- Email: [email protected]
Public Endowment of B Cells
Immunity
Previews Public Endowment of B Cells Lars Hangartner1,* 1The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.016
Using a transgenic mouse strain expressing the human VH1-69 germline gene used by many broadly neutralizing antibodies to influenza A virus, Sangesland et al. show that the VH1-69 gene segment provides the essentials for mounting antibody responses against the conserved hemagglutinin stem epitope. The humoral response to the influenza A virus (IAV) hemagglutinin (HA) is dominated by antibodies to variable epitopes located around the receptor binding site. Due to the variability of their epitopes, these antibodies are highly strain specific and only neutralize the eliciting or closely related IAV strains. Heterosubtypic neutralizing antibodies (hnAbs)—i.e., antibodies that can bind and neutralize multiple strains and subtypes (serotypes) of IAV, are rare but can be found in most individuals at low levels (Corti et al., 2010; Kohler et al., 2014; Sui et al., 2011). hnAbs specific for the conserved epitope located in the stem of IAV HA surface protein are special in that they are preferentially encoded by the VH1-69 germline gene, display a preference for phylogenetic group 1 viruses, and almost exclusively use their heavy chain for binding to HA (Avnir et al., 2014; Corti et al., 2010; Ekiert et al., 2009; Pappas et al., 2014; Wheatley et al., 2015). VH1-69 encoded hnAbs constitute a shared or ‘‘public’’ antibody solution, as very similar B cell clonotypes specific for this epitope can be found in various individuals. While it is quite possible that independent but convergent B cell evolution leads to public solutions, it has also been speculated that mammalian B cell repertoires have evolved to encode for public solutions to improve responses to commonly encountered pathogens. In this issue of Immunity, Sangesland et al. (2019) present a study that uses transgenic mice expressing a single human VH gene in the context of all human D and JH elements to show that the public VH1-69 HA stem solution is indeed inherent to this V region and that the presence of VH1-69 is sufficient to enable antibody responses to this desirable public but subdominant IAV HA epitope. Antibodies capable of slowing viral dissemination during the first days of
infection can be crucial for the survival of the infected host and help to bridge the time until the adaptive immune system has fully kicked in (Hangartner et al., 2006). Part of this first line of defense are natural antibodies—i.e., germline-encoded immunoglobulin M (IgM) antibodies that help to prime the immune system by recruiting antigens to secondary lymphoid organs and by keeping early pathogen dissemination at bay (Ochsenbein and Zinkernagel, 2000). The activity of germline-encoded, bona fide low-affinity antibodies is augmented by their secretion as pentameric or hexameric IgM antibodies whose higher valency of binding can compensate for poor affinity until higher-affinity antibodies have been selected. IgM is also a potent activator of the complement system, which helps both restrict pathogen dissemination and recruit antigens to secondary lymphoid organs. While hardwiring of public specificities into the B cell repertoire is beneficial for surviving common pathogens, it may be at the expense of skewing the antibody repertoire: providing public specificities with a head start will put non-public specificities at a disadvantage and possibly can result in immunodominance. As a matter of fact, immunodominance has proven to be a major issue for the development of universal vaccines against variable viruses such as HIV or influenza virus. While the variable and thus strainspecific epitopes of the surface proteins of these viruses are highly immunogenic, efforts to immunize against their conserved epitopes have proven to be difficult. In the case of influenza viruses, experimental vaccines can elicit antibodies to the conserved stem epitope, but those typically fail to neutralize the virus.
