Infection with the obligate intracellular protozoan Leishmania is thought to be initiated by direct parasitization of macrophages, but the early events following transmission to the skin by vector sand flies have been difficult to examine directly. Using dynamic intravital microscopy and flow cytometry, we observed a rapid and sustained neutrophilic infiltrate at localized sand fly bite sites. Invading neutrophils efficiently captured Leishmania major (L.m.) parasites early after sand fly transmission or needle inoculation, but phagocytosed L.m. remained viable and infected neutrophils efficiently initiated infection. Furthermore, neutrophil depletion reduced, rather than enhanced, the ability of parasites to establish productive infections. Thus, L.m. appears to have evolved to both evade and exploit the innate host response to sand fly bite in order to establish and promote disease.

Biting insects transmit numerous viral, bacterial, and parasitic infections of human and veterinary importance. However, the initial events that occur as pathogens are introduced by these vectors at sites of local feeding (wounds) are poorly understood. On page 970 in this issue, Peters et al. (1) report that early events in vector-mediated injury influence the outcome of infection with the sand–fly–transmitted parasite Leishmania major. Wounds are the points of entry for multiple pathogens, and neutrophils are the first of a wave of inflammatory cells that migrate into these sites. These highly phagocytic cells have been regarded as foot soldiers, armed with toxic oxygen radicals, lytic enzymes, and cationic proteins to destroy the microorganisms they ingest. Indeed, their vital role in efficiently mounting an immune response to pathogens is emphasized by the susceptibility of neutropenic patients to bacterial infections (2). However, in current models, neutrophils are short-lived and undergo programmed cell death (apoptosis). Their corpses, when phagocytosed by macrophages (part of the wound-healing response), have an anti-inflammatory effect. In a twist on this model, van Zandbergen et al. (3) showed that neutrophils internalize L. major and, as these infected cells die, they are engulfed by other immune cells--macrophages. Thus, this allows silent entry of the parasites into their host immune cell of preference.

Professional phagocytes like polymorphonuclear neutrophil granulocytes (PMN) and macrophages (MF) kill pathogens as the first line of defense. These cells possess numerous effector mechanisms to eliminate a threat at first contact. However, several microorganisms still manage to evade phagocytic killing, survive and retain infectivity. Some pathogens have developed strategies to silently infect their preferred host phagocytes. The best example of an immune silencing phagocytosis process is the uptake of apoptotic cells. Immune responses are suppressed by the recognition of phosphatidylserine (PS) on the outer leaflet of their plasma membrane. Taking Leishmania major as a prototypic intracellular pathogen, we showed that these organisms can use the apoptotic "eat me" signal PS to silently enter PMN. PS-positive and apoptotic parasites, in an altruistic way, enable the intracellular survival of the viable parasites. Subsequently these pathogens again use PS exposition, now on infected PMN, to silently invade their definitive host cells, the MF. In this review, we will focus on L. major evasion strategies and discuss other pathogens and their use of the apoptotic "eat me" signal PS to establish infection.