- Email: [email protected]
Uncovering the Anti-Ebola Repertome
Cell Host & Microbe
Previews extruded from the outer membrane (Figure 1B). Furthermore, one might hypothesize that these OMVs are quite susceptible to cationic antimicrobial peptides (CAMPs) and bile acids and, therefore, release their cargo readily upon encountering these toxic substances (Figure 1C). While it would be technically difficult to definitively establish that the in vivo fitness advantage of a hypervesiculation mutant is the direct outcome of these outer membrane modifications, the authors do show that vesiculation provides resistance to cationic peptides and bile salts in vitro and that preadaptation to bile salts or cationic peptides negates the virulence advantage of hypervesiculating strains in vivo. As the authors note, components of the outer membrane are costly to synthesize, and disposal of these components appears wasteful. Of course, there are multiple examples in nature, some of which are listed above, in which organisms shed their outer layers. In contrast to many shed substances such as a molt, fur, or
dead skin that are of little use to the organism, the proteins and lipids shed in OMV could be easily recycled. This suggests the possibility that there are additional functions for these OMV in the host-V. cholerae interaction that remain to be discovered.
REFERENCES Cakar, F., Zingl, F.G., Moisi, M., Reidl, J., and Schild, S. (2018). In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H+/Cl- transporter along the gastrointestinal passage. Proc. Natl. Acad. Sci. USA 115, E2376–E2385. Henderson, J.C., Herrera, C.M., and Trent, M.S. (2017). AlmG, responsible for polymyxin resistance in pandemic Vibrio cholerae, is a glycyltransferase distantly related to lipid A late acyltransferases. J. Biol. Chem. 292, 21205–21215. Hessvik, N.P., and Llorente, A. (2018). Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci. 75, 193–208. Jan, A.T. (2017). Outer Membrane Vesicles (OMVs) of Gram-negative Bacteria: A Perspective Update. Front. Microbiol. 8, 1053.
Malinverni, J.C., and Silhavy, T.J. (2009). An ABC transport system that maintains lipid asymmetry in the gram-negative outer membrane. Proc. Natl. Acad. Sci. USA 106, 8009–8014. Powers, M.J., and Trent, M.S. (2019). Intermembrane transport: Glycerophospholipid homeostasis of the Gram-negative cell envelope. Proc. Natl. Acad. Sci. USA 116, 17147–17155. Provenzano, D., and Klose, K.E. (2000). Altered expression of the ToxR-regulated porins OmpU and OmpT diminishes Vibrio cholerae bile resistance, virulence factor expression, and intestinal colonization. Proc. Natl. Acad. Sci. USA 97, 10220–10224. Roier, S., Zingl, F.G., Cakar, F., Durakovic, S., Kohl, P., Eichmann, T.O., Klug, L., Gadermaier, B., Weinzerl, K., Prassl, R., et al. (2016). A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria. Nat. Commun. 7, 10515. Slauch, J.M., Mahan, M.J., and Mekalanos, J.J. (1994). In vivo expression technology for selection of bacterial genes specifically induced in host tissues. Methods Enzymol. 235, 481–492. Zingl, F.G., Kohl, P., Cakar, F., Leitner, D.R., Mitterer, F., Bonnington, K.E., Rechberger, G.N., Kuehn, M.J., Guan, Z., Reidi, J., et al. (2020). Outer Membrane Vesiculation Facilitates Surface Exchange and In Vivo Adaptation of Vibrio cholerae. Cell Host Microbe. 27, this issue, 225–237.
