Regional Immune Responses in the Lung After Respiratory Virus Infections

Acute respiratory virus infections are the leading communicable cause of illness and death in the world. Upon infection, numerous types of immune cells are involved in the eradication of invading viral pathogens from the lung and ultimately establishing immunological memory at the site of infection. Although these responses are generally beneficial, they are also associated with some degree of pathogenesis. Understanding the genesis and balance of pulmonary immune responses is essential for the rational design of effective vaccines that confer protective immunity. This special issue, “Viral Immunology of the Lung,” presents seven review articles that discuss various aspects of pulmonary virus infections, including virology, pathology, innate and adoptive immune responses, vaccines, and adjuvants.

The first review by Daidoji et al. describes the impact of diverse hemagglutinin (HA) proteins of influenza viruses on host responsiveness, and viral transmissibility and virulence. Although activation of HA protein depends on low pH in the endosomal compartment, a fusion threshold of pH, referred to as the pH threshold, differs between strains and even subtypes. HA proteins with higher pH threshold are associated with strong infectivity and the capacity of the virus to adapt to a broad spectrum of cells/animals. Such propensity explains, in part, the virulence of highly pathogenic avian influenza virus, such as the H5 and H7 strains. Pulmonary diseases can also be induced by systemic viral infection.

Upon respiratory virus infections, sensor cell populations in the lung, such as epithelial cells, macrophages and dendritic cells, sense microbial patterns through pattern recognition receptors, and initiate innate immune responses. Okamoto et al. review signaling pathways downstream of RIG-I-like receptors and toll-like receptors after RNA virus infections. The authors also discuss the distinct contributions of particular innate signaling and resulting secretion of cytokines in the protection and pathogenesis of an influenza virus infection. In this regard, inhibition of excessive expression of proinflammatory cytokines, but not type-I interferons, would be ideal to reduce the undesirable pathogenesis without loss of protection.

The distinct cytokine environments induced by some viral infections significantly impact the differentiation of CD4⁺ helper T (T_H) cell subsets. Miyauchi outlines the generation of each T_H cell subset after respiratory virus infections, and their protective and pathological characteristics. The author also describes the emerging roles of follicular helper T (T_FH) cells and type 1 T_H (T_H1) cells in the neutralizing antibody responses to influenza viruses.

Pulmonary infections also lead to the ectopic formation of inducible bronchus-associated lymphoid tissue (iBALT), wherein local T_H–B cell interactions occur. Takahashi and colleagues describe the unique features of anti-influenza B cell responses in the iBALT. Exposure to higher amount of antigens in the germinal center (GC) of the iBALT results in the generation of virus-specific B cells with enhanced affinity and cross-reactivity among strains. Furthermore, memory B cells established in the lung GCs acquire tissue residency, respond directly to the virus independently with T_H cells, and play a key role in the protection after secondary virus infections. CD8⁺ tissue-resident memory T (T_RM) cells in the lung are also essential for the protective immunity early after reinfection. Takamura provides a comprehensive review regarding how CD8⁺ T_RM cells are generated and maintained in the lung after respiratory virus infections. In particular, unique features of newly defined anatomical niches for CD8⁺ T_RM cells in the lung are discussed.

Intranasal administration of antigen is necessary not only for establishing local immune memory but also for inducing local secretary IgA (s-IgA) antibodies, a key determinant of the protective immunity at the site of infection. Ainai et al. focus on mucosal s-IgA responses induced by anti-influenza vaccines and describe in detail the effectiveness and limitations of currently available influenza vaccines, including live attenuate vaccines, FluMist and Fluenz. The authors discuss the advantages of intranasal administration of whole inactivated vaccines that include intrinsic adjuvant constituents (e.g., viral RNAs) on induction of local s-IgA responses. Finally, Aoshi outlines requirements for the induction of adjuvant activity at the mucosal surfaces. Representative intranasal mucosal adjuvants and their mode of action are also introduced.

I would like to thank all the authors for their valuable contributions to the special issue of Viral Immunology.