The specificity of antibodies typically comes from the heavy- and lightchain complementarity-determining regions (CDRs). While two of the three CDRs for each chain are encoded in the V region gene (CDR1 and 2), the third (CDR3) arises as the result of the V(D)J recombination during B cell ontogeny. Due to higher variability compared to CDR1 and 2, CDR3, especially that of the heavy chain (HCDR3), often provides the essential antigen contacts with the antigen. VH1-69-encoded antibodies are special in that they can evolve from the VH1-69 germline gene with as little as little as one or two V-region substitutions when combined with a properly positioned HCDR3 tyrosine—e.g., replacement of HCDR2 Ile 52a with a smaller small amino acid, such as serine, alanine, and glycine, allows the germline-encoded but polymorphic HCDR2 phenylalanine 54 and the HCDR3 tyrosine to be inserted into adjacent pockets to establish the key contacts (Avnir et al., 2014; Pappas et al., 2014) between antibody and HA stem. Since removal of the HCDR3 tyrosine, but not of the HCDR2 phenylalanine, can be tolerated in many VH1-69 hnAbs, Sangesland et al. speculated that V segment encoded residues form ‘‘primordial’’ germline contacts that enable selection of VH1-69-expressing hnAb precursor B cells. To test their hypothesis, the authors used two transgenic mouse strains expressing either the human VH1-69 or VH1-2 gene segments in conjunction with all human D and JH elements (Figure 1). They then immunized these humanized mouse strains with infectious virions and virus-like particles (VLPs) displaying either full-length HA or a specially crafted ‘‘headless’’ HA lacking the immunodominant head epitopes. The authors found that VH1-69, but not VH1-2,
Immunity 51, October 15, 2019 ª 2019 Elsevier Inc. 601
Immunity
Previews Mouse locus VH
VH
VH
D
VH1-2 humanized JH
hVH1-2
Strain-specific
hD
hJH
Strain-specific
VH1-69 humanized hVH1-69
hD
hJH
Strain-specific and heterosubtypic
was not sufficient to prevent the immunodominant, strain-specific epitopes from taking over eventually, indicating that the VH1-69-encoded public hnAb endowment is not very competitive compared to other epitopes. Nonetheless, the results presented by Sangesgard et al. back current reverse-vaccinology approaches to elicit antibodies against the subdominant broadly neutralizing epitopes of HIV and IAV. Since many of these approaches aim to increase precursor B cell frequencies, e.g., with germline-targeting immunogens, and to seek to avoid immune responses to dominant variable epitopes, e.g., by masking or switching the dominant epitopes, these results are encouraging for the further development of such universally protective vaccines. ACKNOWLEDGMENTS
Figure 1. Assessing the Contribution of the VH Gene Segment to Public Antibody Solutions Antibodies to the conserved stem epitope (yellow circle) of influenza virus hemagglutinin (HA, blue and gray) are difficult to elicit, and immunization of wild-type mice primarily elicits antibodies to the antigenically variable head of HA. Closely related stem-specific and broadly reactive VH1-69-encoded antibodies can be found in many humans, indicating that they constitute a public specificity. VH1-69encoded stem antibodies are special in that they partially rely on germline-encoded residues for strainindependent binding and neutralization. Using a mouse strain that has been genetically engineered to encode for a single human germline gene in combination with human D and J elements, Sangesland et al. could demonstrate that the presence of the VH1-69, but not the human VH1-2, gene segment enabled mice to mount antibodies to the conserved stem-epitope and thereby provide evidence that the public specificity for this type of stem-specific heterosubtypic antibodies is segregating with the VH1-69 gene segment.
humanized mice were able to mount stem-specific antibodies, enrich for B cells expressing B cell receptors (BCRs) with the aforementioned heterosubtypic antibody signatures, and were protected against a heterosubtypic virus challenge. Thereby, they could prove that the VH1-69 region indeed provides all the necessary features for eliciting HAstem-specific hnAbs. In contrast to HIV, where potential vaccine recipients are immunologically naive, most IAV vaccine recipients can be expected to be have been previously exposed to the virus. Sangesgard et al. could show that also in IAV pre-exposed VH1-69 mice, headless-HA VLP immunization could enrich for B cells expressing hnAb signatures and refocus the virus-induced antibody response on the HA-stem hnAb epitope. To demonstrate that their observations are not an artifact of the drastically increased precursor B cell frequencies in the transgenic mice, Sangesgard et al. then used an elegant 602 Immunity 51, October 15, 2019
