Abstract
Epstein-Barr Virus (EBV) causes infectious mononucleosis and establishes lifelong infection associated with cancer and autoimmune disease. To better understand immunity to EBV, we performed a prospective study of natural infection in healthy humans. Transcriptome analysis defined a striking and reproducible expression profile during acute infection but no lasting gene changes were apparent during latent infection. Comparing the EBV response profile to multiple other acute viral infections, including influenza A (influenza), respiratory syncytial virus (RSV), human rhinovirus (HRV), attenuated yellow fever virus (YFV), and Dengue fever virus (DENV), revealed similarity only to DENV. The signature shared by EBV and DENV was also present in patients with hemophagocytic syndromes, suggesting these two viruses cause uncontrolled inflammatory responses. Interestingly, while EBV induced a strong type I interferon response, a subset of interferon induced genes, including MX1, HERC5, and OAS1, were not upregulated, suggesting a mechanism by which viral antagonism of immunity results in a profound inflammatory response. These data provide an important first description of the response to a natural herpesvirus infection in humans.
Highlights
Epstein-Barr virus (EBV) is a herpesvirus that causes lifelong infection in humans
Of 143 subjects followed in the study, 66 experienced primary EBV infection during their undergraduate years [13]
Signature and that observed in other acute viral infections, we theorized that perhaps the signature would more closely resemble that observed during inflammatory syndromes. To this end we examined microarray data obtained from subjects with familial hemophagocytic lymphohistiocytosis (FLH) [19] or subjects presenting with systemic onset juvenile arthritis who were later confirmed to have subclinical macrophage activation syndrome (MAS)
Summary
Epstein-Barr virus (EBV) is a herpesvirus that causes lifelong infection in humans. EBV is estimated to be a causative agent in 1% of all human cancers, [1] including various lymphomas, and nasopharyngeal and gastric carcinomas; [2] and to contribute to autoimmune diseases such as systemic lupus erythematosus (SLE) [3] and multiple sclerosis. [4] the most common consequence of EBV infection is infectious mononucleosis (IM). [5] Primary acquisition of the virus by children before puberty does not generally cause recognizable symptoms, but those who become infected during or after adolescence have a high likelihood of developing IM. [12] there is a dearth of understanding in current research about the host gene changes that occur during natural viral infection with EBV in otherwise healthy humans and whether or not these infections lead to long lasting changes in the immune system. We sought to address these issues by performing transcriptomic studies on human subjects participating in a prospective study of primary EBV infection acquired naturally. We compared these data with gene expression analyses of other acute viral infections, systemic illnesses, and interferon (IFN) driven immune responses. We found the human immune response to EBV has a distinct and reproducible gene expression signature that more closely resembles the dysregulated innate immune responses observed during cytokine storm illness than what is seen during other acute viral infections. We identified a subset of genes that represent likely targets of viral immune evasion mechanisms
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