- Email: [email protected]
Type I Interferon in Malaria: A Balancing Act
TREPAR 1598 No. of Pages 3
Forum
Type I Interferon in Malaria: A Balancing Act Jason Paul Mooney,1 Samuel Crocodile Wassmer,1 and Julius Clemence Hafalla1,* Type I interferons (IFN-Is) can now be considered as the wedge that balances clinical protection to malaria. New studies recently highlighted a central role for IFNIs in orchestrating an immunoregulatory network leading to the dampening of proinflammatory responses, expansion of type 1 regulatory (Tr1) cells, and restriction of humoral immunity during malaria blood stage infection. Plasmacytoid dendritic cells (pDCs) were identified as the major source of IFN-Is. Here, we integrate the findings and provide a model for the mechanisms involved. Natural acquired immunity to malaria is a slow and inefficient process, resulting in the lack of sterilising protection. For successful resolution of Plasmodium bloodstage infections, the host must sense the parasite as foreign, strike a delicate balance between proinflammatory and regulatory immune responses, and mount an effective humoral immune response. Malaria infection elicits an interferong (IFNg)-driven proinflammatory response, which is important for effective clearance. However, an unchecked response can be deleterious to the host, potentially resulting in immune-mediated pathology with a severe or fatal outcome. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, can temper both innate and adaptive immune responses to malaria
infection. Whilst many immune cells produce IL-10, type 1 regulatory T (Tr1) cells produce IL-10 as well as IFNg [1] and are found more abundantly in children with uncomplicated malaria rather than severe disease [2], suggesting their involvement as a major mediator of immune protection. The processes leading to the development of immunoregulatory networks during malaria infection, from how the parasite is recognised to the expansion of Tr1 cells, and how these impact the development of effective B cell and antibody responses, were unknown until recently. Within 2 months, several studies were published, which revealed a comprehensive picture of the role of IFN-Is not only in the generation and control of Tr1, but also in restraining the humoral response to malaria infection. A subset of these reports focused on the identification of pDCs as the cellular source of IFN-Is and how these cells sense the parasite during infection. IFN-Is are a large family of cytokines that includes IFNa and IFNb, which show diverse functions during many infections [3]. Signalling through the common interferon a/b receptor IFNAR, IFN-Is can augment adaptive immune responses and direct humoral immunity. These cytokines activate both dendritic cells (DC), by enhancing MHC and CD80/CD86 expression, and T cells, by increasing survival and clonal expansion. Through controlled human blood stage malaria infections, Montes de Oca et al. [4] found that peripheral blood mononuclear cell (PBMC) cultures stimulated with Plasmodium falciparum-infected erythrocytes can produce IFNa. pDCs were identified as the major source of IFN-Is. Using a blocking antibody to IFNAR, they found that IFN-Is suppressed the production of IFNg and IL-6 from CD4+[65_TD$IF] T cells and monocytes, respectively. The release of proinflammatory cytokines IL-1b and IL17 was also suppressed, although their cellular sources were not identified. Importantly, the stimulation of PBMCs from volunteers following drug treatment
resulted in an IFNAR-dependent increase in both the levels of IL-10 and the frequency of Tr1 cells; IL-10 supressed IFNg and tumour necrosis factor (TNF) responses. Using PBMCs from malaria patients from endemic areas, the authors further showed that IFN-Is promoted IL-10 production. Together, these data reiterated the known regulatory role of IL-10 on IFNg inhibition, whilst further demonstrating that IL-10 production by CD4+ T cells and Tr1 expansion were IFN-I-dependent. The maturation of high-affinity antibodysecreting plasma cells necessitates a direct contact between activated germinal centre B (GC-B) cells and T follicular helper (TfH) cells expressing the inducible T cell costimulator (ICOS) molecule. To assess the roles