H1 and H5 HA dual-staining method to determine heterosubtypic B cell precursor frequencies in humans and matched these frequencies by adoptively transferring transgenic B cells into wildtype (WT) mice. Importantly, they could show that their headless HA VLP could also elicit VH1-69-encoded stem-specific antibodies at human physiological precursor B cell frequency. The study demonstrates that V regions can incorporate the essentials for public antibody solutions, which under the right conditions can enable the immune system to mount antibody responses against difficult but desirable subdominant epitopes. However, the findings in this study also indicate that no matter how well an immunogen has been engineered for optimal presentation of a particular epitope, it will fail if there is not a sufficient number of precursor B cells available. Conversely, also in this model, availability of increased precursor frequencies of desired B cells
L.H. thanks Dennis R. Burton for his critical comments. L.H.’s influenza virus research was supported by Swiss National Science Foundation grants PP00P3_146345 and PP00P3_123429. His current research is supported by NIH grants 5R01 AI136621-02 and 1UM1AI144462-01. DECLARATION OF INTERESTS L.H. holds a US patent covering the generation and use of heterosubtypic antibodies to influenza A viruses (# US9512202B2). REFERENCES Avnir, Y., Tallarico, A.S., Zhu, Q., Bennett, A.S., Connelly, G., Sheehan, J., Sui, J., Fahmy, A., Huang, C.-Y., Cadwell, G., et al. (2014). Molecular signatures of hemagglutinin stemdirected heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog. 10. e1004103. https://doi.org/10.1371/journal. ppat.1004103. Corti, D., Suguitan, A.L., Jr., Pinna, D., Silacci, C., Fernandez-Rodriguez, B.M., Vanzetta, F., Santos, C., Luke, C.J., Torres-Velez, F.J., Temperton, N.J., et al. (2010). Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J. Clin. Invest. 120, 1663–1673. Ekiert, D.C., Bhabha, G., Elsliger, M.-A., Friesen, R.H.E., Jongeneelen, M., Throsby, M., Goudsmit, J., and Wilson, I.A. (2009). Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246–251. Hangartner, L., Zinkernagel, R.M., and Hengartner, H. (2006). Antiviral antibody responses: the two extremes of a wide spectrum. Nat. Rev. Immunol. 6, 231–243. Kohler, I., Scherrer, A.U., Zagordi, O., Bianchi, M., Wyrzucki, A., Steck, M., Ledergerber, B., €nthard, H.F., and Hangartner, L. (2014). Gu Prevalence and predictors for homo- and
Immunity
Previews heterosubtypic antibodies against influenza a virus. Clin. Infect. Dis. 59, 1386–1393. Ochsenbein, A.F., and Zinkernagel, R.M. (2000). Natural antibodies and complement link innate and acquired immunity. Immunol. Today 21, 624–630. Pappas, L., Foglierini, M., Piccoli, L., Kallewaard, N.L., Turrini, F., Silacci, C., Fernandez-Rodriguez, B., Agatic, G., Giacchetto-Sasselli, I., Pellicciotta, G., et al. (2014). Rapid development of broadly influenza neutralizing antibodies through redundant mutations. Nature 516, 418–422.
Sangesland, M., Ronsard, L., Kazer, S.W., Bals, J., Boyoglu-Barnum, S., Yousif, A.S., Barnes, R., Feldman, J., Quirindongo-Crespo, M., McTamney, P.M., et al. (2019). GermlineEncoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus. Immunity 51, this issue, 735–749. Sui, J., Sheehan, J., Hwang, W.C., Bankston, L.A., Burchett, S.K., Huang, C.Y., Liddington, R.C., Beigel, J.H., and Marasco, W.A. (2011). Wide prevalence of heterosubtypic broadly neutralizing hu-
man anti-influenza A antibodies. Clin. Infect. Dis. 52, 1003–1009.
Wheatley, A.K., Whittle, J.R.R., Lingwood, D., Kanekiyo, M., Yassine, H.M., Ma, S.S., Narpala, S.R., Prabhakaran, M.S., MatusNicodemos, R.A., Bailer, R.T., et al. (2015). H5N1 Vaccine-Elicited Memory B Cells Are Genetically Constrained by the IGHV Locus in the Recognition of a Neutralizing Epitope in the Hemagglutinin Stem. J. Immunol. 195, 602–610.
