Defense mechanisms against influenza virus infection in the respiratory tract mucosa

The respiratory tract mucosa is not only the site of infection for influenza viruses but also the site of defense against virus infection. Viruses are initially detected and destroyed non-specifically by innate immune mechanisms, but if the viruses escape the early defense mechanisms, they are detected and eliminated specifically by adaptive immune mechanisms. The major adaptive immune mechanisms are as follows. (i) Specific secretory-IgA (S-IgA) antibodies (Abs) and CTLs (CD8+ cytotoxic T lymphocytes) are involved in the recovery from influenza following viral infection of naive mice. (ii) Preexisting specific S-IgA and IgG Abs in the immunized animals are involved in viral elimination by forming virus-Ig complexes shortly after re-infection. By their polymeric nature, the S-IgA Abs, which are carried to the mucus by transepithelial transport used for dimeric IgA (dIgA) Abs, provide not only protection against homologous virus infection but also cross-protection against drift virus infection. The IgG Abs, which transude from the serum to the mucus by diffusion, provide protection against homologous virus infection. They are largely distributed on the alveolar epithelia to prevent influenza pneumonia. (iii) In the absence of Abs in the pre-immunized animals, the production of specific IgA and IgG Abs by B memory cells is accelerated after re-infection, and these antibodies play a role in viral elimination from day 3 onwards after re-infection. (iv) In epithelial cells of infected animals, specific dIgA Abs being trafficked through the epithelial cells may be involved in the prevention of viral assembly by binding to newly synthesized viral proteins. (v) In the pre-immunized animals, CTL production by memory T cells is also accelerated and these cells appear to participate in the killing of the host cells infected with different subtype viruses (within the same type) from day 3 onwards after re-infection. (vi) Similarly, memory Th1 cells that mediate an accelerated delayed-type hypersensitivity response are involved in blockade of virus replication by secreting IFN-gamma in mice challenged with different subtype viruses. These defense mechanisms suggest that the development of a mucosal vaccine, capable of inducing S-IgA Abs, which provide cross-protection against variant viruses within the same subtype, serum IgG Abs to prevent lethal influenza pneumonia and CTLs, which provide broad cross-protection against different subtype viruses, is strategically important to control influenza.