TLR3-independent activation of mast cells by cytomegalovirus contributes to control of pulmonary infection

Interstitial pneumonia is a life-threatening clinical manifestation of human cytomegalovirus (hCMV) infection. In particular, it can be deadly in patients with hematopoietic malignancies who undergo hematopoietic cell transplantation (HCT) in whom a ‘window of risk’, which is defined by transient immunodeficiency, occurs between hematoablative therapeutic treatment and immunological reconstitution. As few clinical studies have addressed the underlying mechanisms for this phenomenon, a mouse model of HCT and murine cytomegalovirus (mCMV) infection has been established and has revealed a key role for antiviral CD8⁺ T cells in controlling pulmonary infections. Using this mouse model, recent studies have provided evidence for the role of mast cells (MC) in more efficiently recruiting antiviral CD8⁺ T cells to CMV-infected lungs in a process that involves the release of CCL5, a chemokine. MC were found to be direct cellular targets of murine CMV infection and could be activated and degranulated by two mechanisms: the rapid degranulation requiring TLR3/TRIF signaling in non-MC cells and a delayed TLR3/TRIF-independent mechanism. Here, we provide evidence showing that TLR3/TRIF-independent MC activation by CMV is the dominant mechanism in controlling pulmonary infection.

As human cytomegalovirus (hCMV) can establish a life-long latent infection, which under immunocompromised conditions carries a risk of reactivation to recurrent productive infection with multiple organ manifestations, it represents a major risk to patients at transplantation centers worldwide who are solid organ transplantation (SOT) or hematopoietic cell transplantation (HCT) recipients. In particular, the lungs of HCT recipients are susceptible to CMV disease and have a high risk of developing lethal interstitial pneumonia if left untreated. As CMVs are strictly host species-specific, hCMV cannot be studied in animal models. The mCMV model has reproduced most aspects of hCMV pathogenesis that are observed in patients. Specifically, the lungs represent a major site of CMV latency, reactivation, and pathogenesis in both hCMV-infected humans and mCMV-infected mice.^{1, 2, 3, 4} In general, the animal model has been instrumental in mimicking hCMV disease to address principles of CMV–host interactions⁵ and to test new strategies for therapeutic intervention, such as cytoimmunotherapy,⁶ by focused experimental studies.