Casting a Wide Net around Immunity to Malaria Catches p53 Martha M. Cooper,1 Claire Loiseau,1 and Denise L. Doolan1,* 1Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4870, Australia *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.011
The mechanisms underlying acquisition of naturally acquired immunity to malaria are poorly understood. In this issue of Immunity, Tran and colleagues (2019) demonstrate that systems immunology is a powerful tool to decipher molecular and cellular components contributing to this immunity. Malaria remains a global public health problem. Naturally acquired immunity to malaria develops slowly with age and exposure, consistently preventing severe disease and death in millions of people (Doolan et al., 2009). Sterile infectionblocking protective immunity to Plasmodium falciparum has been achieved in preclinical and clinical models but is rarely seen following natural infection, even after years of intense exposure (Doolan et al., 2009). Studies in high-transmission areas have shown that clinical immunity, which controls disease symptoms including fever, and anti-parasite immunity, which controls parasite burden, begin to develop in children over years of repeated infections (Langhorne et al., 2008). However, the cellular immune mechanisms and molecular components that govern the acquisition of clinical (anti-disease) and anti-parasite immunity remain unclear. Systems immunology is a holistic and unbiased approach that harnesses advances in high-throughput technologies and computational analysis to comprehensively profile the molecules, networks, and interactions that contribute
to host-pathogen immunity (Davis et al., 2017). In this issue of Immunity, Tran et al. (2019) apply systems immunology to interrogate immune responses to the first PCR-detectable P. falciparum infection of the malaria season in a welldefined longitudinal cohort of Malian children with asymptomatic, early-febrile, or late-febrile infection. Clinical symptoms of malaria occur only during the blood stage of the Plasmodium spp. parasite life cycle, and immune responses to this stage impact both parasite burden and disease symptoms. It is well established that antigen-specific antibodies are important in blood-stage immunity, but less is known about cellmediated immunity to malaria. Although parasite-infected erythrocytes lack major histocompatibility complex molecules and are therefore not direct targets for T cells, they do trigger innate and adaptive cellular immunity indirectly (Kurup et al., 2019). Effective cellular responses likely represent a fine balance of pro-inflammatory and regulatory responses to kill parasites and limit immunopathology. The resulting complex network of immune
responses includes innate cell types, multiple T cell subsets, and a broad range of cytokines and other immune mediators (Kurup et al., 2019). Despite decades of research and insights into host-pathogen interactions, the development of effective therapeutic interventions to malaria remains elusive and is hampered by our poor understanding of the key cellular and molecular components underlying protective immunity. Addressing this challenge requires additional approaches, and one of the most promising, undertaken by Tran et al. and others, is systems immunology. Most systems-based studies have focused either on controlled human malaria infection (CHMI) models (Cooper et al., 2019) or on a single sampling time point (e.g., infection) in parasite-infected versus uninfected controls. However, CHMI studies do not mimic the natural parasite infection cycle as they are mostly conducted in malaria-naive adults in nonendemic areas (Cooper et al., 2019), and comparing malaria-infected individuals to uninfected controls adds unwanted inter-individual variation into the study.
Immunity 51, October 15, 2019 ª 2019 Elsevier Inc. 603
Previews Public Endowment of B Cells Lars Hangartner1,* 1The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.016
Using a transgenic mouse strain expressing the human VH1-69 germline gene used by many broadly neutralizing antibodies to influenza A virus, Sangesland et al. show that the VH1-69 gene segment provides the essentials for mounting antibody responses against the conserved hemagglutinin stem epitope. The humoral response to the influenza A virus (IAV) hemagglutinin (HA) is dominated by antibodies to variable epitopes located around the receptor binding site. Due to the variability of their epitopes, these antibodies are highly strain specific and only neutralize the eliciting or closely related IAV strains. Heterosubtypic neutralizing antibodies (hnAbs)—i.e., antibodies that can bind and neutralize multiple strains and subtypes (serotypes) of IAV, are rare but can be found in most individuals at low levels (Corti et al., 2010; Kohler et al., 2014; Sui et al., 2011). hnAbs specific for the conserved epitope located in the stem of IAV HA surface protein are special in that they are preferentially encoded by the VH1-69 germline gene, display a preference for phylogenetic group 1 viruses, and almost exclusively use their heavy chain for binding to HA (Avnir et al., 2014; Corti et al., 2010; Ekiert et al., 2009; Pappas et al., 2014; Wheatley et al., 2015). VH1-69 encoded hnAbs constitute a shared or ‘‘public’’ antibody solution, as very similar B cell clonotypes specific for this epitope can be found in various individuals. While it is quite possible that independent but convergent B cell evolution leads to public solutions, it has also been speculated that mammalian B cell repertoires have evolved to encode for public solutions to improve responses to commonly encountered pathogens. In this issue of Immunity, Sangesland et al. (2019) present a study that uses transgenic mice expressing a single human VH gene in the context of all human D and JH elements to show that the public VH1-69 HA stem solution is indeed inherent to this V region and that the presence of VH1-69 is sufficient to enable antibody responses to this desirable public but subdominant IAV HA epitope. Antibodies capable of slowing viral dissemination during the first days of
infection can be crucial for the survival of the infected host and help to bridge the time until the adaptive immune system has fully kicked in (Hangartner et al., 2006). Part of this first line of defense are natural antibodies—i.e., germline-encoded immunoglobulin M (IgM) antibodies that help to prime the immune system by recruiting antigens to secondary lymphoid organs and by keeping early pathogen dissemination at bay (Ochsenbein and Zinkernagel, 2000). The activity of germline-encoded, bona fide low-affinity antibodies is augmented by their secretion as pentameric or hexameric IgM antibodies whose higher valency of binding can compensate for poor affinity until higher-affinity antibodies have been selected. IgM is also a potent activator of the complement system, which helps both restrict pathogen dissemination and recruit antigens to secondary lymphoid organs. While hardwiring of public specificities into the B cell repertoire is beneficial for surviving common pathogens, it may be at the expense of skewing the antibody repertoire: providing public specificities with a head start will put non-public specificities at a disadvantage and possibly can result in immunodominance. As a matter of fact, immunodominance has proven to be a major issue for the development of universal vaccines against variable viruses such as HIV or influenza virus. While the variable and thus strainspecific epitopes of the surface proteins of these viruses are highly immunogenic, efforts to immunize against their conserved epitopes have proven to be difficult. In the case of influenza viruses, experimental vaccines can elicit antibodies to the conserved stem epitope, but those typically fail to neutralize the virus.
