Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

September 23rd, 2010

Monkeypox, smallpox

Confluent Smallpox (Bramwell 1892)
Confluent smallpox1

Vaccination against smallpox ended some 40 years ago. As the vaccinated population gets smaller and the susceptible population gets larger, at least one poxvirus is re-exploring the human population. Not smallpox, of course, but monkeypox, which is becoming dramatically more common in humans than it used to be.2

Monkeypox (which is actually primarily a rodent disease — the monkeys it’s named after were also hapless aberrant hosts, like humans) is closely related to smallpox, and causes a very similar disease in humans — clinically virtually identical, they say (I haven’t seen either myself, and hope I never will), though with a somwhat lower mortality rate. Of course, having a lower mortality rate than smallpox is not exactly high praise: Monkeypox is quite bad enough, with mortality rates of up to 10%.3

Vaccination against smallpox used (and still uses — I just got re-vaccinated a couple weeks ago) live vaccinia virus, which is yet another poxvirus that is similar enough to both smallpox and to monkeypox that it provides excellent protection against infection with either. People who were vaccinated against smallpox are still resistant to infection with monkeypox; but a large and growing population are too young to have received vaccinia, and those people are at least five times more likely to be infected with monkeypox.4 As a result, there’s been a 20-fold increase in monkeypox infections in the Democratic Republic of Congo, and there has been at least one well-publicized case where the disease was shipped into the US in pet rodents.5

Smallpox in california, 1919
Smallpox in California, 1919 (click for larger version)6

A recent paper, looking for animal models of monkeypox that accurately reflect the human situation (so that different vaccines and treatments can be tested) finds that cynomologous macaques [a species of monkey] are susceptible and have similar symptoms as humans:

Animals started to show clinical signs of disease, including decreased appetite and activity, by day 3. … By 6–8 days post-exposure, macules began to form in all animals and macaques were also inactive, somnolent, and exhibited depressed posture. … Lesions progressed to papules by day 10 and evolved to vesicular and pustular stages by 12–14 days post-exposure. … Two non-survivors had too many lesions to count (>2000).3

The lesions they talk about here (macules, papules, vesicles and pustules) are, of course, the titular small pox. Not many people today still remember the pox, so I’ve included some pictures from the good old days.  You’re welcome!

Smallpox vaccination poster
“Hei, siudy, divchata, zhyvo!” (Poster advising vaccination against smallpox, ca. 1920)

  1. Byrom Bramwell
    Atlas of Clinical Medicine v.I, pl.XXIII, p.169
    Edinburgh, Constable, 1892[]
  2. Rimoin, A., Mulembakani, P., Johnston, S., Lloyd Smith, J., Kisalu, N., Kinkela, T., Blumberg, S., Thomassen, H., Pike, B., Fair, J., Wolfe, N., Shongo, R., Graham, B., Formenty, P., Okitolonda, E., Hensley, L., Meyer, H., Wright, L., & Muyembe, J. (2010). Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo Proceedings of the National Academy of Sciences, 107 (37), 16262-16267 DOI: 10.1073/pnas.1005769107
    Pierre Formenty, Mohammed O. Muntasir, Inger Damon, Vipul Chowdhary, Martin L. Opoka, Charlotte Monimart, Elmangory M. Mutasim, Jean-Claude Manuguerra, Whitni B. Davidson, Kevin L. Karem, Jeanne Cabeza, Sharlenna Wang, Mamunur R. Malik, Thierry Durand, Abdalhalim Khalid, Thomas Rioton, Andrea Kuong-Ruay, Alimagboul A. Babiker, Mubarak E.M. Karsani, & Magdi S. Abdalla (2010). Human Monkeypox Outbreak Caused by Novel Virus Belonging to Congo Basin Clade, Sudan, 2005 Emerging Infectious Diseases, 16 (10) : 10.3201/eid1610.100713[]
  3. Nalca, A., Livingston, V., Garza, N., Zumbrun, E., Frick, O., Chapman, J., & Hartings, J. (2010). Experimental Infection of Cynomolgus Macaques (Macaca fascicularis) with Aerosolized Monkeypox Virus PLoS ONE, 5 (9) DOI: 10.1371/journal.pone.0012880[][]
  4. Rimoin, A., Mulembakani, P., Johnston, S., Lloyd Smith, J., Kisalu, N., Kinkela, T., Blumberg, S., Thomassen, H., Pike, B., Fair, J., Wolfe, N., Shongo, R., Graham, B., Formenty, P., Okitolonda, E., Hensley, L., Meyer, H., Wright, L., & Muyembe, J. (2010). Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo Proceedings of the National Academy of Sciences, 107 (37), 16262-16267 DOI: 10.1073/pnas.1005769107[]
  5. Hutson CL, Lee KN, Abel J, Carroll DS, Montgomery JM, Olson VA, Li Y, Davidson W, Hughes C, Dillon M, Spurlock P, Kazmierczak JJ, Austin C, Miser L, Sorhage FE, Howell J, Davis JP, Reynolds MG, Braden Z, Karem KL, Damon IK, & Regnery RL (2007). Monkeypox zoonotic associations: insights from laboratory evaluation of animals associated with the multi-state US outbreak. The American journal of tropical medicine and hygiene, 76 (4), 757-68 PMID: 17426184[]
  6. Public health reports, Volume 36, Part 1, Issues 1-25 (January-June, 1921)
    U.S. Public Health Service
    Government Printing Office[]
September 20th, 2010