of IFN-Is in this adaptive immune process, Zander et al. [5] and Sebina et al. [6] infected C57BL/6 mice with the nonlethal parasites Plasmodium yoelii (17XNL) and/or Plasmodium chabaudi chabaudi AS. Both studies demonstrated that blockade of IFNAR signalling resulted in better parasite control, higher numbers of ICOS+ TfH and GC-B cells in the spleen, and elevated titres of parasitespecific circulating antibodies. In agreement with the findings of the human study [4], Zander et al. also established that IFNIs promote the expansion of Tr1 (CD4+Blimp1+Tbet+) cells that coproduce IL-10 and IFNg [5]. While both studies elegantly demonstrated that IFN-Is impede humoral immunity following acute blood stage infection [5,6], they diverged in their identification of the cell type responsible for this IFN-I-mediated regulation. Using CD11ccre[6_TD$IF]Ifnar1fl/fl conditional knock-out mice, Sebina et al. [6] found that IFN-Is signalled through CD11c+ cells (presumably conventional DC, cDC, although activated T cells can express this marker) to limit the number of TfH and GC-B cells. In contrast, Zander et al. [5], using mixed bone-marrow chimeras, demonstrated that T cell-derived IL-10 and IFN g, likely to originate from Tr1 cells, were sufficient to restrict TfH cell
Trends in Parasitology, Month Year, Vol. xx, No. yy
1
TREPAR 1598 No. of Pages 3
numbers, antibody production, and parasite control.
(A) IEs
IFNγ
B Tr1
NK Spaulding et al. [7] and Yu et al. [8] IL-10 focused on the cellular source of IFN-Is pDC and sensing mechanisms during infection ? of C57BL/6J mice with the lethal parasite Mo TNF P. yoelii (17X/YM). Consistent with the T IFN-I Th1 results obtained in humans [4], both studcDC ies identified pDCs as the major proIFNγ ducers of IFN-Is. Spaulding et al. [7] used Ifnb-Yfp+/+ reporter mice to directly PBMCs IL-6 IL-17 Mo demonstrate IFN-I-production by pDCs, IL-1β whilst Yu et al. [8] depleted pDCs and showed marked reduction in the levels (B) Bone marrow of IFN-Is. Spaulding et al. [7] established RNA DNA/RNA ? that the production of IFN-Is occurred in IL-6 the bone marrow and blood 36 h postAcvaon Regulaon infection. Both studies, using gene-defiMDA5 cGAS TLR7 MAVS STING Mφ cient animals, showed that the production of high levels of IFN-Is was dependent on pDC MyD88 the intracellular RNA sensor toll like IRF3 CD169+ receptor 7 (TLR7) upstream of the myeIRF7 SOCS1 loid differentiation response 88 (MyD88), (a) (b) and Yu et al. [8] implicated the transcription factor interferon regulatory factor 7 Blood IFN-I (IRF7) in this pathway. Both studies diverged from here, with Spaulding IEs Spleen et al. [7] showing that intracellular DNA sensor stimulator of IFN genes (STING) facilitated the activation of CD169+[67_TD$IF] (siacDC loadhesin+) macrophages, which then (c) (d) primed pDCs to secrete IFN-Is. In conBlimp+ trast, Yu et al. [8] suggested that cyclic Tbet+ GMP-AMP synthase (cGAS) and melaTh1 Tr1 noma differentiation-associated protein ? PC 5 (MDA5) functions in pDCs as DNA IL-10 IFNγ IFNγ and RNA sensors, respectively, signalling through STING and mitochondrial antiviLymph node ral signalling (MAVS) leading to the expression of suppressor of cytokine signalling 1 (SOCS1) via IRF3. Then, SOCS1 GC-B ICOS+ TfH can negatively regulate MyD88-mediated IFN-I production. In agreement with the Germinal center human study [4], these findings demonstrated that early recognition of malaria blood stage parasites leads to the production of proinflammatory responses Figure 1. Proposed Model for the Impact of Type I Interferons (IFN-Is) Following Blood-Stage marked by elevated IFN-I, IFNg, TNF Malaria Parasite Infection. (A) In humans, the stimulation of peripheral blood mononuclear cells (PBMCs), and IL-6. However, it remains unclear including T cells, B cells, natural killer (NK) cells, conventional dendritic cells (cDCs), plasmocytoid dendritic cells (pDCs), and monocytes (Mo) by Plasmodium falciparum-infected erythrocytes (IE) leads to the production the timing at which parasite-specific and secretion of IFN-Is, which in turn promotes interleukin 10 (IL-10)-producing type 1 regulatory cells (Tr1) and pathways stimulate pDCs and thus, (Figure legend continued on the bottom of the next page.)
