The attachment of Schistosoma mansoni cercariae to mammalian skin is specifically stimulated by L-arginine. As L-arginine is an unsuitable signal for a specific identification of mammalian skin we examined the following 5 hypotheses to explain the advantage of the cercarial sensitivity to L-arginine. (1) A Schistosoma infection lowered the arginine concentration in the serum of mice, and this could enable the cercariae to avoid attachments to already infected mice. However, the infection did not reduce the arginine concentration in the skin and the cercarial attachment responses to it. (2) Creeping cercariae showed chemotactic orientation specifically along increasing L-arginine gradients. L-arginine could act as a pheromone which could guide cercariae towards common penetration sites. However, the cercarial acetabular gland contents were not attractive and they did not (in contrast to previous reports) contain much arginine. (3) Schistosomula (transformed cercariae) could use L-arginine to produce nitric oxide (NO) for blood vessel dilation during their migration in the host. However, in vitro the transformed cercariae did not convert L-arginine into citrulline and NO. (4) Schistosomula could bind L-arginine from the surrounding tissues and so escape the cellular immune attack (which needs L-arginine as the precursor of NO). However, transformed cercariae bound no more L-arginine than L-serine and L-lysine. (5) Schistosomula, migrating parallel to the surface in the mammalian epidermis, are dependent on information on their position between the inner and the surface layers of the skin. In the mouse skin, they adjusted their body axis with the ventral side toward the deeper (arginine-residue rich) epidermis layers. When migrating in agar, they showed chemo-orientation toward serum, and D-glucose and L-arginine were the stimulating compounds therein. The burrowing schistosomula adjusted their body axis (as in the epidermis) with the ventral side toward the higher concentration of L-arginine and not of glucose. We argue that the sensitivity for L-arginine has its primary function in orientation within mammalian skin and in location of blood vessels.

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Cercariae of Diplostomum spathaceum penetrate the skin of fish, and then migrate along blood vessels and tissues towards the head and the eye-lens. We studied their orientation behaviour in tail fins of guppies and in chemical concentration gradients within agar-filled choice chambers. In fins, they entered veins and orientated cranially, independent of the blood flow and living cells. In choice chambers, they were attracted by a small molecular fraction of fish serum, D-glucose (at 1, 10, and 1000 mM), D-mannose, D-maltotriose and Cl-ions, whereas D-glucosamine repelled them (even at 1 . 0 nM). Amino acids were not attractive, but arginine in tetrapeptides attracted at concentrations as low as 1 mM and melatonin at 0 . 4-4 . 3 pM. We suggest a preliminary model for the behaviour of diplostomula in fish fins and attracting (+) or repelling (x) host cues: (1) migration towards deeper skin layers and avoidance of skin surface, cues: Cl-ions (+ and x), glucose (+), glucosamine (x), light radiation (x); (2) orientation in cranial direction, cue: Cl-ions (+) ; (3) localization of blood vessels, cues : glucose (+), arginine-residues (+); (4) localization of the retina, cue: melatonin (+). A comparison with the navigation mechanisms of tissue-migrating schistosomules and hookworm larvae reveals an enormous diversity of strategies.

The survival of skin penetrating cercariae depends on information on the direction to move toward deeper layers in the epidermis (the direction of further migration) and toward the surface (direction which must be avoided when migrating). We tested the hypothesis that parasites can use their photo-sensitivity for orientation away from the light-exposed skin surface towards darker locations. Cercariae of species invading humans ( Schistosoma mansoni), birds ( Trichobilharzia ocellata) and fish ( Diplostomum spathaceum) oriented towards light sources when free swimming in cuvettes. However, they shifted to a negative photo-orientation when migrating in agar substrates after penetration and transformation to schistosomula. This is a first hint that parasites may use photo-orientation when they navigate in host tissues.