Jpn. J. Infect. Dis., 57, 236-247, 2004
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Review
Defense Mechanisms against Influenza Virus Infection in the Respiratory Tract Mucosa
Shin-ichi Tamura* and Takeshi Kurata1
Laboratory of Prevention of Viral Diseases (Research Foundation for Microbial Diseases of Osaka University), Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871 and 1Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
(Received June 16, 2004. Accepted September 17, 2004)
*Corresponding author: Mailing address: Laboratory of Prevention of Viral Diseases (Research Foundation for Microbial Diseases of Osaka University), Research Institute for Microbial Diseases, Osaka University, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan. Tel: +81-6-6879-4251, Fax: +81-6-6879-4250, E-mail: stamura@biken.osaka-u.ac.jp
CONTENTS:
1. Introduction
2. Innate immunity against influenza
2-1. Effectors
2-2. Enhancement of innate immunity
3. Adaptive immunity against influenza
3-1. Roles of antigen-presenting cells
3-2. Roles of T and B cells
4. Mucosal immune system in the respiratory tract
4-1. Common mucosal immune system
4-2. Nasopharyngeal-associated lymphoid tissue
4-3. Secretion of S-IgA Abs
5. Recovery from influenza following primary viral infection by
adaptive immune responses
5-1. Primary Ab responses
5-2. T cell-mediated immune responses
5-3. Involvement of both Abs and CTLs in the recovery from influenza
6. Prevention of influenza following secondary viral infection
by adaptive immune responses
6-1. Preexisting Abs
6-2. Secondary Ab responses
6-3. Secondary T cell-mediated immune responses
7. Basis for the development of an effective mucosal influenza
vaccine and perspectives
Summary: 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-g 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.