MHC on the brain

Needleman et al 2010 Fig 1
Needleman et al, 1 Fig 1: Section of rat vidual cortext stained for MHC class I (green) and nuclei (red)
Needleman et al Fig 1
Needleman et al, 1 Fig 1: Section of rat vidual cortext stained for MHC class I (green) and nuclei (red)

I said the other day that not all MHC class I molecules are involved in immunity, and used HFE as an illustration of one that’s not directly involved in immunity. It’s worth mentioning, though, that even those MHC class I molecules that are involved in immunity, aren’t necessarily always involved in immunity.

That may need a little clarification. “MHC class I” molecules include a wide range of members. The ones most people think about2 are the classical members of the family, reasonably enough called “classical MHC class I“, or perhaps MHC class Ia molecules. These are very clearly immune molecules. They’re receptors for cytotoxic T cells and for natural killer cells, they select cells in the thymus, they do everything you’d expect an immune molecule to do.

There are many other family members, though, that are “non-classical” MHC class I, or MHC class Ib molecules. They’re clearly members of the same family, based on their structure: Many of them look, at first and even second glance, almost exactly like a class Ia molecule (see here for some structures). Some of these have clear immune functions (some CD1 molecules seem to be involved in the immune control of certain bacteria, for example).

But others don’t have any apparent immune function. As I say, HFE is one such molecule. It’s a class Ib molecule that looks very much like a class Ia, but it seem to be strictly involved in regulation of iron metabolism. There are quite a few others, as well.

This isn’t surprising. The ancestors of the first MHC class I molecules were probably some kind of cell-interaction molecules, evolved to interface with other cell-surface molecules. The MHC module retains that capability, and it’s a useful tool to include in your generic molecule-binding toolkit. It’s not surprising that variants of MHC class I bind iron, or pheromone receptors, or antibodies, or what have you; because that capability was part of their initial and underlying function.

Which brings me back to my original comment. Not only do variants of MHC class I have various interface capabilities, so do the classical class I molecules themselves. And there’s at least one context where it seems that classical MHC class I molecules act purely in this ancient cell/cell interaction process, without any hint of an immune function: Classical MHC class I molecules are involved in brain development and, perhaps, function. 3

I’m not going to go into a lot of details on the mechanism or the role. For one thing, I don’t know much about brain development; for another, it’s still pretty mysterious as to what exactly MHC class I molecules are doing. But there they are, in the brain during development, and if you get rid of MHC there are at least some subtle defects in brain development.

What I mainly get out of these papers is that brain researchers get much prettier pictures than do immunologists. Admire the ones here1 while we wait for them to figure out what’s going on.

  1. Needleman, L., Liu, X., El-Sabeawy, F., Jones, E., & McAllister, A. (2010). MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1006087107[][][]
  2. Well, to the extent that most people think about MHC at all, which I realize isn’t all that much[]
  3. Goddard, C., Butts, D., & Shatz, C. (2007). Regulation of CNS synapses by neuronal MHC class I Proceedings of the National Academy of Sciences, 104 (16), 6828-6833 DOI: 10.1073/pnas.0702023104

    Zohar O, Reiter Y, Bennink JR, Lev A, Cavallaro S, Paratore S, Pick CG, Brooker G, & Yewdell JW (2008). Cutting edge: MHC class I-Ly49 interaction regulates neuronal function. Journal of immunology (Baltimore, Md. : 1950), 180 (10), 6447-51 PMID: 18453559

    Goddard CA, Butts DA, & Shatz CJ (2007). Regulation of CNS synapses by neuronal MHC class I. Proceedings of the National Academy of Sciences of the United States of America, 104 (16), 6828-33 PMID: 17420446

    Huh, G. (2000). Functional Requirement for Class I MHC in CNS Development and Plasticity Science, 290 (5499), 2155-2159 DOI: 10.1126/science.290.5499.2155[]

September 7th, 2010

Assassination or accident?