Uncovering the Anti-Ebola Repertome Seiya Yamayoshi1 and Yoshihiro Kawaoka1,2,3,* 1Division
of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA 3Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.chom.2020.01.014 2Department
Ebolavirus disease is a global threat. In this issue, Khurana et al. reveal the antibody response against all ebolavirus proteins by analyzing longitudinal antibody repertoires of an Ebola survivor from disease onset. Antibodies against VP40 and GP are found to predominate and two protective antigenic sites in GP identified. Zaire Ebolavirus (EBOV) caused the largest outbreak of Ebolavirus disease with a high case-fatality rate between 2013 and 2016 in West Africa, particularly Liberia, Guinea, and Sierra Leone. Since 2018 in the Democratic Republic of the Congo, this virus has been causing what is now the second-largest outbreak with approximately 3,300 cases, of which 2,200 have been fatal. As of December 2019, the case fatality rate was approxi-
mately 66%. During these outbreaks, several anti-EBOV therapies, including monoclonal antibodies, antisera, lowmolecular-weight compounds, and siRNAs, were administered to Ebola patients (Lee et al., 2019). However, these therapies were statistically ineffective against EBOV infection in humans. In contrast, ring vaccination based on recombinant vesicular stomatitis virus harboring EBOV GP (rVSV-ZEBOV) have
been highly effective (Henao-Restrepo et al., 2017). In fact, rVSV-ZEBOV has been approved for use in humans for the prevention of EBOV infection by the European Medicines Agency and the US Food and Drug Administration. EBOV GP is a major protein on the virion surface and plays an essential role in virus entry, meaning that inhibition of GP functions––such as attachment to cellular receptors, post-translational
Cell Host & Microbe 27, February 12, 2020 ª 2020 Published by Elsevier Inc. 163
Cell Host & Microbe
Previews Control mice
EBOV
Mice immunized with the GP peptide
YYY Y Y YY Y
Y Y Y Y Y Y YYY Y Y Y Y YY Y Y Y Y YYY Y Y Ebola survivor Figure 1. Peptides Derived from Epitopes in GP-Protected Mice from EBOV Infection The antibody repertoire against the EBOV proteome was analyzed by using serum samples collected at various time points after disease onset. Antibodies against VP40 and GP predominated. Two synthetic peptides identified as major antigenic epitopes protected mice from EBOV challenge.
proteolytic cleavage of GP in the endosome, and fusion between the viral envelope and the host cell membrane––stops EBOV propagation in vitro and in vivo. Therefore, EBOV GP is a primary target for vaccine development and antiviral immunotherapy. To elucidate the antibody response and establish an effective antiviral monoclonal antibody therapy, a time-course analysis of the B cell responses against GP in four Ebola survivors, and the identification of human protective monoclonal antibodies against pan-EBOV GP were conducted, respectively. Because most of the recent studies on vaccine development (rVSV-ZEBOV and other EBOV vaccines) and monoclonal antibody therapies (ZMapp, etc.) exclusively focused on EBOV GP, little is known about the antibody responses against the entire EBOV proteome. In this issue, Khurana et al. (2020) analyzed changes in the antibody repertoire against all of the viral proteins (i.e., structural and nonstructural), including NP, VP35, VP40, VP30, VP24, L, and sGP, as well as GP, for 1 year after the onset of Ebolavirus disease. To achieve this, they used two approaches: surface plasmon resonance
with immobilized recombinant EBOV protein or peptide to measure the quality and quantity of antibodies in serum samples and a phage library that displayed EBOV protein fragments (named genome-fragment phage display library; GFPDL) to elucidate the epitopes of antibodies at the peptide level. For analytes, serum samples obtained from a natural (only standard-care-treatmentprovided) Ebola survivor during the acute, recovering, and recovered phases were utilized. They found that VP40 and GP were the primary and secondary targets for the antibody response (Figure 1) and that the affinity maturation of the antibodies progressed gradually. The phage display analysis identified major antigenic sites in VP40 and GP. Two GP peptides derived from the major antigenic sites of GP (the C terminus of GP1 and GP2) elicited neutralizing antibodies in rabbits and protected mice from lethal challenge infection with mouse-adapted EBOV (Figure 1). Although this study analyzed samples from only one Ebola survivor, the authors successfully identified two protective antigenic epitopes in GP. Thus, this GFPDL approach is useful
164 Cell Host & Microbe 27, February 12, 2020