The specificity of antibodies typically comes from the heavy- and lightchain complementarity-determining regions (CDRs). While two of the three CDRs for each chain are encoded in the V region gene (CDR1 and 2), the third (CDR3) arises as the result of the V(D)J recombination during B cell ontogeny. Due to higher variability compared to CDR1 and 2, CDR3, especially that of the heavy chain (HCDR3), often provides the essential antigen contacts with the antigen. VH1-69-encoded antibodies are special in that they can evolve from the VH1-69 germline gene with as little as little as one or two V-region substitutions when combined with a properly positioned HCDR3 tyrosine—e.g., replacement of HCDR2 Ile 52a with a smaller small amino acid, such as serine, alanine, and glycine, allows the germline-encoded but polymorphic HCDR2 phenylalanine 54 and the HCDR3 tyrosine to be inserted into adjacent pockets to establish the key contacts (Avnir et al., 2014; Pappas et al., 2014) between antibody and HA stem. Since removal of the HCDR3 tyrosine, but not of the HCDR2 phenylalanine, can be tolerated in many VH1-69 hnAbs, Sangesland et al. speculated that V segment encoded residues form ‘‘primordial’’ germline contacts that enable selection of VH1-69-expressing hnAb precursor B cells. To test their hypothesis, the authors used two transgenic mouse strains expressing either the human VH1-69 or VH1-2 gene segments in conjunction with all human D and JH elements (Figure 1). They then immunized these humanized mouse strains with infectious virions and virus-like particles (VLPs) displaying either full-length HA or a specially crafted ‘‘headless’’ HA lacking the immunodominant head epitopes. The authors found that VH1-69, but not VH1-2,
Immunity 51, October 15, 2019 ª 2019 Elsevier Inc. 601
Immunity
Previews Mouse locus VH
VH
VH
D
VH1-2 humanized JH
hVH1-2
Strain-specific
hD
hJH
Strain-specific
VH1-69 humanized hVH1-69
hD
hJH
Strain-specific and heterosubtypic
was not sufficient to prevent the immunodominant, strain-specific epitopes from taking over eventually, indicating that the VH1-69-encoded public hnAb endowment is not very competitive compared to other epitopes. Nonetheless, the results presented by Sangesgard et al. back current reverse-vaccinology approaches to elicit antibodies against the subdominant broadly neutralizing epitopes of HIV and IAV. Since many of these approaches aim to increase precursor B cell frequencies, e.g., with germline-targeting immunogens, and to seek to avoid immune responses to dominant variable epitopes, e.g., by masking or switching the dominant epitopes, these results are encouraging for the further development of such universally protective vaccines. ACKNOWLEDGMENTS
Figure 1. Assessing the Contribution of the VH Gene Segment to Public Antibody Solutions Antibodies to the conserved stem epitope (yellow circle) of influenza virus hemagglutinin (HA, blue and gray) are difficult to elicit, and immunization of wild-type mice primarily elicits antibodies to the antigenically variable head of HA. Closely related stem-specific and broadly reactive VH1-69-encoded antibodies can be found in many humans, indicating that they constitute a public specificity. VH1-69encoded stem antibodies are special in that they partially rely on germline-encoded residues for strainindependent binding and neutralization. Using a mouse strain that has been genetically engineered to encode for a single human germline gene in combination with human D and J elements, Sangesland et al. could demonstrate that the presence of the VH1-69, but not the human VH1-2, gene segment enabled mice to mount antibodies to the conserved stem-epitope and thereby provide evidence that the public specificity for this type of stem-specific heterosubtypic antibodies is segregating with the VH1-69 gene segment.