I have as much respect for viruses’ ability to manipulate their host as the next guy, and I’m probably more of a fan of viral immune evasion than that next guy. But I still do think that coincidences do happen.

A paper from John Trowsdale and colleagues1 shows that Kaposi’s Sarcoma Herpesvirus (KSHV) destroys HFE, and they suggest that this is “a molecular mechanism targeted by KSHV to achieve a positive iron balance.” Without dissing their observations (which are perfectly convincing) I’m not entirely convinced by their conclusion. Still, it’s an interesting suggestion, and I’m keen to see some kind of followup to it.

The reason I’m not convinced is that this has the look of a spillover effect to me. We already know that KSHV attacks MHC class I molecules via its K3 and K5 molecules, and that it does so by targeting the cell-surface pool to lysosomes. This is a very familiar pattern; most, if not all, herpesviruses block MHC class I molecules. Although it’s been hard to formally prove “why” herpesviruses do this,2 the general assumption is that this allows the virus to at least partially avoid recognition by T cells, and this lets the virus survive better — perhaps because it builds a larger population very early, or perhaps because it is able to last longer late, or whatever.

At any rate, there’s a fairly simple and logical reason why it would make sense for KSHV to block MHC class I molecules, and as I say they do, in fact, do this. Now, why would they attack HFE? HFE is an iron-binding protein that’s involved in the regulation of iron metabolism. Why would KSHV be interested in iron metabolism?

Quite a few pathogens are actually very concerned about iron metabolism, of course. Bacteria generally need iron for their metabolism,3 and pathogenic bacteria have evolved ways of grabbing iron away from their hosts (while their hosts have evolved way of holding on tighter and tighter to that iron). But in general viruses, as opposed to bacteria, don’t have specific needs for iron. Trowsdale’s group makes the argument — and offers some experimental evidence — that KSHV does in fact want iron. “KSHV presumably down-regulates HFE to affect iron homeostasis,” they say, and “These results indicated an iron requirement for lytic KSHV and with the virus targeting HFE to satisfy this demand.” However, I don’t think they really show this directly; they show that there are changes in iron receptors in the presence of KSHV, but as far as I can see they don’t show that the presence or absence of iron actually affects the virus in any way.

HFE complex HLA-A2 complex
HFE heavy chain (red) complexed with beta-2 microblogulin (blue) HLA-A2 (classical MHC class I) heavy chain (red) complexed with beta-2 microblogulin (blue) and a peptide (green)

So let’s say KSHV doesn’t really care about iron per se. Why is the virus attacking this iron receptor, then? To me, the simpler solution is that it’s just a side effect of the virus attack on MHC class I, because HFE is in fact an MHC class I molecule.4 Not all MHC class I molecules are involved in immunity, and HFE is the classic counterexample, an MHC class I molecule that has a clear non-immune role. 5

Even though HFE has a different role, it has a very similar structure to the classical MHC class I molecules — see the images to the right (click for larger versions), and for more comparisons see my post from a couple of years ago, “MHC Molecules: The Sitcom“.  It doesn’t have the peptide bound in the top groove (green in the HLA-A2 complex here) that classical MHC class I molecules use to provide specific signals to T cells, but it’s very similar. It’s plausible — at least to me — that the virus doesn’t care in the least about iron metabolism, but is just attacking everything on the cell surface that looks like an MHC class I molecule, and HFE is getting caught in the covering fire.

Interestingly, though, this isn’t the first time this has been proposed.  A few years ago a paper from Drakesmith et al proposed pretty much the same model for HIV, via the HIV immune evasion molecule nef.  Nef downregulates a large number of immune-related molecules, and also downregulates HFE. Drakesmith et al, like Trowsdale’s group, argue that this is “deliberate”, and that the modified iron metabolism directly benefits HIV;6 but I don’t know if that’s been followed up (Trowsdale’s paper, surprisingly, doesn’t cite Drakesmith et al).

I’m open to the idea that viruses do “want” to tweak iron metabolism, because that would be pretty cool, but so far I’m leaning to notion that HFE is just an accidental victim of the viral war on immunity.