2
Trends in Parasitology, Month Year, Vol. xx, No. yy
TREPAR 1598 No. of Pages 3
balance overall IFN-I production. In addition, further studies are needed to firmly establish the link between parasite-mediated IFN-I-production and the subsequent generation of Tr1 cells in this lethal infection model.
parasite Plasmodium berghei has been demonstrated to prompt IFN-Is in hepatocytes [10]. Another consequence of the activation of this immunoregulatory network, as noted by Montes de Oca [68_TD$IF]et al. [4], is its potential involvement in the lack of long-term protection afforded by the RTS,S/AS01 human malaria vaccine in endemic areas [11]. Indeed, it is conceivable that the circumsporozoite proteinbased malaria vaccine was unable to overcome this immunoregulatory network, leading to a hindered generation of antibodies directed against the preerythrocytic cycle of P. falciparum in humans. A better understanding of the factors influencing this immunoregulatory pathway elicited during natural malaria infections and its subsequent response to specific vaccinations might therefore pave the way to a new generation of optimised human malaria vaccines.
Taken together, these new findings in humans and animal models reveal the fine details of the IFN-I-driven, multifaceted immunoregulatory network triggered by early exposure to malaria parasites that has lasting consequences on regulating the balance between pathogen clearance and self-protection (Figure 1). These results provide new insights not only into the mechanisms underlying the acquisition of immune protection against severe malaria in endemic areas, but also into how parasite density is kept under control by the immune system of the host. However, the resulting persistent ‘asymptomatic’ infection is not, as commonly perceived, beneficial to the indi- [69_TD$IF]Acknowledgements vidual, and leads to major health, J.P.M. was funded by MRC/DFID Concordat developmental, and productivity impair- agreement Grant number MR/P000959/1. J.C.H. was supported by NC3Rs grant NC/L000601/1 ments [9].
and Royal Society grants UF120026, RG130034
The findings compiled here also raise the intriguing possibility that the IFN-I-led immunoregulatory network is initiated as early as malaria pre-erythrocytic infection, tipping the balance against long-term protection. In fact, pre-erythrocytic infection with the rodent malaria
and CH160018. S.C.W. was supported by NIH/NIAID award U19AI089676-01S1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 1
*Correspondence: [email protected] (J.C. Hafalla). http://dx.doi.org/10.1016/j.pt.2016.12.010
References 1. Freitas do Rosario, A.P. (2012) IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J. Immunol. 188, 1178–1190 2. Walther, M. (2009) Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 5, e1000364 3. McNab, F. (2015) Type I interferons in infectious disease. Nat. Rev. Immunol. 15, 87–103 4. Montes de Oca, M. (2016) Type I interferons regulate immune responses in humans with bloodstage Plasmodium falciparum infection. Cell Rep. 17, 399–412 5. Zander, R.A. (2016) Type I interferons induce T regulatory 1 responses and restrict humoral immunity during experimental malaria. PLoS Pathog. 12, e1005945 6. Sebina, I. (2016) IFNAR1-signalling obstructs ICOSmediated humoral immunity during non-lethal bloodstage Plasmodium Infection. PLoS Pathog. 12, e1005999 7. Spaulding, E. (2016) STING-licensed macrophages prime type I IFN production by plasmacytoid dendritic cells in the bone marrow during severe Plasmodium yoelii malaria. PLoS Pathog. 12, e1005975 8. Yu, X. (2016) Cross-regulation of two type I interferon signaling pathways in plasmacytoid dendritic cells controls anti-malaria immunity and host mortality. Immunity 45, 1093–1107 9. Chen, I. (2016) "Asymptomatic" malaria: a chronic and debilitating infection that should be treated. PLoS Med. 13, e1001942 10. Liehl, P. (2014) Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection. Nat. Med. 20, 47–53 11. Olotu, A. et al. (2016) Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children. N. Engl. J. Med. 374, 2519–2529
