Jerome P Vanderberg, PhD, Professor

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We study the biology and invasiveness of the sporozoite, malaria's infectious agent. Mosquitoes introduce sporozoites into a host by injecting them into nonvascular skin tissue as the mosquitoes secrete saliva while probing for a blood source. To infect the host, these sporozoites must then reach a blood vessel, from where they can travel to the liver. We are interested in how sporozoites are deposited in the dermis of the skin by the mosquito, and then move through the tissue to recognize and invade a blood vessel. We have shown that vaccination of animals against sporozoites leads to formation of antibodies that inhibit sporozoite motility and block the invasion of blood vessels by sporozoites. So, we assess the role of immunity to malaria in blocking sporozoite invasion of the blood. The mosquito’s saliva is necessary for it to take a blood meal. Therefore, we also investigate whether host immunity to mosquito saliva (during formation of the classic mosquito bite reaction) affects the mosquito’s ability to take a blood meal or the sporozoite’s ability to migrate through the bite region to a blood vessel. Much of what we do involves intravital microscopical observations of mosquito feeding on an anesthetized mouse (as in Vanderberg and Frevert, 2004).

Fig 1. A mosquito probes with its proboscis (orange) through dermis of mouse skin and deposits malaria sporozoites that express Green Fluorescent Protein (green). Movie file

Fig 2. After deposition in skin, sporozoites continue to move within dermis. Movie File

Fig 3. Details of probing by mosquito proboscis (associated with induction of hematoma by proboscis), and accompanied by sporozoite release, after which sporozoites continue to migrate within dermis. Movie file (large file: may take some time to load)

Fig 4. Invasion of a dermal blood vessel by a sporozoite. Note sporozoite moving into bottom of drawn circle and then moving rapidly into the upward flow of the blood. Movie file

Fig 5. Trails left behind sporozoites (spz) as they move through an in vito substratum. Sporozoites must search for a blood vessel as they migrate through the skin (as in Stewart & Vanderberg 1988, 1992).

Fig 6. In vitro video showing sporozoites exhibiting gliding motility. Anti-sporozoite antibodies flow in from left side of field rapidly immobilizing sporozoite and then forming circumsporozoite precipitation reaction at trailing end of sporozoite. The question that was asked was whether this antibody-mediated immobilization occurs in vivo after deposition of sporozoites by mosquitoes. This was approached by intravital microscopy, as in the next two Figures. Movie file

Fig 7. Proboscis introduces sporozoites into dermis of mouse previously immunized against sporozoites with irradiated sporozoites. Immunization was as with the first successful immunization of humans by Vanderberg and associates at NYU (Clyde et al. 1973). Sporozoites continue moving actively for 1-2 minutes after injection into skin. Movie file

Fig 8. Approximately 2-3 minutes after their injection into skin, sporozoites stop moving within immunized mouse. No sporozoites were seen to invade blood vessels in these immunized mice. Similar results were obtained in mice that had been passively immunized by intravenous injection of monoclonal antibodies against sporozoites. This immobilization of sporozoites within the skin appears to be the first manifestation of protective immunity in sporozoite-induced immunity. Movie file

Fig 9. Confocal microscopy of sporozoites (green) injected into skin by mosquitoes. Confocal stack of dermis is 36 µm in thickness . (as in Vanderberg and Frevert, 2004). Left image shows stack with autofluorescent background to show skin architecture. The presence of parasite intradermal vesicles remaining within skin after sporozoite introduction by mosquitoes implies that these vesicles may be taken up by dermal dendritic cells and become involved in the induction of an immune response against sporozoites.

Fig 10. Mosquito feeding on a hematoma formed by lacerated cutaneous blood vessel. Mouse had undergone immediate cutaneous hypersensitization prior to mosquito bite. Note flow of edematous fluid along left side of field after withdrawal of proboscis. The effects of the “mosquito bite reaction” on delivery and migration of sporozoites is being studied. Movie file

Selected Publications

1. Kebaier, C. and J. P. Vanderberg. Re-ingestion of Plasmodium berghei sporozoites after delivery into the host by mosquitoes.  Am. J. Trop. Med. Hyg. 2006 Dec:75(6);1200-1204
2. Vanderberg JP, Frevert U. Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes. Int J Parasitol. 2004 Aug;34(9):991-6.
3. Mota MM; Pradel G; Vanderberg JP; Hafalla JC; Frevert U; Nussenzweig RS; Nussenzweig V; Rodriguez A.Migration of Plasmodium sporozoites through cells before infection. Science.2001;291:141 (#J17776)
4. Sidjanski SP; Vanderberg JP; Sinnis P. Anopheles stephensi salivary glands bear receptors for region I of the circumsporozoite protein of Plasmodium falciparum. Molecular & Biochemical Parasitology.1997;90:33 (#J03169)
5. Sidjanski S; Vanderberg JP. Delayed migration of Plasmodium sporozoites from the mosquito bite site to the blood. American journal of tropical medicine & hygiene. 1997;57:426 (#J09817)
6. Mathews GV; Sidjanski S; Vanderberg JP. Inhibition of mosquito salivary gland apyrase activity by antibodies produced in mice immunized by bites of Anopheles stephensi mosquitoes. American journal of tropical medicine & hygiene.1996;55:417 (#J04494)
7. Stewart MJ; Vanderberg JP. Electron microscopic analysis of circumsporozoite protein trail formation by gliding malaria sporozoites. Journal of protozoology. 1992;39:663 (#J11690)
8. Clyde, D., H. Most, V. McCarthy and J. P. Vanderberg. Immunization of man against sporozoite-induced falciparum malaria. Am. J. Med. Sci. 1973;266:169-177. (#J32670)