to identify major antigenic sites of other pathogens including viruses and bacterium. On the basis of these results, it may be possible to predict vaccine efficacy according to the amount of antibody against each protective epitope. Furthermore, this epitope-guided antibody measurement might identify vaccinees who would need a booster vaccination. However, it needs to be confirmed whether the identified protective epitopes are commonly targeted by other Ebola survivors and whether non-survivors also raise antibodies against the identified protective epitopes. In addition, other conformational protective antigenic sites should be explored because the GFPDL may not have included such epitopes. The subject in this study maintained a high level of immunoglobulin M (IgM) antibody against EBOV proteins at 1 year after disease onset (Khurana et al., 2020), demonstrating long-lasting exposure to EBOV protein antigens (so-called inferring occult persistent infection). After viral RNA levels in blood fall below the detection limit of quantitative RTPCR, EBOV presents in immunologically separated sites (eyes, testis, etc.) in many Ebola survivors (Sneller et al., 2019). Some such individuals, as well as some individuals without virus, suffer from post-Ebola syndrome, symptoms of which include joint and muscle pain and various neurological problems (Scott et al., 2016). IgM serum levels could probably be used to identify Ebola survivors who maintain EBOV in the body; however, regimens that eradicate EBOV from the body have not yet been established. The predominance of anti-VP40 antibodies in the serum samples from this Ebola survivor (Khurana et al., 2020) needs to be confirmed in other Ebola survivors. The unconventional secretion of VP40 as a soluble monomer from the infected cells (Reynard et al., 2011) might accelerate the anti-VP40 antibody production. Although a role for a high anti-VP40 antibody titer has yet to be characterized, and the contribution of anti-VP40 antibodies to protection in vivo has not been reported, the increase in anti-VP40 antibody titer occurred with similar timing as the reduction in viral RNA in the serum sample, suggesting that the anti-VP40 antibodies could play an important role in suppressing virus replication in vivo. Furthermore, VP40, as
Cell Host & Microbe
Previews well as NP, VP24, VP30, and VP35, have been shown to elicit protective immune responses (cytotoxic T lymphocyte activity, antibody-dependent effector cell activation, etc.) against EBOV in an animal model (Wilson et al., 2001; Wilson and Hart, 2001). Since rVSV-ZEBOV and other developing vaccines specifically target efficient production of anti-GP antibodies, we should also consider other immune responses against all EBOV proteins. An inactivated whole-virion vaccine might be suitable for such a purpose. ACKNOWLEDGMENT We thank Susan Watson for scientific editing. This research was supported by Research Program on Emerging and Re-emerging Infectious Diseases from AMED (JP19fk0108029h0002 and JP19fm0208101j0001); a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan (No. 16H06429,
16K21723, and 16H06434); and a fund for the Promotion of Joint International Research (Fostering Joint International Research [B]) from Japan Society for the Promotion of Science (JSPS) (JP18KK0225). REFERENCES Henao-Restrepo, A.M., Camacho, A., Longini, I.M., Watson, C.H., Edmunds, W.J., Egger, M., Carroll, M.W., Dean, N.E., Diatta, I., Doumbia, M., et al. (2017). Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola C¸a Suffit!). Lancet 389, 505–518. Khurana, S., Ravichandran, S., Hahn, M., Coyle, E.M., Stonier, S.W., Zak, S.E., Kindrachuk, J., Davey, R.T.J., Dye, J.M., and Chertow, D.S. (2020). Longitudinal human antibody repertoire against complete viral proteome following acute Ebola virus infection reveals protective sites for vaccine design. Cell Host Microbe 27, this issue, 262–276. Lee, J.S., Adhikari, N.K.J., Kwon, H.Y., Teo, K., Siemieniuk, R., Lamontagne, F., Chan, A., Mishra, S., Murthy, S., Kiiza, P., et al. (2019). Anti-Ebola
therapy for patients with Ebola virus disease: a systematic review. BMC Infect. Dis. 19, 376. Reynard, O., Reid, S.P., Page, A., Mateo, M., Alazard-Dany, N., Raoul, H., Basler, C.F., and Volchkov, V.E. (2011). Unconventional secretion of Ebola virus matrix protein VP40. J. Infect. Dis. 204 (Suppl 3 ), S833–S839. Scott, J.T., Sesay, F.R., Massaquoi, T.A., Idriss, B.R., Sahr, F., and Semple, M.G. (2016). PostEbola Syndrome, Sierra Leone. Emerg. Infect. Dis. 22, 641–646. Sneller, M.C., Reilly, C., Badio, M., Bishop, R.J., Eghrari, A.O., Moses, S.J., Johnson, K.L., Gayedyu-Dennis, D., Hensley, L.E., Higgs, E.S., et al.; PREVAIL III Study Group (2019). A Longitudinal Study of Ebola Sequelae in Liberia. N. Engl. J. Med. 380, 924–934. Wilson, J.A., and Hart, M.K. (2001). Protection from Ebola virus mediated by cytotoxic T lymphocytes specific for the viral nucleoprotein. J. Virol. 75, 2660–2664. Wilson, J.A., Bray, M., Bakken, R., and Hart, M.K. (2001). Vaccine potential of Ebola virus VP24, VP30, VP35, and VP40 proteins. Virology 286, 384–390.
