Effect of Gamma Radiation on Brugia L3 Development In vivo and the Kinetics of Granulomatous Inflammation Induced by These Parasites

Abstract

Previous studies have shown that the downregulation of parasite-specific cellular immune response in Brugia-infected jirds requires viable worms but is not dependent on microfilariae (MF) for either induction or maintenance of this phenomenon. To clarify further which life cycle stages induce filarial hyporesponsiveness, jirds were infected intraperitoneally with third stage larvae (L3) exposed to 0, 15, 25, 35, 45, or 90 krad of gamma radiation to differentially alter L3 development. Necropsies were performed at 7, 14, 28, and 118 days postinoculation (DPI). The degree of parasite development, intraperitoneal inflammation, and pulmonary granulomatous inflammation (PGRN) to parasite antigen-coated beads embolized in the lungs were monitored at the time of necropsy. Parasite survival and worm lengths were inversely related to the irradiation dose. Gamma radiation at 35, 45, or 90 krad prevented larval molt to the adult stage. Some parasites irradiated with 15 or 25 krad developed beyond fourth stage larvae (L4) to infertile adult females. The PGRN peaked at 14 DPI in all infected groups. Downregulation of the PGRN occurred after 14 DPI in groups that received nonirradiated L3 or L3 irradiated with 15 krad. No significant decrease of the PGRN occurred in groups that received parasites irradiated with more than 15 krad. Significant peritoneal inflammation as indicated by an increase in macrophages occurred only in jirds that received nonirradiated L3. These data demonstrate the importance of the adult stages in inducing downmodulation in the absence of MF and suggest that the L4 may also play a role in the induction of this phenomenon. An alternate conclusion is that parasite burden and not developmental stage is important in the induction of this hyporesponsive state.

Poorer NF‐κB signaling by microfilariae in macrophages from BALB/c mice affects their ability to produce cytotoxic levels of nitric oxide to kill microfilariae

“…Presence of granuloma covering the surface of filariae supports the importance of macrophages in anti-filarial immunity [46,47]. We show here that the NF-jB/AP-1 signal in macrophages in response to mf stimulation varies between C57Bl/6 and BALB/c mice and the NF-jB signal is critical for the NOmediated microfilaricidal activity of C57Bl/6 macrophages.…”

Effects of gamma radiation on Brugia malayi infective larvae and their intracellular Wolbachia bacteria

“…If this is true, our finding that radiation cleared Wolbachia in L3 may explain the observation that irradiated larvae induce less inflammation in jirds after i.p injection than normal larvae (Nasarre et al 1997). The present study showed that jirds infected with normal B. malayi L3 did not develop antibodies to Wolbachia wsp until the onset of microfilarial patency.…”

“…The mechanisms responsible for this immunity are poorly understood (Devaney and Osborne 1990). Irradiated L3 are developmentally stunted (reduced growth and molting), and they do not induce normal inflammatory responses in host tissues (as measured by recruitment of macrophages) (Nasarre et al 1997).…”

Down Regulation of Macrophage Activation inBrugia pahangi-Infected Jirds (Meriones unguiculatus)

“…The macrophage is a major cellular component of the granuloma and is often present covering the surfaces of filariae (23,42,44) and other nematodes (24). The role of the macrophage in the immune response to metazoan parasites has been thoroughly investigated in murine schistosomiasis, in which it has been shown that macrophage activation is important in resistance (4,20,21,37).…”