Complement Resistance Acquired During Acute to Persistent Rubulavirus Infection

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For many RNA virus infections, an initial acute infection can transition to a prolonged or persistent infection, in which infected cells survive and continue to produce progeny virus. Complement (C’) is a powerful innate immune system which can directly lyse virus-infected cells or neutralize virus (1-4), but the role of C’ in controlling persistent respiratory RNA virus infections is not well understood. Given that viruses have mechanisms to block C’-mediated cell lysis, persistent infections can set up a prolonged inflammation cycle – where activated C’ continues to provide damaging inflammation, but viral inhibitory mechanisms block elimination of pathogen and infected cells. This project emerged from our striking findings that during an initial acute infection of human lung cells with the Rubulavirus Parainfluenza virus 5 (PIV5), infected cells are very sensitive to C’-mediated lysis. Importantly however, after transitioning to a persistent infection, PIV5-infected cells are nearly completely resistant to C’ lysis. Our transcriptomics data show that PIV5 acutely infected cells have low level expression of C’ inhibitors, but this shifts to high level expression of cellular C’ inhibitors Factor H, Factor I, Vitronectin and Clusterin in persistently infected cells. Our central hypothesis is that PIV5 persistently infected cells acquire resistance to C’-mediated lysis due to their acquired ability to express high levels of C’ inhibitors Factor H and Vitronectin. Our goals are to identify: 1) the mechanisms for acquiring C’ resistance during the PIV5 acute-to-persistent transition (Aim 1), and 2) consequences of this shift for production of C’-resistant virus (Aim 2). Aim 1 will define the mechanism for differential sensitivity of airway cells to C’-mediated lysis during transition from acute to persistent infection. Engineered respiratory tract cell lines and primary tracheal or bronchial air-liquid interface (ALI) cell cultures will be used to test the hypothesis that synthesis of C’ inhibitors Factor H and Vitronectin by persistently infected cells results in conditioning of the cells to be resistant to C’-mediated lysis. Aim 2 will identify C’ factors associated with virus particles derived from acute versus persistently infected cells and define the sensitivity of persistent virus to C’- mediated neutralization. Proteomics and biochemical assays will test the hypothesis that virus derived from persistently infected cells will be C’-resistant due to recruitment of Factor H or Vitronectin. Results from our work on C’ interactions with persistent RNA virus infections will have strong potential to inform therapeutics, given: 1) the clinical impact of prolonged viral respiratory infections, 2) polymorphisms in C’ genes can correlate with severity of viral infections, and 3) clinical trials for respiratory tract infections are underway with drugs that modulate C’ responses.