The NET Effect of Neutrophils during Helminth Infection Darine W. El-Naccache,1 Fei Chen,1 Neil Chen,1 and William C. Gause1,* 1Center for Immunity and Inflammation and Department of Medicine, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ 07103, USA *Correspondence: [email protected] https://doi.org/10.1016/j.chom.2020.01.013
Recent studies show that neutrophils mediate both tissue damage and host protection in response to multicellular parasites. In this issue of Cell Host & Microbe, Bouchery et al. demonstrate the importance of neutrophil extracellular traps in helminth damage after primary infections. Pick up a recent Immunology textbook and more often than not, myeloid cells are distinctly separated according to the particular infectious or stimulating agent; within these groupings, eosinophils, basophils, and mast cells are linked to type 2 responses to allergens or parasitic worms (helminths) while macrophages and neutrophils are linked to type 1 responses triggered by microbial infections, including viruses and bacteria. Increasingly, it is clear that, indeed, myeloid cells show considerable heterogeneity and distinct functions in response to a broad range of infecting pathogens, including
helminths. These large multicellular parasites stimulate alternatively activated (M2) macrophages, which can promote tissue repair in response to the considerable damage these multicellular helminths may cause as they traffick through vital organs. Furthermore, recent studies indicate that helminth-primed M2 macrophages can also mediate acquired resistance to helminths in the skin, lung, and intestine, often through arginase-1dependent mechanisms, and can directly kill parasites in vitro (Chen et al., 2014; Yap and Gause, 2018). It should also be noted that M2 macrophages themselves
show heterogeneity exhibiting varying phenotypes and requirements for differentiation depending on the particular pathogen or other activating insult and the specific tissue microenvironment in which they are stimulated. It now appears that neutrophils are also alternatively activated (N2) during helminth infection, expressing many genes associated with type 2 immunity and in some cases also expressed by M2 macrophages (Chen et al., 2014). Shortly after helminth invasion of the lung, neutrophils are rapidly recruited to this tissue and, when there, contribute to lung tissue damage and
Cell Host & Microbe 27, February 12, 2020 ª 2020 Published by Elsevier Inc. 165
Previews extruded from the outer membrane (Figure 1B). Furthermore, one might hypothesize that these OMVs are quite susceptible to cationic antimicrobial peptides (CAMPs) and bile acids and, therefore, release their cargo readily upon encountering these toxic substances (Figure 1C). While it would be technically difficult to definitively establish that the in vivo fitness advantage of a hypervesiculation mutant is the direct outcome of these outer membrane modifications, the authors do show that vesiculation provides resistance to cationic peptides and bile salts in vitro and that preadaptation to bile salts or cationic peptides negates the virulence advantage of hypervesiculating strains in vivo. As the authors note, components of the outer membrane are costly to synthesize, and disposal of these components appears wasteful. Of course, there are multiple examples in nature, some of which are listed above, in which organisms shed their outer layers. In contrast to many shed substances such as a molt, fur, or
dead skin that are of little use to the organism, the proteins and lipids shed in OMV could be easily recycled. This suggests the possibility that there are additional functions for these OMV in the host-V. cholerae interaction that remain to be discovered.
REFERENCES Cakar, F., Zingl, F.G., Moisi, M., Reidl, J., and Schild, S. (2018). In vivo repressed genes of Vibrio cholerae reveal inverse requirements of an H+/Cl- transporter along the gastrointestinal passage. Proc. Natl. Acad. Sci. USA 115, E2376–E2385. Henderson, J.C., Herrera, C.M., and Trent, M.S. (2017). AlmG, responsible for polymyxin resistance in pandemic Vibrio cholerae, is a glycyltransferase distantly related to lipid A late acyltransferases. J. Biol. Chem. 292, 21205–21215. Hessvik, N.P., and Llorente, A. (2018). Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci. 75, 193–208. Jan, A.T. (2017). Outer Membrane Vesicles (OMVs) of Gram-negative Bacteria: A Perspective Update. Front. Microbiol. 8, 1053.
