Alveolar macrophages take the lead in fighting influenza virus

Influenza viruses cause acute respiratory infections and affect 5-15% of the world’s population each year, making it one of the most pressing public health concerns. The breadth of protection offered by current seasonal influenza vaccines is very limited due to the antigenic changes in circulating influenza viruses. Therefore, developing more broadly protective, or “universal” influenza vaccines that also provides long-term immunity against divergent influenza virus strains is of high importance in mitigating disease brought on by seasonal epidemics and the occasional pandemics.

Like Comment

The paper in Nature Communications is here:

Written by Wenqian He and Gene Tan.

Antibodies targeting the conserved epitopes of influenza viruses have been discovered and shown to provide broad protection. Recent studies indicate that these broadly-neutralizing antibodies (bnAbs) require Fc-Fc gamma receptor (FcgR) interactions for optimal protection in vivo1. However, the innate effector cell population(s) responsible for mediating this protection remain largely unknown.  

Towards better understanding which innate immune cells are involved in antibody-dependent cell-mediated protection, we identified several murine non-neutralizing antibodies (nonNAbs) that are protective against divergent influenza virus challenges. We hypothesized that protective nonNAbs that do not have measurable in vitro neutralization activity would solely rely on FcgR interactions for protection in vivo. In combination with a series of depletion experiments in the mouse model, we thought this would provide a clearer picture of the identity of innate immune cells involved in antibody-dependent cell-mediated responses.

We focused our attention on three cell populations: alveolar macrophages, natural killer cells and neutrophils. In mice, alveolar macrophages and neutrophils express the full complement of FcgRs, which includes three activating receptors and one inhibitory receptor, while natural killer cells express one of each. In our depletion experiments, we found that alveolar macrophages, not natural killer cells or neutrophils, played the dominant role in conferring nonNAb-mediated protection. We also demonstrated that alveolar macrophages are required for protection at suboptimal concentrations of bnAbs. These two observations correlate well with our previous studies indicating that alveolar macrophages are indeed the effector cells that mediated the Fc-dependent protection provided by both murine and human broadly binding antibodies1,2. Moreover, our data indicate that the inflammatory cytokine/chemokine release and phagocytosis activity induced by the interactions between antibodies and alveolar macrophages may be involved in the observed protection. While alveolar macrophages are important for Fc-mediated immunity in mice, it remains to be determined if alveolar macrophages work in a similar manner in humans.

 Interestingly, the method by which the depletion studies were performed indicated that a residential population of innate immune cells (i.e. alveolar macrophage) played a more important role than inflammatory cells (e.g. neutrophils and natural killer cells) during an acute viral infection. Given the role of these resident sentinel cells not only in Fc-mediated immunity, but also in tissue development, homeostasis and injury repair, it is evident that alveolar macrophages are involved in multiple pathways that require more research.

 In conclusion, our findings highlight the importance of alveolar macrophages in controlling influenza virus infection, as well as shed light on how the innate and adaptive immune system cooperate to achieve an optimal antiviral state. Meanwhile, our work reveals several mechanisms by which broadly reactive antibodies work.

 You can find more details about our paper here:


1.     DiLillo DJ, Tan GS, Palese P, Ravetch JV. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat. Med. 2014 Feb;20(2):143–51. PMCID: PMC3966466

2.     DiLillo DJ, Palese P, Wilson PC, Ravetch JV. Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection. J. Clin. Invest. American Society for Clinical Investigation; 2016 Feb;126(2):605–10. PMCID: PMC4731186

Gene Tan

Assistant Professor, J. Craig Venter Institute