Protect against malaria 1941In 2008, I talked about maybe 100-200 papers here on Mystery Rays. Here are some of my favorite publications of 2008. I’m not saying these are the most important of the year, or anything like that; these are just papers that I thought covered something cool and did so in a nice clean way. As with last year, I managed to narrow it down to 12 subjects, but this time I couldn’t quite cut it down to 12 specific papers this year. Whatever, dude.  In no particular order:

  1. Malaria vaccines. People have been working on effective malaria vaccines for decades, without much to show for it. In 2008, clinical trials with a new vaccine candidate showed encouraging, though not overwhelming, protection. (I talked about malaria eradication here and here.)

    Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. 1
    Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. 2

  2. Mechanism of action of alum adjuvant. Alum has been the by far the most common adjuvant used in human vaccines, but until recently we didn’t know how it works. There were a bunch of papers in 2008 that at last offered explanations for alum’s effect: It acts through a particular branch of the innate immune sensor mechanism. (I talked about alum here and here.)

    Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122-1126. 3
    The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol. 2008 Aug;38(8):2085-9. 4
    Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol. 2008 Jul 1;181(1):17-21. 5

  3. Immune evasion by tumor cells has been shown in a number of cases.  This year, it was shown that natural killer (NK) cells — or at least an NK cell receptor — in important in controlling tumors. (I talked about this paper here.)

    NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. Immunity 28, 571-580. 6

  4. HSV-infected ganglionT cells recognize latently-infected neurons. The most characteristic aspect of herpesviruses is their ability to become latent — to set up a long-term (often lifelong) infection in some cell type, without destroying the infected cells, and without being eliminated by the immune system. Herpes simplex viruses are the archetypal herpesvirus, yet in the past few years it’s become apparent that everything we thought we knew about herpes simplex latency is wrong. Herpes simplex latent infection turns out to be recognized and controlled, but not eliminated by immune T cells. (Here is my post on this paper.)

    Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268-271. 7

  5. … What’s more, the view that HSV sets up a latent infection and then only rarely reactivates also turns out to be wrong. It seems that HSV is constantly reactivating from latent infection, but mainly in very short bursts. If you don’t monitor patients very, very closely — like swabbing them several times a day — you’ll miss most of the reactivations, so that it looks as if reactivation is rare.

    Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J. Infect. Dis. 198, 1141-1149 8

  6. … and even before latent infection, immune control may be critical. There seems to be a very narrow window of opportunity for immune responses to attack a herpes simplex infection before the virus slips up into neurons and establishes the latent infection. (More here.)

    CD8(+) T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunol. Cell Biol. 86, 666-675 9

  7. Immunodeficiency virus immune escape. One of the major barriers to immune control of HIV is the virus’s ability to mutate and escape recognition by the immune system. This has been recognized for a long time, but techniques to measure and analyze this continue to improve. Here’s a representative paper looking in detail at immunodeficiency virus immune escape.

    Vaccination and Timing Influence SIV Immune Escape Viral Dynamics In Vivo. PLoS Pathog 4(1): e12 10

  8. Adenovirus evades NK cells. The first virus that was shown to have a way of blocking recognition by T cells was adenovirus, via its E3gp19k protein. Identified in the 1970s, there were a flurry of articles on the protein, and then it kind of languished, as people assumed the story was mined out. In 2008, though, it was shown that E3gp19k is much more potent that originally believed, because it also blocks recognition by natural killer (NK) cells. Another reminder that viruses are capable of much more subtlety than we give them credit for. (I talked about this here.)

    Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B. J. Virol. 82, 4585-4594 11

  9. A new mechanism of immune evasion. One of the rather puzzling things about viral immune evasion is that even closely-related viruses often seem to have evolved their own, independent, approaches to the problem. Kalus Fruh showed that rhesus cytomegalovirus has a really weird way of blocking T cell recognition, a mechanism that so far seems to be unique to this virus.  In the past, weird virus immune evasion things have led to important advances in normal cell biology; maybe this will, too.

    Signal Peptide-Dependent Inhibition of MHC Class I Heavy Chain Translation by Rhesus Cytomegalovirus. PLoS Pathogens PLoS Pathog 4, e1000150. 12

  10. Cancer vaccination remains tantalizingly close but just out of reach; clinical trials still show occasional spectacular successes coupled with more failures. One of the problems is to identify tumor antigens that are suitable targets for common vaccines. Endogenous retroviruses may, perhaps, be such a target. (More on HERVs and immunity here.)

    Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest 118, 1099-1109 13

  11. T cell activationGenome sequencing has been getting faster and cheaper at an amazing pace. We’re now entering an age when viruses can be tracked through epidemics by whole-genome sequencing, following through mutations and viral evolution throughout the epidemic and using the sequence to predict and analyze the stages of the epidemic. (More here.)

    Transmission pathways of foot-and-mouth disease virus in the United Kingdom in 2007. PLoS Pathog. 4, e1000050 14

  12. Meticulous tracking of T cells demonstrated last year that for CD4 T cells it is possible to count the tiny handful of naïve T cells for any one specificity, hidden though they are in the ocean of other T cells. This year Leo LeFrancois appled the same technique to cytotoxic T lymphocytes (CTL) and proposed that the number of naïve T cells is a major determinant of the entire downstream immune response. (Post is here.)

    Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859-869. 15


  1. Abdulla, S., Oberholzer, R., Juma, O., Kubhoja, S., Machera, F., Membi, C., Omari, S., Urassa, A., Mshinda, H., Jumanne, A., Salim, N., Shomari, M., Aebi, T., Schellenberg, D. M., Carter, T., Villafana, T., Demoitie, M. A., Dubois, M. C., Leach, A., Lievens, M., Vekemans, J., Cohen, J., Ballou, W. R., and Tanner, M. (2008). Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. doi:10.1056/NEJMoa0807773[]
  2. Bejon, P., Lusingu, J., Olotu, A., Leach, A., Lievens, M., Vekemans, J., Mshamu, S., Lang, T., Gould, J., Dubois, M. C., Demoitie, M. A., Stallaert, J. F., Vansadia, P., Carter, T., Njuguna, P., Awuondo, K. O., Malabeja, A., Abdul, O., Gesase, S., Mturi, N., Drakeley, C. J., Savarese, B., Villafana, T., Ballou, W. R., Cohen, J., Riley, E. M., Lemnge, M. M., Marsh, K., and von Seidlein, L. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. doi:10.1056/NEJMoa0807381[]
  3. Eisenbarth, S. C., Colegio, O. R., O’Connor, W., Sutterwala, F. S., and Flavell, R. A. (2008). Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122-1126. doi:10.1038/nature06939
    Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome.
    Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, Bergen IM, Castillo R, Lambrecht BN, Tschopp J.
    J Immunol. 2008 Sep 15;181(6):3755-9.[]
  4. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity.
    Franchi L, Núñez G.
    Eur J Immunol. 2008 Aug;38(8):2085-9. []
  5. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3.
    Li H, Willingham SB, Ting JP, Re F.
    J Immunol. 2008 Jul 1;181(1):17-21. []
  6. Guerra, N., Tan, Y. X., Joncker, N. T., Choy, A., Gallardo, F., Xiong, N., Knoblaugh, S., Cado, D., Greenberg, N. R., and Raulet, D. H. (2008). NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. Immunity 28, 571-580. doi:10.1016/j.immuni.2008.02.016[]
  7. Knickelbein, J. E., Khanna, K. M., Yee, M. B., Baty, C. J., Kinchington, P. R., and Hendricks, R. L. (2008). Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268-271. DOI: 10.1126/science.1164164[]
  8. Mark, K. E., Wald, A., Magaret, A. S., Selke, S., Olin, L., Huang, M. L., and Corey, L. (2008). Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J. Infect. Dis. 198, 1141-1149. DOI: 10.1086/591913[]
  9. Wakim, L. M., Jones, C. M., Gebhardt, T., Preston, C. M., and Carbone, F. R. (2008). CD8(+) T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection. Immunol. Cell Biol. 86, 666-675; doi:10.1038/icb.2008.47[]
  10. Loh, L., Petravic, J., Batten, C., Jane, Davenport, M., P., and Kent, S., J. (2008). Vaccination and Timing Influence SIV Immune Escape Viral Dynamics In Vivo. PLoS Pathog 4(1): e12. doi:10.1371/journal.ppat.0040012[]
  11. McSharry, B. P., Burgert, H. G., Owen, D. P., Stanton, R. J., Prod’homme, V., Sester, M., Koebernick, K., Groh, V., Spies, T., Cox, S., Little, A. M., Wang, E. C., Tomasec, P., and Wilkinson, G. W. (2008). Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B. J. Virol. 82, 4585-4594. doi: 10.1128/JVI.02251-07.[]
  12. Powers, C. J., and Fruh, K. (2008). Signal Peptide-Dependent Inhibition of MHC Class I Heavy Chain Translation by Rhesus Cytomegalovirus. PLoS Pathogens PLoS Pathog 4, e1000150. doi:10.1371/journal.ppat.1000150[]
  13. Takahashi, Y., Harashima, N., Kajigaya, S., Yokoyama, H., Cherkasova, E., McCoy, J. P., Hanada, K., Mena, O., Kurlander, R., Abdul, T., Srinivasan, R., Lundqvist, A., Malinzak, E., Geller, N., Lerman, M. I., and Childs, R. W. (2008). Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest 118, 1099-1109. doi:10.1172/JCI34409.[]
  14. Cottam, E. M., Wadsworth, J., Shaw, A. E., Rowlands, R. J., Goatley, L., Maan, S., Maan, N. S., Mertens, P. P., Ebert, K., Li, Y., Ryan, E. D., Juleff, N., Ferris, N. P., Wilesmith, J. W., Haydon, D. T., King, D. P., Paton, D. J., and Knowles, N. J. (2008). Transmission pathways of foot-and-mouth disease virus in the United Kingdom in 2007. PLoS Pathog. 4, e1000050. doi:10.1371/journal.ppat.1000050[]
  15. Obar, J. J., Khanna, K. M., and Lefrancois, L. (2008). Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859-869. doi:10.1016/j.immuni.2008.04.010[]