Inflammatory Responses to Migrating Brugia pahangi Third-Stage Larvae

Abstract

Despite being central to parasite establishment and subsequent host pathological and immunologic responses, host-parasite interactions during early third-stage filarial larva (L3) migration are poorly understood. These studies aimed to define early tissue migration of Brugia pahangi L3 in the gerbil (Meriones unguiculatus) and measure host cellular responses during this period. Gerbils were intradermally inoculated in the hind limb with 100 B. pahangi L3, and necropsies were performed at various times. At 3 h, most L3 (96.3%) were recovered from tissues associated with the infection site, with marked L3 migration occurring by 24 h. Larvae were dispersed throughout the lymphatics at 7 days postinfection (dpi), and at 28 dpi, most parasites were recovered from the spermatic cord lymphatics. Parasites were identified histologically at all time points. Inflammatory cells, primarily neutrophils, were frequently observed around larvae in the dermis and muscle near the injection site at 3 h and 24 h. Levels of interleukin-6 (IL-6) and tumor necrosis factor-␣ mRNA peaked at 3 h in all tissues, with IL-6 levels also high in the spleen at 28 dpi. Levels of IL-4 mRNA were elevated in all tissues at 28 dpi. These observations demonstrate that L3 migrate quickly through various tissues and into lymph nodes in a predictable pattern. Migrating L3 induce an early acute inflammatory response that is modulated as parasites establish in the lymphatics. Polarization of the host response towards a dominant Th2-like profile is present at 7 dpi and is well established by 28 dpi in this permissive host.It is generally accepted that third-stage filarial nematode infective larvae (L3) emerge from the mosquito labia during feeding, accumulate in a pool of hemolymph, and enter the host through the wound left by the mosquito vector (13). While the L3 are apparently unable to penetrate intact skin, their early migrations require movements through the connective tissues of the skin to lymphatic vessels and, in some cases, the blood vascular system. These events have been demonstrated experimentally by feeding Brugia-infected mosquitoes on cats (14, 17) and gerbils (3) and by in vivo studies involving the application of L3 to punctured skin (14). Furthermore, previous studies by Ah et al. (1) have clearly shown that L3 can actively and rapidly migrate through a variety of complex tissues following placement on the surface of the gerbil eyeball. The mechanisms utilized by the larvae during this early migratory phase through these various tissues have not been defined.Early migrations of L3 through the tissues of the skin not only are central to the successful establishment of parasites but are also likely to be important in the initial induction of the host response. It is expected that these responses are involved in the elimination or inhibition of incoming L3 during early migrations. The migration of L3 into the skin may also be uniquely involved in defining the nature of subsequent immune responses to parasite antigens. Based on various in ...

Quiescent Innate Response to Infective Filariae by Human Langerhans Cells Suggests a Strategy of Immune Evasion

“…LC typically produce cytokines when activated. That the L3 failed to induce cytokine secretion (except IL-6) finds support in previous studies of B. malayi infection in jirds, where a transient neutrophil infiltrate was found surrounding the L3 in the dermis, a process that was preceded by increases in IL-6 and TNF-␣ mRNAs (21). IL-10 is another cytokine thought to be involved in suppression of the immune response to filarial parasites (22); however, whether IL-10 is produced in the skin following filarial infection is still being defined.…”

Brugia pahangi: Immunization with early L3 ES alters parasite migration, and reduces microfilaremia and lymphatic lesion formation in gerbils (Meriones unguiculatus)

“…Earlier studies by Ah and his coworkers (1973) demonstrated that vector derived Brugia pahangi L3 are capable of extensive rapid migration through a variety of tissue types. In order to quantitatively study this early migration, an in vivo intradermal inoculation model has been established using B. pahangi infections in gerbils (Chirgwin et al, 2006; Porthouse et al, 2006). In this model, L3s are required to move through the connective tissues of the skin prior to establishment in the lymphatics mimicking the natural early L3 migration pattern more closely than infections induced by either subcutaneous and intraperitoneal (IP) inoculations.…”

Attempts to Image the Early Inflammatory Response during Infection with the Lymphatic Filarial Nematode Brugia pahangi in a Mouse Model

“…Studies in the only fully permissive rodent host of Brugia species, the Mongolian jird, demonstrated that L3 rapidly migrated from the site of injection in the hind limb to the lymphatic system, with the majority of developing adults establishing in the lymphatics of the spermatic cord [27,28]. In the present study, we observed sections through filarial worms in the local lymphatic vessels of the infected limb at the latest time point examined (21 days p.i.)…”