Malinverni, J.C., and Silhavy, T.J. (2009). An ABC transport system that maintains lipid asymmetry in the gram-negative outer membrane. Proc. Natl. Acad. Sci. USA 106, 8009–8014. Powers, M.J., and Trent, M.S. (2019). Intermembrane transport: Glycerophospholipid homeostasis of the Gram-negative cell envelope. Proc. Natl. Acad. Sci. USA 116, 17147–17155. Provenzano, D., and Klose, K.E. (2000). Altered expression of the ToxR-regulated porins OmpU and OmpT diminishes Vibrio cholerae bile resistance, virulence factor expression, and intestinal colonization. Proc. Natl. Acad. Sci. USA 97, 10220–10224. Roier, S., Zingl, F.G., Cakar, F., Durakovic, S., Kohl, P., Eichmann, T.O., Klug, L., Gadermaier, B., Weinzerl, K., Prassl, R., et al. (2016). A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria. Nat. Commun. 7, 10515. Slauch, J.M., Mahan, M.J., and Mekalanos, J.J. (1994). In vivo expression technology for selection of bacterial genes specifically induced in host tissues. Methods Enzymol. 235, 481–492. Zingl, F.G., Kohl, P., Cakar, F., Leitner, D.R., Mitterer, F., Bonnington, K.E., Rechberger, G.N., Kuehn, M.J., Guan, Z., Reidi, J., et al. (2020). Outer Membrane Vesiculation Facilitates Surface Exchange and In Vivo Adaptation of Vibrio cholerae. Cell Host Microbe. 27, this issue, 225–237.
Uncovering the Anti-Ebola Repertome Seiya Yamayoshi1 and Yoshihiro Kawaoka1,2,3,* 1Division
of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA 3Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.chom.2020.01.014 2Department
Ebolavirus disease is a global threat. In this issue, Khurana et al. reveal the antibody response against all ebolavirus proteins by analyzing longitudinal antibody repertoires of an Ebola survivor from disease onset. Antibodies against VP40 and GP are found to predominate and two protective antigenic sites in GP identified. Zaire Ebolavirus (EBOV) caused the largest outbreak of Ebolavirus disease with a high case-fatality rate between 2013 and 2016 in West Africa, particularly Liberia, Guinea, and Sierra Leone. Since 2018 in the Democratic Republic of the Congo, this virus has been causing what is now the second-largest outbreak with approximately 3,300 cases, of which 2,200 have been fatal. As of December 2019, the case fatality rate was approxi-
mately 66%. During these outbreaks, several anti-EBOV therapies, including monoclonal antibodies, antisera, lowmolecular-weight compounds, and siRNAs, were administered to Ebola patients (Lee et al., 2019). However, these therapies were statistically ineffective against EBOV infection in humans. In contrast, ring vaccination based on recombinant vesicular stomatitis virus harboring EBOV GP (rVSV-ZEBOV) have
been highly effective (Henao-Restrepo et al., 2017). In fact, rVSV-ZEBOV has been approved for use in humans for the prevention of EBOV infection by the European Medicines Agency and the US Food and Drug Administration. EBOV GP is a major protein on the virion surface and plays an essential role in virus entry, meaning that inhibition of GP functions––such as attachment to cellular receptors, post-translational
Cell Host & Microbe 27, February 12, 2020 ª 2020 Published by Elsevier Inc. 163
Cell Host & Microbe
Previews Control mice
EBOV
Mice immunized with the GP peptide
YYY Y Y YY Y
Y Y Y Y Y Y YYY Y Y Y Y YY Y Y Y Y YYY Y Y Ebola survivor Figure 1. Peptides Derived from Epitopes in GP-Protected Mice from EBOV Infection The antibody repertoire against the EBOV proteome was analyzed by using serum samples collected at various time points after disease onset. Antibodies against VP40 and GP predominated. Two synthetic peptides identified as major antigenic epitopes protected mice from EBOV challenge.