Immunology and Infection Department, Faculty of
Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
suppresses parasite-specific CD4+ T cell responses (Th1). IFN-I reduces levels of interferon g(IFNg), tumour necrosis factor (TNF), IL-1b, IL-17, and monocyte-derived IL-6. (B) In mice, early blood-stage infection results in the production of IFN-Is from bone-marrow pDCs via sensing through TRL7/MyD88/IRF7. pDCs IFN-I signaling and its regulation through SOCS1 is dependent on (a) direct sensing of parasite RNA/DNA in pDCs or (b) through CD169+ macrophages (MF) sensing, through STING, of an unknown ligand. Subsequently, IFN-Is also reduce the activation of T follicular helper (TfH) and germinal centre B (GC-B) cells. This leads to the diminished production of parasite-specific antibodies by plasma cells (PCs), possibly through CD11c+ cDCs, which (c) inhibits T helper type 1 (Th1) cells and/or (d) both IL-10 and interferon g (IFNg) provided by Tr1 cells, which express the transcription factors B-lymphocyte-induced maturation protein 1 (Blimp1) and T-box transcription factor (Tbet). Intracellular factors are shown in italics. TLR7, Toll-like receptor 7; MyD88, myeloid differentiation 88; IRF, interferon regulatory factor; cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; MDA5, melanoma differentiation-associated protein 5; MAVS, mitochondrial antiviral-signalling; SOCS1, suppressor of cytokine signalling 1; CD[64_TD$IF]169, sialoadhesin; ICOS, inducible T cell costimulator.
Trends in Parasitology, Month Year, Vol. xx, No. yy
3
Forum
Type I Interferon in Malaria: A Balancing Act Jason Paul Mooney,1 Samuel Crocodile Wassmer,1 and Julius Clemence Hafalla1,* Type I interferons (IFN-Is) can now be considered as the wedge that balances clinical protection to malaria. New studies recently highlighted a central role for IFNIs in orchestrating an immunoregulatory network leading to the dampening of proinflammatory responses, expansion of type 1 regulatory (Tr1) cells, and restriction of humoral immunity during malaria blood stage infection. Plasmacytoid dendritic cells (pDCs) were identified as the major source of IFN-Is. Here, we integrate the findings and provide a model for the mechanisms involved. Natural acquired immunity to malaria is a slow and inefficient process, resulting in the lack of sterilising protection. For successful resolution of Plasmodium bloodstage infections, the host must sense the parasite as foreign, strike a delicate balance between proinflammatory and regulatory immune responses, and mount an effective humoral immune response. Malaria infection elicits an interferong (IFNg)-driven proinflammatory response, which is important for effective clearance. However, an unchecked response can be deleterious to the host, potentially resulting in immune-mediated pathology with a severe or fatal outcome. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, can temper both innate and adaptive immune responses to malaria
