INFLUENZA VIRUS AND IMMUNIZATION
Influenza A virus causes respiratory tract infections, which are occasionally complicated by secondary bacterial infections. Influenza A virus replicates in epithelial cells and leukocytes resulting in the production of chemokines and cytokines, which favor the extravasation of blood mononuclear cells and the development of antiviral and Th1-type immune response. Influenza A virus-infected respiratory epithelial cells produce limited amounts of chemokines (RANTES, MCP-1, IL-8) and IFN-α/β, whereas monocytes/macrophages readily produce chemokines such as RANTES, MIP-1α, MCP-1, MCP-3, IP-10 and cytokines TNF-α, IL-1β, IL-6, IL-18 and IFN-α/β. The role of influenza A virus-induced inflammatory response in relation to otitis media is being discussed.
Significant progress has been made in understanding the process of influenza A virus replication in cell culture; however, much less is known about the genetic control of virus-host interactions in disease. This review provides an overview of the genetic analysis of influenza virus biology. The functional map of the individual genes of influenza A virus is presented as well as the status of our current understanding of pathogenesis. Influenza has a segmented genome so it is possible to obtain reassortants that contain novel combinations of genome segments derived from different viruses. This is a very useful genetic tool and is also an important aspect of influenza evolution and biology. Human influenza viruses originate from avian strains of influenza virus so that influenza infection is at its basis a zoonosis. Influenza virus strains are host-restricted, however, and avian strains must be adapted to the human host. So questions of host-range and interaction with host factors are important determinants of the ability of influenza virus to cause disease in humans. Host-range is restricted primarily due to host-specific interactions of the ribonucleo capsid and the viral receptor. There are two classes of drugs for inhibiting influenza infection, amantadine HCl and neuraminidase inhibitors. The mode of action and basis for resistance to these drugs are presented. Prospective targets for antiviral therapy are also discussed. For the induction of mucosal immune responses by intranasal vaccination, cholera toxin B subunits (CTB) and Escherichia coli heat-labile toxin (LT) are often administered as mucosal adjuvants in order to enhance immune responses to mucosally co-administered bystander antigens. However, these toxin also are the causative agents of diarrhea. There is a demand for the establishment of an effective and safer adjuvant or vaccine that elicits mucosal immunity, but does not require the use of CTB or LT adjuvants. In order to induce protective mucosal immune responses in the nasal area against influenza virus infection, we have examined the recombinant protein composed of the complement component, C3d, which is fused to the secreted form of hemagglutinin (sHA-mC3d3) in the influenza-BALB/c mouse model. The fusion protein sHA-mC3d3, the secretory form of hemagglutinin, and the transmembrane form of HA (tmHA) from the influenza virus were intranasally administered to the mice with or without CTB containing a trace amount of holotoxin (CTB*) as an adjuvant. After intranasal administration of these proteins with CTB*, all mice produced nasal IgA and serum IgG antibodies (Abs) against the viral HA. In addition, viral infection was completely inhibited in these mice. In contrast, in the absence of the adjuvant, only sHA-mC3d3-induced locally secreted IgA and serum IgG Abs and provided complete protection against the influenza virus challenge. Thus, C3d fused to the influenza HA antigen is an effective and safe tool for mucosal vaccination.