proteolytic cleavage of GP in the endosome, and fusion between the viral envelope and the host cell membrane––stops EBOV propagation in vitro and in vivo. Therefore, EBOV GP is a primary target for vaccine development and antiviral immunotherapy. To elucidate the antibody response and establish an effective antiviral monoclonal antibody therapy, a time-course analysis of the B cell responses against GP in four Ebola survivors, and the identification of human protective monoclonal antibodies against pan-EBOV GP were conducted, respectively. Because most of the recent studies on vaccine development (rVSV-ZEBOV and other EBOV vaccines) and monoclonal antibody therapies (ZMapp, etc.) exclusively focused on EBOV GP, little is known about the antibody responses against the entire EBOV proteome. In this issue, Khurana et al. (2020) analyzed changes in the antibody repertoire against all of the viral proteins (i.e., structural and nonstructural), including NP, VP35, VP40, VP30, VP24, L, and sGP, as well as GP, for 1 year after the onset of Ebolavirus disease. To achieve this, they used two approaches: surface plasmon resonance
with immobilized recombinant EBOV protein or peptide to measure the quality and quantity of antibodies in serum samples and a phage library that displayed EBOV protein fragments (named genome-fragment phage display library; GFPDL) to elucidate the epitopes of antibodies at the peptide level. For analytes, serum samples obtained from a natural (only standard-care-treatmentprovided) Ebola survivor during the acute, recovering, and recovered phases were utilized. They found that VP40 and GP were the primary and secondary targets for the antibody response (Figure 1) and that the affinity maturation of the antibodies progressed gradually. The phage display analysis identified major antigenic sites in VP40 and GP. Two GP peptides derived from the major antigenic sites of GP (the C terminus of GP1 and GP2) elicited neutralizing antibodies in rabbits and protected mice from lethal challenge infection with mouse-adapted EBOV (Figure 1). Although this study analyzed samples from only one Ebola survivor, the authors successfully identified two protective antigenic epitopes in GP. Thus, this GFPDL approach is useful
164 Cell Host & Microbe 27, February 12, 2020
to identify major antigenic sites of other pathogens including viruses and bacterium. On the basis of these results, it may be possible to predict vaccine efficacy according to the amount of antibody against each protective epitope. Furthermore, this epitope-guided antibody measurement might identify vaccinees who would need a booster vaccination. However, it needs to be confirmed whether the identified protective epitopes are commonly targeted by other Ebola survivors and whether non-survivors also raise antibodies against the identified protective epitopes. In addition, other conformational protective antigenic sites should be explored because the GFPDL may not have included such epitopes. The subject in this study maintained a high level of immunoglobulin M (IgM) antibody against EBOV proteins at 1 year after disease onset (Khurana et al., 2020), demonstrating long-lasting exposure to EBOV protein antigens (so-called inferring occult persistent infection). After viral RNA levels in blood fall below the detection limit of quantitative RTPCR, EBOV presents in immunologically separated sites (eyes, testis, etc.) in many Ebola survivors (Sneller et al., 2019). Some such individuals, as well as some individuals without virus, suffer from post-Ebola syndrome, symptoms of which include joint and muscle pain and various neurological problems (Scott et al., 2016). IgM serum levels could probably be used to identify Ebola survivors who maintain EBOV in the body; however, regimens that eradicate EBOV from the body have not yet been established. The predominance of anti-VP40 antibodies in the serum samples from this Ebola survivor (Khurana et al., 2020) needs to be confirmed in other Ebola survivors. The unconventional secretion of VP40 as a soluble monomer from the infected cells (Reynard et al., 2011) might accelerate the anti-VP40 antibody production. Although a role for a high anti-VP40 antibody titer has yet to be characterized, and the contribution of anti-VP40 antibodies to protection in vivo has not been reported, the increase in anti-VP40 antibody titer occurred with similar timing as the reduction in viral RNA in the serum sample, suggesting that the anti-VP40 antibodies could play an important role in suppressing virus replication in vivo. Furthermore, VP40, as
Cell Host & Microbe