infection. Whilst many immune cells produce IL-10, type 1 regulatory T (Tr1) cells produce IL-10 as well as IFNg [1] and are found more abundantly in children with uncomplicated malaria rather than severe disease [2], suggesting their involvement as a major mediator of immune protection. The processes leading to the development of immunoregulatory networks during malaria infection, from how the parasite is recognised to the expansion of Tr1 cells, and how these impact the development of effective B cell and antibody responses, were unknown until recently. Within 2 months, several studies were published, which revealed a comprehensive picture of the role of IFN-Is not only in the generation and control of Tr1, but also in restraining the humoral response to malaria infection. A subset of these reports focused on the identification of pDCs as the cellular source of IFN-Is and how these cells sense the parasite during infection. IFN-Is are a large family of cytokines that includes IFNa and IFNb, which show diverse functions during many infections [3]. Signalling through the common interferon a/b receptor IFNAR, IFN-Is can augment adaptive immune responses and direct humoral immunity. These cytokines activate both dendritic cells (DC), by enhancing MHC and CD80/CD86 expression, and T cells, by increasing survival and clonal expansion. Through controlled human blood stage malaria infections, Montes de Oca et al. [4] found that peripheral blood mononuclear cell (PBMC) cultures stimulated with Plasmodium falciparum-infected erythrocytes can produce IFNa. pDCs were identified as the major source of IFN-Is. Using a blocking antibody to IFNAR, they found that IFN-Is suppressed the production of IFNg and IL-6 from CD4+[65_TD$IF] T cells and monocytes, respectively. The release of proinflammatory cytokines IL-1b and IL17 was also suppressed, although their cellular sources were not identified. Importantly, the stimulation of PBMCs from volunteers following drug treatment
resulted in an IFNAR-dependent increase in both the levels of IL-10 and the frequency of Tr1 cells; IL-10 supressed IFNg and tumour necrosis factor (TNF) responses. Using PBMCs from malaria patients from endemic areas, the authors further showed that IFN-Is promoted IL-10 production. Together, these data reiterated the known regulatory role of IL-10 on IFNg inhibition, whilst further demonstrating that IL-10 production by CD4+ T cells and Tr1 expansion were IFN-I-dependent. The maturation of high-affinity antibodysecreting plasma cells necessitates a direct contact between activated germinal centre B (GC-B) cells and T follicular helper (TfH) cells expressing the inducible T cell costimulator (ICOS) molecule. To assess the roles of IFN-Is in this adaptive immune process, Zander et al. [5] and Sebina et al. [6] infected C57BL/6 mice with the nonlethal parasites Plasmodium yoelii (17XNL) and/or Plasmodium chabaudi chabaudi AS. Both studies demonstrated that blockade of IFNAR signalling resulted in better parasite control, higher numbers of ICOS+ TfH and GC-B cells in the spleen, and elevated titres of parasitespecific circulating antibodies. In agreement with the findings of the human study [4], Zander et al. also established that IFNIs promote the expansion of Tr1 (CD4+Blimp1+Tbet+) cells that coproduce IL-10 and IFNg [5]. While both studies elegantly demonstrated that IFN-Is impede humoral immunity following acute blood stage infection [5,6], they diverged in their identification of the cell type responsible for this IFN-I-mediated regulation. Using CD11ccre[6_TD$IF]Ifnar1fl/fl conditional knock-out mice, Sebina et al. [6] found that IFN-Is signalled through CD11c+ cells (presumably conventional DC, cDC, although activated T cells can express this marker) to limit the number of TfH and GC-B cells. In contrast, Zander et al. [5], using mixed bone-marrow chimeras, demonstrated that T cell-derived IL-10 and IFN g, likely to originate from Tr1 cells, were sufficient to restrict TfH cell
Trends in Parasitology, Month Year, Vol. xx, No. yy
1
TREPAR 1598 No. of Pages 3
numbers, antibody production, and parasite control.
