Immunity versus pathology
Influenza-associated morbidity and mortality due to yearly epidemics and sporadic, devastating pandemics are a significant health and economic burden. Severe complications arising from highly virulent viruses are associated with rapid, massive inflammatory cell infiltration. Although neutrophils are the predominant cell population recruited to the lung in response to pandemic influenza viruses, the mechanisms by which they gain entry to the respiratory tract remain unclear. We demonstrated a previously unknown contribution of the gelatinase matrix metalloprotease (MMP) 9 to influenza pathogenesis by mediating excessive neutrophil migration into the lung, which not only controls viral replication, but also contributes to morbidity (PLOS Pathogen, 2012
). Neutrophil migration was dependent on MMP9 secretion and dependent on toll-like receptor (TLR) signaling in non-hematopoietic cells and was mediated in part by TNFα. Innate recognition of influenza virus therefore provides a mechanism that facilitates recruitment of neutrophils through chemokines and enables their motility within the tissue via MMP9-mediated cleavage of the basement membrane (Movie 1
), which could be exploited for therapeutic purposes.
Movie 1: Neutrophil recruitment to the lung in response to influenza virus infection: (1) TLR signaling in response to influenza virus infection of epithelial cells induces a local chemokine gradient (2) that attracts neutrophils from the periphery (3). Neutrophil motility in the parenchyma following diapedesis is mediated by the proteolytic activity of MMP9, which is controlled by TLR signaling-induced TNFα (4).
We are currently looking into the contribution of MMPs in other cell populations to influenza virus pathogenesis. For example, T cells are crucial in resolving influenza by killing virus-infected cells in the respiratory tissues. T cell migration to the infected respiratory epithelium is crucial for their effector responses. How T cells are induced and maintained, and migrate to infected tissues has important implications in the outcome after viral infection and is of great interest. We showed that T cell immunity to influenza virus is regulated by the adhesion receptor CD44 by regulating T cell survival (Immunity, 2010
). The summation of signals to T cells during migration and adhesion to the extracellular matrix can critically impact their development and homeostasis (reviewed in
Frontiers in Immunological Memory, 2012
). We are currently investigating the role of MMPs in T cell migration and function.
Defective immunity in the elderly
Most natural infections in humans are restricted to the nasal mucosa and the upper respiratory tract and are resolved before causing lung pathology. The nasal associated lymphoid tissue (NALT) is the first immune tissue that is exposed to inhaled pathogens and is crucial for optimal mucosal immunity. Furthermore, we demonstrated that mucosal adjuvants can enhance and boost immunity to respiratory viruses (European Journal of Immunology, 2006
). Replication-capable vaccines that specifically target the upper respiratory tract and NALT, such as cold-adapted viruses, mimic natural infection and induce superior cross-reactive immunity compared to inactivated intramuscular vaccines. Very little is known about the requirements for T cell migration to the NALT following influenza virus infection or vaccination. We observed that L-Selectin, among other integrins, is critical for the migration of CD8 T cells to this mucosal site and demonstrated that T cell responses at the mucosal surfaces of the aged NALT were greatly reduced (unpublished observation). We are now identifying the requirements (T cell-intrinsic and environmental defects) for cold-adapted influenza virus-mediated immunity in the aged.
Past and ongoing studies that give new insights into the requirements for cellular immunity during viral pathogenesis could elucidate the balance between protection and pathology. Understanding the mechanisms that lead to effective mucosal immunity therefore has considerable therapeutic relevance.
Research was made possible by grants from
National Institute for Allergy and Infectious Diseases,
National Institute for Aging, and the
American Foundation for Aging Research.