No abstract

Nontypeable Haemophilus influenzae (NTHi) is considered a major pathogen underlying middle ear infection. This study characterized the role of Toll-like receptor 4 in the innate immune responses to acute otitis media induced by NTHi in mice. We used C3H/HeJ mice, which have nonfunctional Toll-like receptor 4, and normal wild-type C3H/HeN mice. NTHi were injected into the tympanic bulla, and middle ear effusions and tissues were collected. In C3H/HeN mice, the severity of acute otitis media decreased promptly with a significant reduction in bacterial recovery from middle ear effusions 48 h after injection. In contrast, all C3H/HeJ mice had otitis media at all time points examined, and increasing bacterial counts from middle ear effusions were detected in C3H/HeJ mice 72 h after injection. Expression of intracellular adhesion molecule-1 by the middle ear mucosa paralleled the number of polymorphonuclear cells in the middle ear in both strains. The findings of transmission electron microscopy revealed that phagocytosis and phagosome maturation of polymorphonuclear cells was impaired in C3H/HeJ mice. Our findings indicate that Toll-like receptor 4 plays a part in the early accumulation and functional promotion of polymorphonuclear cells in the middle ear for eradicating NTHi infection.

Parasite molecules offer unique advantages for the treatment of immunologicical disorders, and several candidate molecules have been shown to be effective. In our studies, it was shown that a factor inducing immunoglobulin E from filarial nematode parasites was suppressive in animal models of immunological disorders such as allergy and insulin dependent diabetes mellitus (IDDM). The Th1/Th2 paradigm of CD4+ T helper cell subsets can provide the basis for the development of new types of drugs and of novel strategies for the treatment of allergic and autoimmune disorders by parasite molecules. In our experimental system, parasite molecules from a filarial nematode parasite led to the down-regulation of the allergic reaction in animal models. In the majority of hosts, infection with helminths is associated with markedly reduced cellular immune reactions and polarization of T cell responses to Th2 and Th3 types. Some studies have suggested that the stimulation of host immunoregulatory networks with parasite molecules leading to the synthesis of anti-inflammatory cytokines (interleukin10, transforming growth factor-beta (TGF-beta and others) can provide new therapy for immunological disorders. It is known that parasites produce some types of molecule that mimic host molecules such as CD40 ligand, TGF-beta and macrophage migration inhibitory factor. These molecules are also candidates for medicinal agents. This review describes many of the latest possibilities in this field and shows how they can be best put to use for the development of medicinal agents, molecular target identification, and for prioritization.

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Calponin, a calmodulin-binding protein of smooth muscle that inhibits the actin-myosin interaction by binding to actin, was shown to bind to myosin and to stimulate the ATPase activity of myosin to some extent. Actin abolished this myosin-linked, stimulatory effect of calponin. Ca(2+)-calmodulin affected neither the myosin-binding activity nor the stimulatory effect of calponin. We further presented a few data which suggest that calponin may exert regulatory activity toward myosin in quite a different way from caldesmon, another smooth muscle protein that binds to myosin, actin, and calmodulin.