Abstract
Little is known about the role of complement (C’) in infections with highly prevalent circulating human coronaviruses such as OC43, a group of viruses of major public health concern. Treatment of OC43-infected human lung cells with human serum resulted in C3 deposition on their surfaces and generation of C5a, indicating robust C’ activation. Real-time cell viability assays showed that in vitro C’-mediated lysis of OC43 infected cells requires C3, C5 and C6 but not C7, and was substantially delayed as compared to rapid C’-mediated killing of parainfluenza virus type 5 (PIV5)-infected cells. In cells co-infected with OC43 and PIV5, C’-mediated lysis was delayed, similar to OC43 infected cells alone, suggesting that OC43 infection induced dominant inhibitory signals. When OC43-infected cells were treated with human serum, their cell surfaces contained both Vitronectin (VN) and Clusterin (CLU), two host cell C’ inhibitors that can alter membrane attack complex (MAC) formation and C’-mediated killing. VN and CLU were not bound to OC43-infected cells after treatment with antibody-depleted serum. Reconstitution experiments with purified IgG and VN showed that human antibodies are both necessary and sufficient for VN recruitment to OC43-infected lung cells–novel findings with implications for CoV pathogenesis.
Highlights
Human respiratory viruses are a major public health concern and impose a huge burden on the economy and the health care industry
OC43 nucleocapsid (NP) protein (Figure 1A) or for propidium iodide (PI) as a measure of cell death (Figure 1B). These timecourse studies demonstrated that OC43 productively infected ~70%–80% of the cells by 48 hpi with minimal cell death (i.e., PI staining)
The kinetics of NHS-mediated killing of OC43 infected cells was compared to PIV5infected cells, since we have previously shown that parainfluenza virus type 5 (PIV5) is neutralized by what appears to be mechanisms that are complement-dependent but specific antibody-independent [25,27,31,32]
Summary
Human respiratory viruses are a major public health concern and impose a huge burden on the economy and the health care industry. Non-influenza related respiratory virus infections account for nearly 40 billion dollars annually in direct and indirect medical costs in the United States alone, with similar costs for chronic conditions such as hypertension and congestive heart failure [1]. Pathogens associated with these illnesses include enveloped RNA viruses, such as coronaviruses, which remain highly prevalent in the human population, with reoccurring seasonal infections. Soluble and cell membraneassociated proteins coordinate C’-mediated defenses against viral infections This can include multiple mechanisms such as direct virus recognition and neutralization, B and T cell activation, leukocyte recruitment and stimulation, and virus opsonization by immune cells [3,4,5]. Viruses have evolved strategies to prevent C’ pathway activation and execution, which may contribute to viral pathogenesis and disease (e.g., [6,7,8,9])
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