humanized mice were able to mount stem-specific antibodies, enrich for B cells expressing B cell receptors (BCRs) with the aforementioned heterosubtypic antibody signatures, and were protected against a heterosubtypic virus challenge. Thereby, they could prove that the VH1-69 region indeed provides all the necessary features for eliciting HAstem-specific hnAbs. In contrast to HIV, where potential vaccine recipients are immunologically naive, most IAV vaccine recipients can be expected to be have been previously exposed to the virus. Sangesgard et al. could show that also in IAV pre-exposed VH1-69 mice, headless-HA VLP immunization could enrich for B cells expressing hnAb signatures and refocus the virus-induced antibody response on the HA-stem hnAb epitope. To demonstrate that their observations are not an artifact of the drastically increased precursor B cell frequencies in the transgenic mice, Sangesgard et al. then used an elegant 602 Immunity 51, October 15, 2019
H1 and H5 HA dual-staining method to determine heterosubtypic B cell precursor frequencies in humans and matched these frequencies by adoptively transferring transgenic B cells into wildtype (WT) mice. Importantly, they could show that their headless HA VLP could also elicit VH1-69-encoded stem-specific antibodies at human physiological precursor B cell frequency. The study demonstrates that V regions can incorporate the essentials for public antibody solutions, which under the right conditions can enable the immune system to mount antibody responses against difficult but desirable subdominant epitopes. However, the findings in this study also indicate that no matter how well an immunogen has been engineered for optimal presentation of a particular epitope, it will fail if there is not a sufficient number of precursor B cells available. Conversely, also in this model, availability of increased precursor frequencies of desired B cells
L.H. thanks Dennis R. Burton for his critical comments. L.H.’s influenza virus research was supported by Swiss National Science Foundation grants PP00P3_146345 and PP00P3_123429. His current research is supported by NIH grants 5R01 AI136621-02 and 1UM1AI144462-01. DECLARATION OF INTERESTS L.H. holds a US patent covering the generation and use of heterosubtypic antibodies to influenza A viruses (# US9512202B2). REFERENCES Avnir, Y., Tallarico, A.S., Zhu, Q., Bennett, A.S., Connelly, G., Sheehan, J., Sui, J., Fahmy, A., Huang, C.-Y., Cadwell, G., et al. (2014). Molecular signatures of hemagglutinin stemdirected heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog. 10. e1004103. https://doi.org/10.1371/journal. ppat.1004103. Corti, D., Suguitan, A.L., Jr., Pinna, D., Silacci, C., Fernandez-Rodriguez, B.M., Vanzetta, F., Santos, C., Luke, C.J., Torres-Velez, F.J., Temperton, N.J., et al. (2010). Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J. Clin. Invest. 120, 1663–1673. Ekiert, D.C., Bhabha, G., Elsliger, M.-A., Friesen, R.H.E., Jongeneelen, M., Throsby, M., Goudsmit, J., and Wilson, I.A. (2009). Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246–251. Hangartner, L., Zinkernagel, R.M., and Hengartner, H. (2006). Antiviral antibody responses: the two extremes of a wide spectrum. Nat. Rev. Immunol. 6, 231–243. Kohler, I., Scherrer, A.U., Zagordi, O., Bianchi, M., Wyrzucki, A., Steck, M., Ledergerber, B., €nthard, H.F., and Hangartner, L. (2014). Gu Prevalence and predictors for homo- and
Immunity
Previews heterosubtypic antibodies against influenza a virus. Clin. Infect. Dis. 59, 1386–1393. Ochsenbein, A.F., and Zinkernagel, R.M. (2000). Natural antibodies and complement link innate and acquired immunity. Immunol. Today 21, 624–630. Pappas, L., Foglierini, M., Piccoli, L., Kallewaard, N.L., Turrini, F., Silacci, C., Fernandez-Rodriguez, B., Agatic, G., Giacchetto-Sasselli, I., Pellicciotta, G., et al. (2014). Rapid development of broadly influenza neutralizing antibodies through redundant mutations. Nature 516, 418–422.
