A couple of months ago, I talked about a paper from the Sigal lab,1 that demonstrated a role for cytotoxic T lymphocytes (CTL) in protecting mice against ectromelia infection very early after infection. A recent paper in Nature Medicine2 makes a remarkably similar observation with malaria.
I’m sure I don’t have to run through the human costs of malaria here, or the enormous benefits that an effective malaria vaccine might bring. In fact, we are on the verge of having a vaccine against malaria, just as we have been on the verge of a vaccine for the past 40 years, because that’s about how long it’s been known that irradiated sporozoites confer strong protection against malaria.3
But I’m not here to be snarky about malaria vaccines, especially since I really don’t know much about the subject. Instead, let’s focus on the similarities between this parasite and the poxvirus ectromelia. Both establish an initial infection in the skin — the parasite, through a mosquito bite; the virus, through superficial cuts and scratches. They both then trickle out slowly from this initial site and seed the liver, where they both replicate extensively. Both then spread through the blood (viremia or parasitemia).
Of course, there are plenty of differences, too. For example, ectromelia is usually fatal during the liver stage, while for Plasmodium the liver is merely a staging spot. Another difference is the route they take to the liver; ectromelia is believed to reach the liver mainly through the lymph, whereas for Plasmodium sporozoites the lymph is apparently a dead end4 and sporozoites infect the liver via the blood.5 (The beautiful image to the right is not, in fact, a late Pollock, but is an image of sporozoite motility in the dermis from Amino et al. )
That second difference leads to a critical difference in interpretation. Sigal’s group observed ectromelia-specific CTL in the draining lymph node very early (3 days after infection). Because ectromelia travels through the lymph to the liver, they conclude that the CTL were probably protecting the mice by killing ectromelia-infected cells in the lymph nodes.
In contrast, Chakravarty et al find malaria-specific CTL in the draining nodes very early (2 days after infection). Because malaria travels through the blood to the liver, the CTL in the lymph nodes presumably aren’t blocking traffic to the liver. Instead, they reached a different conclusion: The draining lymph nodes are the site in which CTL are primed against sporozoite proteins, and the primed CTL then travel to the liver and provide protection there:
We show that a protective anti-sporozoite CD8+ T-cell response, however, originates early in lymphoid tissues linked not to the liver but to the cutaneous infection site. … In fact, we did not find appreciable evidence for CD8+ T-cell priming in the CLN, although the target antigen in this model (circumsporozoite protein) is expressed by sporozoites in early phases of liver infection.
I said (about the ectromelia paper): “One caveat I have is that I’m not convinced that the draining lymph node is the critical spot. At least in this paper, it’s shown that CTL are active there, but not that CTL activity in the node is essential. It’s also possible that the virus spreads through some other route, and that other route is also blocked by CTL.” Luis6 tells me he agrees that’s a possibility and was already working on ways to test it. The malaria paper might strengthen that possibility, but I think the diseases actually are different enough that it’s still not clear how applicable the one is to the other. Both papers, though, give a new appreciation for the power and flexibility of CTL.
- Xu, R. H., Fang, M., Klein-Szanto, A., & Sigal, L. J. (2007). Memory CD8+ T cells are gatekeepers of the lymph node draining the site of viral infection. Proc Natl Acad Sci U S A, 104(26), 10992-10997. [↩]
- CD8(+) T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Chakravarty, S., Cockburn, I. A., Kuk, S., Overstreet, M. G., Sacci, J. B., and Zavala, F. (2007). Nat Med 13, 1035 – 1041. [↩]
- Nussenzweig RS, Vanderberg J, Most H, Orton C. Protective immunity produced by the injection of x-irradiated sporozoites of Plasmodium berghei. Nature. 1967 Oct 14;216(5111):160-2. [↩]
- Yamauchi, L. M., Coppi, A., Snounou, G., & Sinnis, P. (2007). Plasmodium sporozoites trickle out of the injection site. Cell Microbiol, 9(5), 1215-1222. [↩]
- Amino, R., Thiberge, S., Shorte, S., Frischknecht, F., & Menard, R. (2006). Quantitative imaging of Plasmodium sporozoites in the mammalian host. C R Biol, 329(11), 858-862. [↩]
- Rolling his eyes at this statement of the obvious[↩]