donor variations were observed in our study. Gene polymorphisms within TREM-1 have been linked to the development of inflammation and sepsis 54 , and it has been reported that there is a positive association between patients carrying the TREM-1 rs2234237T allele and the development of severe malaria, due to the presence of higher levels of soluble TREM-1 in the plasma of these patients 55 . Given that polymorphisms in EV-A71 receptors, scavenger receptor class B member 2 (SCARB2) and P-selectin glycoprotein ligand-1 (PSGL-1), have been shown to affect EV-A71 susceptibility and infection respectively 56 , genomic variations within TREM-1 could also play a probable role in modulating EV-A71 infection and outcomes.…”

Section: Discussionmentioning

confidence: 99%

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

Amrun

Tan

Rickett

et al. 2020

Sci Rep

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Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. However, reasons for the severe pathogenesis remain undefined. To investigate this, infection and viral kinetics of EV-A71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterised in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV-A71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV-A71 isolates, although the extent of activation varied. Importantly, several pathways were found to be specific to the severe isolate, including triggering receptor expressed on myeloid cells 1 (TREM-1) signalling. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets. Hand, foot and mouth disease (HFMD) is a febrile illness that predominantly affects infants and young children, and is characterised by rash and blisters on the hands, mouth, feet and bottoms 1-3. Outbreaks of HFMD are caused by human enterovirus group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus A71 (EV-A71) 1,4,5. While often benign and self-limiting 2 , the disease can cause cardiopulmonary and neurological complications such as myocarditis, brainstem encephalitis, aseptic meningitis, and neurogenic pulmonary oedema, which can be fatal 6,7. The severe manifestations of HFMD are often associated with cases of EV-A71 infections, rather than coxsackievirus A16 8. EV-A71 belongs to the Enterovirus A species, Enterovirus genus, from the Picornaviridae family 9,10. The virus has a positive-sense RNA genome of 7.4 kb and encodes for four structural (VP1-4) and seven non-structural (2A-C and 3A-D) proteins 9. First isolated in California, USA, in 1969 11 , the virus is transmitted via the oral-foecal route, saliva and respiratory secretions 12. Based on the sequence analysis of VP1 gene, the virus can be broadly categorised into six genogroups: A, B, C, D, E and F 7,10,13. Whereas genogroup A contains the Californian prototype virus BrCr, genogroups B and C consist of various strains, and are further categorised into sub-genogroups B0-B5 and C1-C5 10. B and C genogroups are globally distributed, whereas D, and E and F are limited to India and Africa respectively 7,10. After the almost total eradication of poliovirus, EV-A71 is now noted as one of the most prevalent neurotropic enteroviruses, and is especially endemic in the Asia-Pacific region 14-17. Currently, the

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“…Another plausible explanation could be attributed to the host genetic factors, as donor-to-donor variations were observed in our study. Gene polymorphisms within TREM-1 have been linked to the development of inflammation and sepsis (44), and it has been reported that there is a positive association between patients carrying the TREM-1 rs2234237T allele and the development of severe malaria, due to the presence of higher levels of soluble TREM-1 in the plasma of these patients (45). Given that polymorphisms in EV71 receptors, scavenger receptor class B member 2 (SCARB2) and P-selectin glycoprotein ligand-1 (PSGL-1), have been shown to affect EV71 susceptibility and infection respectively (46), genomic variations within TREM-1 could also therefore play a role in modulating EV71 infection and outcomes.…”

Section: Discussionmentioning

confidence: 99%

TREM-1 activation is a key regulator in driving severe pathogenesis of enterovirus 71 infection

Amrun

Rickett

et al. 2019

Preprint

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word count: 175 words 27 Text word count: 5421 words 28 Abstract (175 words) 29Hand, foot and mouth disease (HFMD), caused by enterovirus 71 (EV71), presents 30 mild to severe disease, and sometimes fatal neurological and respiratory 31 manifestations. However, reasons for the severe pathogenesis remain undefined. To 32 investigate this, infection and viral kinetics of EV71 isolates from clinical disease (mild, 33 moderate and severe) from Sarawak, Malaysia, were characterized in human 34 rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood 35 mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher 36 EV71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways 37 triggered by all EV71 isolates, although the extent of activation varied. Importantly, 38 several pathways were found to be specific to the severe isolate, including triggering 39 receptor expressed on myeloid cells 1 (TREM-1) signaling. Depletion of TREM-1 in 40 EV71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-41 inflammatory genes, and reduced viral loads for the moderate and severe isolates. 42Mechanistically, this is the first report describing the transcriptome profiles during 43 EV71 infections in primary human cells, and the involvement of TREM-1 in the severe 44 disease pathogenesis, thus providing new insights for future treatment targets. 45 48 mouth, feet and bottoms (1-3). Outbreaks of HFMD are caused by human enterovirus 49 group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus 50 71 (EV71) (1, 4, 5). While often benign and self-limiting (2), the disease can cause 51 cardiopulmonary and neurological complications such as myocarditis, brainstem 52 encephalitis, aseptic meningitis, and neurogenic pulmonary edema, which can be fatal 53 (6, 7). The severe manifestations of HFMD are often associated with cases of EV71 54 infections, rather than coxsackievirus A16 (8). 55

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Triggering receptor expressed on myeloid cells 1 (TREM‐1) and cytokine gene variants in complicated and uncomplicated malaria

Abstract: Higher plasma levels of sTREM-1 alone or relative to sTREML-1 during malaria predispose to the phenotype of severe malaria. Carriage of the TREM1 rs2234237T allele appears to be a risk factor for the development of severe malaria.

Cited by 21 publications

References 50 publications

Atypical activation of dendritic cells by Plasmodium falciparum

Atypical activation of dendritic cells by Plasmodium falciparum

TREM-1 activation is a potential key regulator in driving severe pathogenesis of enterovirus A71 infection

TREM-1 activation is a key regulator in driving severe pathogenesis of enterovirus 71 infection

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