| Microbial pathogens and mammalian hosts have evolved exquisite mechanisms to infect, immunize, and evade their counterparts. The viral pathogens respiratory syncytial virus (RSV) and Sendai virus infect the lungs of their host, causing bronchiolitis and croup, sometimes resulting in hospitalization. Resolution of this infection requires elimination of infected cells by virus-specific cytotoxic lymphocytes followed by nonphlogistic clearance of apoptotic cellular corpses by viable macrophages. The latter requires activation of PI3K/Akt and MEK/ERK signaling cascades by the chemokine CCL5 during Sendai viral infection. Without this CCL5 macrophage survival signal, mice exhibit increased inflammation of the airways, overwhelming viral infection, and increased mortality. This novel phenomenon of chemokine pro-survival signaling in the context of respiratory infection could shed light on host pathogen interactions during respiratory viral infections, potentially leading to new, individually tailored treatments and vaccine strategies. While apoptosis of macrophages is detrimental in the acute phase of infection, apoptosis of hyperplastic epithelial cells in the chronic, repair phase of infection is crucial for normal homeostasis of the airway epithelium. Abnormal blockade of ciliated cell apoptosis by persistent epidermal growth factor receptor (EGFR) signaling in C576BL/6 mice leads to hyperplastic ciliated cells in the chronic phase after pulmonary infection by Sendai virus. Simultaneous persistence of the cytokine, interleukin-13 (IL-13), promotes ciliated cell to goblet cell transdifferentiation, leading to mucous hypersecretion—one of the hallmarks of chronic airway disease. Blockade of EGFR and IL-13 signals in the chronic phase after Sendai viral infection blocks epithelial hyperplasia, thus restoring normal airway epithelial homeostasis. Hence, modulation of apoptosis by CCL5 and EGFR in acute and chronic disease settings yields opposite results. During the acute phase of viral infection, pro-survival signaling by CCL5 is crucial for viral clearance and host survival, while in the chronic phase, persistent prosurvival signaling by EGFR causes chronic airway disease by altering normal epithelial homeostasis and causing epithelial cell hyperplasia. |