Sangesland, M., Ronsard, L., Kazer, S.W., Bals, J., Boyoglu-Barnum, S., Yousif, A.S., Barnes, R., Feldman, J., Quirindongo-Crespo, M., McTamney, P.M., et al. (2019). GermlineEncoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus. Immunity 51, this issue, 735–749. Sui, J., Sheehan, J., Hwang, W.C., Bankston, L.A., Burchett, S.K., Huang, C.Y., Liddington, R.C., Beigel, J.H., and Marasco, W.A. (2011). Wide prevalence of heterosubtypic broadly neutralizing hu-
man anti-influenza A antibodies. Clin. Infect. Dis. 52, 1003–1009.
Wheatley, A.K., Whittle, J.R.R., Lingwood, D., Kanekiyo, M., Yassine, H.M., Ma, S.S., Narpala, S.R., Prabhakaran, M.S., MatusNicodemos, R.A., Bailer, R.T., et al. (2015). H5N1 Vaccine-Elicited Memory B Cells Are Genetically Constrained by the IGHV Locus in the Recognition of a Neutralizing Epitope in the Hemagglutinin Stem. J. Immunol. 195, 602–610.
Casting a Wide Net around Immunity to Malaria Catches p53 Martha M. Cooper,1 Claire Loiseau,1 and Denise L. Doolan1,* 1Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4870, Australia *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.011
The mechanisms underlying acquisition of naturally acquired immunity to malaria are poorly understood. In this issue of Immunity, Tran and colleagues (2019) demonstrate that systems immunology is a powerful tool to decipher molecular and cellular components contributing to this immunity. Malaria remains a global public health problem. Naturally acquired immunity to malaria develops slowly with age and exposure, consistently preventing severe disease and death in millions of people (Doolan et al., 2009). Sterile infectionblocking protective immunity to Plasmodium falciparum has been achieved in preclinical and clinical models but is rarely seen following natural infection, even after years of intense exposure (Doolan et al., 2009). Studies in high-transmission areas have shown that clinical immunity, which controls disease symptoms including fever, and anti-parasite immunity, which controls parasite burden, begin to develop in children over years of repeated infections (Langhorne et al., 2008). However, the cellular immune mechanisms and molecular components that govern the acquisition of clinical (anti-disease) and anti-parasite immunity remain unclear. Systems immunology is a holistic and unbiased approach that harnesses advances in high-throughput technologies and computational analysis to comprehensively profile the molecules, networks, and interactions that contribute
to host-pathogen immunity (Davis et al., 2017). In this issue of Immunity, Tran et al. (2019) apply systems immunology to interrogate immune responses to the first PCR-detectable P. falciparum infection of the malaria season in a welldefined longitudinal cohort of Malian children with asymptomatic, early-febrile, or late-febrile infection. Clinical symptoms of malaria occur only during the blood stage of the Plasmodium spp. parasite life cycle, and immune responses to this stage impact both parasite burden and disease symptoms. It is well established that antigen-specific antibodies are important in blood-stage immunity, but less is known about cellmediated immunity to malaria. Although parasite-infected erythrocytes lack major histocompatibility complex molecules and are therefore not direct targets for T cells, they do trigger innate and adaptive cellular immunity indirectly (Kurup et al., 2019). Effective cellular responses likely represent a fine balance of pro-inflammatory and regulatory responses to kill parasites and limit immunopathology. The resulting complex network of immune
responses includes innate cell types, multiple T cell subsets, and a broad range of cytokines and other immune mediators (Kurup et al., 2019). Despite decades of research and insights into host-pathogen interactions, the development of effective therapeutic interventions to malaria remains elusive and is hampered by our poor understanding of the key cellular and molecular components underlying protective immunity. Addressing this challenge requires additional approaches, and one of the most promising, undertaken by Tran et al. and others, is systems immunology. Most systems-based studies have focused either on controlled human malaria infection (CHMI) models (Cooper et al., 2019) or on a single sampling time point (e.g., infection) in parasite-infected versus uninfected controls. However, CHMI studies do not mimic the natural parasite infection cycle as they are mostly conducted in malaria-naive adults in nonendemic areas (Cooper et al., 2019), and comparing malaria-infected individuals to uninfected controls adds unwanted inter-individual variation into the study.
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