(A) IEs
IFNγ
B Tr1
NK Spaulding et al. [7] and Yu et al. [8] IL-10 focused on the cellular source of IFN-Is pDC and sensing mechanisms during infection ? of C57BL/6J mice with the lethal parasite Mo TNF P. yoelii (17X/YM). Consistent with the T IFN-I Th1 results obtained in humans [4], both studcDC ies identified pDCs as the major proIFNγ ducers of IFN-Is. Spaulding et al. [7] used Ifnb-Yfp+/+ reporter mice to directly PBMCs IL-6 IL-17 Mo demonstrate IFN-I-production by pDCs, IL-1β whilst Yu et al. [8] depleted pDCs and showed marked reduction in the levels (B) Bone marrow of IFN-Is. Spaulding et al. [7] established RNA DNA/RNA ? that the production of IFN-Is occurred in IL-6 the bone marrow and blood 36 h postAcvaon Regulaon infection. Both studies, using gene-defiMDA5 cGAS TLR7 MAVS STING Mφ cient animals, showed that the production of high levels of IFN-Is was dependent on pDC MyD88 the intracellular RNA sensor toll like IRF3 CD169+ receptor 7 (TLR7) upstream of the myeIRF7 SOCS1 loid differentiation response 88 (MyD88), (a) (b) and Yu et al. [8] implicated the transcription factor interferon regulatory factor 7 Blood IFN-I (IRF7) in this pathway. Both studies diverged from here, with Spaulding IEs Spleen et al. [7] showing that intracellular DNA sensor stimulator of IFN genes (STING) facilitated the activation of CD169+[67_TD$IF] (siacDC loadhesin+) macrophages, which then (c) (d) primed pDCs to secrete IFN-Is. In conBlimp+ trast, Yu et al. [8] suggested that cyclic Tbet+ GMP-AMP synthase (cGAS) and melaTh1 Tr1 noma differentiation-associated protein ? PC 5 (MDA5) functions in pDCs as DNA IL-10 IFNγ IFNγ and RNA sensors, respectively, signalling through STING and mitochondrial antiviLymph node ral signalling (MAVS) leading to the expression of suppressor of cytokine signalling 1 (SOCS1) via IRF3. Then, SOCS1 GC-B ICOS+ TfH can negatively regulate MyD88-mediated IFN-I production. In agreement with the Germinal center human study [4], these findings demonstrated that early recognition of malaria blood stage parasites leads to the production of proinflammatory responses Figure 1. Proposed Model for the Impact of Type I Interferons (IFN-Is) Following Blood-Stage marked by elevated IFN-I, IFNg, TNF Malaria Parasite Infection. (A) In humans, the stimulation of peripheral blood mononuclear cells (PBMCs), and IL-6. However, it remains unclear including T cells, B cells, natural killer (NK) cells, conventional dendritic cells (cDCs), plasmocytoid dendritic cells (pDCs), and monocytes (Mo) by Plasmodium falciparum-infected erythrocytes (IE) leads to the production the timing at which parasite-specific and secretion of IFN-Is, which in turn promotes interleukin 10 (IL-10)-producing type 1 regulatory cells (Tr1) and pathways stimulate pDCs and thus, (Figure legend continued on the bottom of the next page.)
2
Trends in Parasitology, Month Year, Vol. xx, No. yy
TREPAR 1598 No. of Pages 3
balance overall IFN-I production. In addition, further studies are needed to firmly establish the link between parasite-mediated IFN-I-production and the subsequent generation of Tr1 cells in this lethal infection model.
parasite Plasmodium berghei has been demonstrated to prompt IFN-Is in hepatocytes [10]. Another consequence of the activation of this immunoregulatory network, as noted by Montes de Oca [68_TD$IF]et al. [4], is its potential involvement in the lack of long-term protection afforded by the RTS,S/AS01 human malaria vaccine in endemic areas [11]. Indeed, it is conceivable that the circumsporozoite proteinbased malaria vaccine was unable to overcome this immunoregulatory network, leading to a hindered generation of antibodies directed against the preerythrocytic cycle of P. falciparum in humans. A better understanding of the factors influencing this immunoregulatory pathway elicited during natural malaria infections and its subsequent response to specific vaccinations might therefore pave the way to a new generation of optimised human malaria vaccines.
