In This Issue

doi:10.4049/jimmunol.1890026

IL-6 Drives Muscle Wasting during IAV Infection

Infection with influenza A virus (IAV) can result in the development of acute respiratory distress syndrome (ARDS). Patients surviving ARDS demonstrate muscle dysfunction, but the precise mechanisms driving association between IAV infection and muscle dysfunction are unknown. In this issue, Radigan et al. (p. 484) sought to determine if IL-6, which accumulates rapidy in airway lavages after IAV infection, is necessary for the development of muscle dysfunction via activation of STAT3 and the muscle-specific ubitquitin ligase atrogin-1. Treatment of IAV-infected mice with the IL-6R Ab tocilizumab attenuated IAV-induced muscle dysfunction. Additionally, treatment of differentiated myotubes with recombinant IL-6, but not IAV, promoted muscle degradation that was dependent on upregulation of JAK/STAT, FOXO3a, and atrogin-1. Consistent with these observations, IAV-infected mice deficient for atrogin-1 displayed attenuated muscle dysfunction despite increased levels of IL-6 in the lung. Together, these results demonstrate that IL-6 released in the lung following IAV infection activates STAT3 and FOXO3a in neighboring muscle, which induces expression of atroginin-1 and promotes muscle degeneration. Future studies could elucidate whether these pathways can be targeted to preserve muscle mass in patients with IAV-induced ARDS.

Corneal Hypoxia

Herpes simplex virus-1 infection in the cornea can cause herpes stromal keratitis (HSK), which is characterized by chronic lesions associated with inflammation and infiltration of different immune cell subsets. Rao and Suvas (p. 514) observed that HSK lesion progression coincides with the development of hypoxia and induction hypoxia–associated genes. The progression of HSK lesions during murine Herpes simplex virus-1 corneal infection correlated with increased staining by the chemical hypoxia marker pimonidazole hydrochloride as well as increased neutrophil infiltration. Further analysis demonstrated that hypoxia-associated glycolytic genes are upregulated in HSK corneas. In particular, the hypoxia-inducible factor (HIF) isoform HIF-1a showed protein stabilization in infiltrating leukocytes, whereas nuclear localization of HIF-2a was observed in corneal epithelial cells. Both of these effects were inhibited in mice treated with acriflavine, although treatment led to enhanced neutrophil infiltration, as well as reduced CD4⁺ T cell and myeloid cell infiltration, ultimately increasing corneal opacity. Together, these data indicate that hypoxia-associated genes contribute to pathogenesis of corneal HSK.

Impact of CMV and Aging on CD8 T Cell Repertoires

Immunosenescence can be exacerbated by chronic pathogens such as CMV. A current hypothesis is that rapid expansion of CMV-specific CD8⁺ memory T cells exacerbates competition among naive and memory repertoires for homeostatic survival signals, thereby reducing T cell repertoire diversity. To date, the impact of CMV on T cell repertoires in aging humans remains uncharacterized. In this issue, Lindau et al. (p. 476) surveyed T cell clones from 543 subjects across a wide range of ages and demonstrated that the proportion of large clones (defined as the most numerous 0.1% of clones) is elevated in CMV positive individuals and gradually increases with age. Examination of the CD8⁺ T cell repertoires of CMV seropositive elderly individuals showed that large clones dominated the memory repertoires of these individuals and were CMV-reactive. The authors also demonstrated that although T cell repertoires in the elderly grow to accommodate CMV-driven clonal expansion, the underlying diversity and clonal structure is maintained. Together, these results demonstrate that maintenance of large CMV-reactive T cell clones throughout life does not compromise overall repertoires. Instead, the authors propose that exacerbated immunosenensce in elderly CMV-positive individuals is due to alterations in cellular function, rather than a reduction in repertoire diversity of CD8⁺ T cells.

Fishy IFN

The RIG-I–like receptor (RLR) signaling pathway is highly conserved between zebrafish and mammalian species, although fish have more type I IFN members. In this issue, Li et al. (p. 559) characterized the major vault protein (MVP) in zebrafish, which is induced by viral infection in humans and promotes IFN production. Zebrafish MVP share 65% similarity with human MVP, and is shown to be a negative regulator of IFN production. Zebrafish MVP can recruit TANK-binding kinase 1 (TBK1) and promote cytoplasmic aggregation, as well as lysosomal degradation, which in turn decreases IFN responses. Together, these findings show that zebrafish MVP can negatively regulate IFN responses through its interaction with TBK1.