  1. Rhodes DA, Boyle LH, Boname JM, Lehner PJ, & Trowsdale J (2010). Ubiquitination of lysine-331 by Kaposi’s sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation. Proceedings of the National Academy of Sciences of the United States of America PMID: 20805500[]
  2. I put “why” in quotes because obviously it’s not planned. But it’s easier than saying, “why herpesviruses have evolved this ability” or “what selective advantage this ability confers to the herpesviruses”.[]
  3. I say “generally” because I’m not a bacteriologist, and no doubt there’s some bizarre oddball bug that doesn’t need iron to get along. But I don’t know any of them. As far as I know bacteria all need iron[]
  4. It’s a class Ib molecule, a non-classical MHC class I molecule, but it is MHC class I.[]
  5. It’s worth noting that HFE might — just might — have an immune role, too. There are T cells that recognize HFE. It’s not clear, at least to me, what these T cells do, and whether they have a real function or if it’s just a case –another case? — of accidental spillover.
    Rohrlich PS, Fazilleau N, Ginhoux F, Firat H, Michel F, Cochet M, Laham N, Roth MP, Pascolo S, Nato F, Coppin H, Charneau P, Danos O, Acuto O, Ehrlich R, Kanellopoulos J, & Lemonnier FA (2005). Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proceedings of the National Academy of Sciences of the United States of America, 102 (36), 12855-60 PMID: 16123136[]
  6. Drakesmith H, Chen N, Ledermann H, Screaton G, Townsend A, & Xu XN (2005). HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 102 (31), 11017-22 PMID: 16043695[]
September 2nd, 2010

Immunity under natural selection

HapMap 3, officially announced in today’s issue of Nature,1 is an “integrated data set of common and rare alleles” in human populations, built from “1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations“. 

As well as being a resource for genome-wide studies, there are a number of things that can be done with the data directly. One of those is to help identify regions that are under positive natural selection. The authors found a number of them, including several immune-related genes in the Kenyan population.

A little sadly for me, none of these genes are ones I’m particularly familiar with. The three that are listed are:

  • CD226.  This is an activating NK cell receptor. An allelic variant in CD226 has been linked to a number of autoimmune diseases,2 so it wouldn’t be surprising to learn that it’s under some form of selection.  I didn’t check the actual SNP that was shown to be selected, to see if it’s the same one that’s linked to autoimmunity.

  • ITGAE.  This is an integrin3 that’s apparently involved in lymphocyte trafficking.  Allelic variants in ITGAE have been linked to a number of diseases including sarcoidosis4 and ischemic stroke.5

  • DPP7 is dipeptidyl-peptidase 7.  Although I’ve had a strong interest in peptidases for a while6 because of their influence on MHC class I antigen presentation, DPP7 seems to have an unrelated role, that of preventing apoptosis of resting lymphocytes. I don’t know of any links between DPP7 and disease, but obviously altering lymphocyte survival could impact lots of things. 

I’m sure that any more immune-related genes are under strong selection — we know that MHC genes are very strongly and rapidly selected, for example — but they don’t necessarily send up flags in this sort of analysis. 

  1. The International HapMap 3 Consortium (2010). Integrating common and rare genetic variation in diverse human populations Nature, 47, 52-58 DOI: 10.1038/nature09298[]
  2. Douroudis K, Kingo K, Silm H, Reimann E, Traks T, Vasar E, & Kõks S (2010). The CD226 Gly307Ser gene polymorphism is associated with severity of psoriasis. Journal of dermatological science, 58 (2), 160-1 PMID: 20399620

    Maiti AK, Kim-Howard X, Viswanathan P, Guillén L, Qian X, Rojas-Villarraga A, Sun C, Cañas C, Tobón GJ, Matsuda K, Shen N, Cherñavsky AC, Anaya JM, & Nath SK (2010). Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology (Oxford, England), 49 (7), 1239-44 PMID: 20338887[]

  3. Intergrins are cell-surface molecules often involved in cell-cell interactions[]
  4. Heron M, Grutters JC, Van Moorsel CH, Ruven HJ, Kazemier KM, Claessen AM, & Van den Bosch JM (2009). Effect of variation in ITGAE on risk of sarcoidosis, CD103 expression, and chest radiography. Clinical immunology (Orlando, Fla.), 133 (1), 117-25 PMID: 19604725[]
  5. Luke MM, O’Meara ES, Rowland CM, Shiffman D, Bare LA, Arellano AR, Longstreth WT Jr, Lumley T, Rice K, Tracy RP, Devlin JJ, & Psaty BM (2009). Gene variants associated with ischemic stroke: the cardiovascular health study. Stroke; a journal of cerebral circulation, 40 (2), 363-8 PMID: 19023099[]
  6. Pubmed link to my peptidase papers[]