Previews well as NP, VP24, VP30, and VP35, have been shown to elicit protective immune responses (cytotoxic T lymphocyte activity, antibody-dependent effector cell activation, etc.) against EBOV in an animal model (Wilson et al., 2001; Wilson and Hart, 2001). Since rVSV-ZEBOV and other developing vaccines specifically target efficient production of anti-GP antibodies, we should also consider other immune responses against all EBOV proteins. An inactivated whole-virion vaccine might be suitable for such a purpose. ACKNOWLEDGMENT We thank Susan Watson for scientific editing. This research was supported by Research Program on Emerging and Re-emerging Infectious Diseases from AMED (JP19fk0108029h0002 and JP19fm0208101j0001); a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan (No. 16H06429,
16K21723, and 16H06434); and a fund for the Promotion of Joint International Research (Fostering Joint International Research [B]) from Japan Society for the Promotion of Science (JSPS) (JP18KK0225). REFERENCES Henao-Restrepo, A.M., Camacho, A., Longini, I.M., Watson, C.H., Edmunds, W.J., Egger, M., Carroll, M.W., Dean, N.E., Diatta, I., Doumbia, M., et al. (2017). Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola C¸a Suffit!). Lancet 389, 505–518. Khurana, S., Ravichandran, S., Hahn, M., Coyle, E.M., Stonier, S.W., Zak, S.E., Kindrachuk, J., Davey, R.T.J., Dye, J.M., and Chertow, D.S. (2020). Longitudinal human antibody repertoire against complete viral proteome following acute Ebola virus infection reveals protective sites for vaccine design. Cell Host Microbe 27, this issue, 262–276. Lee, J.S., Adhikari, N.K.J., Kwon, H.Y., Teo, K., Siemieniuk, R., Lamontagne, F., Chan, A., Mishra, S., Murthy, S., Kiiza, P., et al. (2019). Anti-Ebola
therapy for patients with Ebola virus disease: a systematic review. BMC Infect. Dis. 19, 376. Reynard, O., Reid, S.P., Page, A., Mateo, M., Alazard-Dany, N., Raoul, H., Basler, C.F., and Volchkov, V.E. (2011). Unconventional secretion of Ebola virus matrix protein VP40. J. Infect. Dis. 204 (Suppl 3 ), S833–S839. Scott, J.T., Sesay, F.R., Massaquoi, T.A., Idriss, B.R., Sahr, F., and Semple, M.G. (2016). PostEbola Syndrome, Sierra Leone. Emerg. Infect. Dis. 22, 641–646. Sneller, M.C., Reilly, C., Badio, M., Bishop, R.J., Eghrari, A.O., Moses, S.J., Johnson, K.L., Gayedyu-Dennis, D., Hensley, L.E., Higgs, E.S., et al.; PREVAIL III Study Group (2019). A Longitudinal Study of Ebola Sequelae in Liberia. N. Engl. J. Med. 380, 924–934. Wilson, J.A., and Hart, M.K. (2001). Protection from Ebola virus mediated by cytotoxic T lymphocytes specific for the viral nucleoprotein. J. Virol. 75, 2660–2664. Wilson, J.A., Bray, M., Bakken, R., and Hart, M.K. (2001). Vaccine potential of Ebola virus VP24, VP30, VP35, and VP40 proteins. Virology 286, 384–390.
The NET Effect of Neutrophils during Helminth Infection Darine W. El-Naccache,1 Fei Chen,1 Neil Chen,1 and William C. Gause1,* 1Center for Immunity and Inflammation and Department of Medicine, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ 07103, USA *Correspondence: [email protected] https://doi.org/10.1016/j.chom.2020.01.013
Recent studies show that neutrophils mediate both tissue damage and host protection in response to multicellular parasites. In this issue of Cell Host & Microbe, Bouchery et al. demonstrate the importance of neutrophil extracellular traps in helminth damage after primary infections. Pick up a recent Immunology textbook and more often than not, myeloid cells are distinctly separated according to the particular infectious or stimulating agent; within these groupings, eosinophils, basophils, and mast cells are linked to type 2 responses to allergens or parasitic worms (helminths) while macrophages and neutrophils are linked to type 1 responses triggered by microbial infections, including viruses and bacteria. Increasingly, it is clear that, indeed, myeloid cells show considerable heterogeneity and distinct functions in response to a broad range of infecting pathogens, including
helminths. These large multicellular parasites stimulate alternatively activated (M2) macrophages, which can promote tissue repair in response to the considerable damage these multicellular helminths may cause as they traffick through vital organs. Furthermore, recent studies indicate that helminth-primed M2 macrophages can also mediate acquired resistance to helminths in the skin, lung, and intestine, often through arginase-1dependent mechanisms, and can directly kill parasites in vitro (Chen et al., 2014; Yap and Gause, 2018). It should also be noted that M2 macrophages themselves
show heterogeneity exhibiting varying phenotypes and requirements for differentiation depending on the particular pathogen or other activating insult and the specific tissue microenvironment in which they are stimulated. It now appears that neutrophils are also alternatively activated (N2) during helminth infection, expressing many genes associated with type 2 immunity and in some cases also expressed by M2 macrophages (Chen et al., 2014). Shortly after helminth invasion of the lung, neutrophils are rapidly recruited to this tissue and, when there, contribute to lung tissue damage and
Cell Host & Microbe 27, February 12, 2020 ª 2020 Published by Elsevier Inc. 165