Taken together, these new findings in humans and animal models reveal the fine details of the IFN-I-driven, multifaceted immunoregulatory network triggered by early exposure to malaria parasites that has lasting consequences on regulating the balance between pathogen clearance and self-protection (Figure 1). These results provide new insights not only into the mechanisms underlying the acquisition of immune protection against severe malaria in endemic areas, but also into how parasite density is kept under control by the immune system of the host. However, the resulting persistent ‘asymptomatic’ infection is not, as commonly perceived, beneficial to the indi- [69_TD$IF]Acknowledgements vidual, and leads to major health, J.P.M. was funded by MRC/DFID Concordat developmental, and productivity impair- agreement Grant number MR/P000959/1. J.C.H. was supported by NC3Rs grant NC/L000601/1 ments [9].
and Royal Society grants UF120026, RG130034
The findings compiled here also raise the intriguing possibility that the IFN-I-led immunoregulatory network is initiated as early as malaria pre-erythrocytic infection, tipping the balance against long-term protection. In fact, pre-erythrocytic infection with the rodent malaria
and CH160018. S.C.W. was supported by NIH/NIAID award U19AI089676-01S1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 1
*Correspondence: [email protected] (J.C. Hafalla). http://dx.doi.org/10.1016/j.pt.2016.12.010
References 1. Freitas do Rosario, A.P. (2012) IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J. Immunol. 188, 1178–1190 2. Walther, M. (2009) Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 5, e1000364 3. McNab, F. (2015) Type I interferons in infectious disease. Nat. Rev. Immunol. 15, 87–103 4. Montes de Oca, M. (2016) Type I interferons regulate immune responses in humans with bloodstage Plasmodium falciparum infection. Cell Rep. 17, 399–412 5. Zander, R.A. (2016) Type I interferons induce T regulatory 1 responses and restrict humoral immunity during experimental malaria. PLoS Pathog. 12, e1005945 6. Sebina, I. (2016) IFNAR1-signalling obstructs ICOSmediated humoral immunity during non-lethal bloodstage Plasmodium Infection. PLoS Pathog. 12, e1005999 7. Spaulding, E. (2016) STING-licensed macrophages prime type I IFN production by plasmacytoid dendritic cells in the bone marrow during severe Plasmodium yoelii malaria. PLoS Pathog. 12, e1005975 8. Yu, X. (2016) Cross-regulation of two type I interferon signaling pathways in plasmacytoid dendritic cells controls anti-malaria immunity and host mortality. Immunity 45, 1093–1107 9. Chen, I. (2016) "Asymptomatic" malaria: a chronic and debilitating infection that should be treated. PLoS Med. 13, e1001942 10. Liehl, P. (2014) Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection. Nat. Med. 20, 47–53 11. Olotu, A. et al. (2016) Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children. N. Engl. J. Med. 374, 2519–2529
Immunology and Infection Department, Faculty of
Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
suppresses parasite-specific CD4+ T cell responses (Th1). IFN-I reduces levels of interferon g(IFNg), tumour necrosis factor (TNF), IL-1b, IL-17, and monocyte-derived IL-6. (B) In mice, early blood-stage infection results in the production of IFN-Is from bone-marrow pDCs via sensing through TRL7/MyD88/IRF7. pDCs IFN-I signaling and its regulation through SOCS1 is dependent on (a) direct sensing of parasite RNA/DNA in pDCs or (b) through CD169+ macrophages (MF) sensing, through STING, of an unknown ligand. Subsequently, IFN-Is also reduce the activation of T follicular helper (TfH) and germinal centre B (GC-B) cells. This leads to the diminished production of parasite-specific antibodies by plasma cells (PCs), possibly through CD11c+ cDCs, which (c) inhibits T helper type 1 (Th1) cells and/or (d) both IL-10 and interferon g (IFNg) provided by Tr1 cells, which express the transcription factors B-lymphocyte-induced maturation protein 1 (Blimp1) and T-box transcription factor (Tbet). Intracellular factors are shown in italics. TLR7, Toll-like receptor 7; MyD88, myeloid differentiation 88; IRF, interferon regulatory factor; cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; MDA5, melanoma differentiation-associated protein 5; MAVS, mitochondrial antiviral-signalling; SOCS1, suppressor of cytokine signalling 1; CD[64_TD$IF]169, sialoadhesin; ICOS, inducible T cell costimulator.
Trends in Parasitology, Month Year, Vol. xx, No. yy
3