Tipping the balance in favor of protective immunity during influenza virus infection.

C alibrating immune responses to levels that control infection while minimizing damage to host tissues is the primary challenge facing the immune system. Disease manifestations associated with most infections result from host inflammatory responses that, in some cases, are of sufficient magnitude to result in death. Influenza virus infections occasionally fall into this category. The outcome of human influenza virus infection is heavily influenced by the virulence of the viral strain and the host’s immune status. In this issue of PNAS, Aldridge et al. (1) investigate inflammatory responses induced by influenza virus and discover that recruitment of TNF and inducible NOS (iNOS)-producing dendritic cells (TipDCs) correlates with viral strain virulence. Recruitment of TipDCs is substantially greater in mice infected with highly pathogenic influenza virus, and recruitment depends on chemotactic cytokine receptor 2 (CCR2), a chemokine receptor that responds to monocyte chemotactic protein (MCP)-1, MCP-3, and MCP-5. Aldridge et al. demonstrate that CCR2-mediated recruitment of TipDCs enhances viral clearance at later stages of infection by enhancing virus-specific T cell responses. CCR2-mediated recruitment of inf lammatory monocytes is essential for defense against a range of microbial pathogens (2). Early studies demonstrated that CCR2-deficient mice are extremely susceptible to infection with the intracellular bacterial pathogen Listeria monocytogenes (3), and subsequent studies have also implicated CCR2mediated recruitment of inflammatory cells in defense against Cryptococcus neoformans (4), Toxoplasma gondii (5), and Mycobacterium tuberculosis (Mtb) (6), which, like influenza virus, is principally, but not exclusively, a respiratory tract pathogen. CCR2-deficient mice are more susceptible to Mtb infection (6) and have diminished T cell responses in lungdraining lymph nodes. These results suggested that CCR2-recruited monocytes might promote T cell priming. This notion is supported by a subsequent study (7), which used bone marrow chimeras to show that monocyte recruitment to the lungs of tuberculosis-infected mice requires their expression of CCR2 but that T cells traffic to the lung regardless of whether they express CCR2. The role of CCR2-mediated monocyte recruitment during Mtb infection varies, however, depending on the size of the initial inoculum used to infect mice. CCR2deficient mice infected with a low inoculum of aerosolized Mtb survive normally and control infection (8), whereas infection with a high inoculum of Mtb is poorly controlled in CCR2-deficient mice. Although the magnitude of initial Mtb infection determines whether CCR2-mediated monocyte recruitment contributes to protection, after inf luenza virus infection the benefits of CCR2-mediated monocyte recruitment may depend on the virulence of the viral strain. Much has been learned about inf luenza virus virulence and virally-induced inf lammatory responses from studies of the recently reconstructed highly-virulent inf luenza virus strain that caused the calamitous 1918 inf luenza epidemic. This viral strain, in mouse models, grows more rapidly and induces much greater neutrophil and macrophage recruitment than less virulent viruses (9). An analysis of the inf lammatory response induced in infected mice by the 1918 inf luenza virus after pulmonary inoculation demonstrated, compared with other inf luenza viruses, the most rapid and dramatic induction of inf lammatory cytokines and activation of inf lammatory cascades (10). Additional studies also showed that the 1918 inf luenza virus induces markedly greater recruitment of macrophages to lungs of infected mice (11). CCR2-mediated recruitment of monocytes during influenza virus infection contributes to early innate immune responses and adaptive T cell responses.