From Proteins to People: Cytomegalovirus Modulation of Host Cellular Responses and Its Implications on Health Equity

Abstract

Human cytomegalovirus (CMV) is one of the nine known human herpesviruses that causes significant disease burden in the developed world. As a natural pathogen in mice, murine CMV (MCMV) serves as an ideal animal model to investigate virus-host interactions and the molecular mechanisms essential for CMV pathogenesis. CMV is known as a master manipulator of host responses by modulating essential aspects of host biology, such as the post-transcriptional machinery and innate immune responses. While the genome of HCMV is known, many genes remain uncharacterized, and its ability to evade the host’s anti-viral responses is still not fully understood. To understand the uncharacterized M72 viral gene, we identified multiple subunits of the Carbon Catabolite Repression 4-Negative on TATA-less (CCR4-NOT) complex as potential functional interactors with M72. The CCR4-NOT complex is one of the major deadenylases in eukaryotic cells and is implicated in every step of RNA metabolism, making it a top candidate for viral pathogens to manipulate. Through our investigation, we show that M72 interacts with the CCR4-NOT complex through the CNOT1 subunit. We also show that M72 interacts with the regions of CNOT1 that are essential for recruiting the deadenylases to the complex. Furthermore, we reveal that M72 and CNOT are required for normal MCMV replication. Altogether, suggesting a novel function for M72 in modulating the CCR4-NOT complex and a pro-viral role for CNOT1 in MCMV pathogenesis. To further investigate MCMV’s ability to manipulate host anti-viral responses, we sought to understand how the host sensor Z-nucleic acid Binding Protein 1 (ZBP1) is regulated during MCMV infection. Through a biotin-proximity labeling screening, we identified the interferon-inducible Guanylate Binding Protein 2 (GBP2) as a potential regulator of ZBP1 during MCMV infection. We found that GBP2 is upregulated early in infection and recruited to the c-terminal domain of ZBP1 that is responsible for interferon-β transcription. We also show that in the absence of GBP2, there is a 1000-fold defect in MCMV replication, accompanied by increased expression of mouse interferon-β. Our data suggest that GBP2’s pro-viral role depends on the GTPase and GTPase effector domains of GBP2, as well as the presence of ZBP1. Altogether, our data suggest that GBP2 may be restricting the IFN-1 response to MCMV infection by regulating ZBP1. Finally, CMV disproportionately impacts racial and ethnic minorities in the United States due to socioeconomic and environmental factors. There are currently no federally enforced guidelines or screening programs for individuals who are immunocompromised to be informed about CMV. While there have been many states that have passed legislation addressing congenital CMV, there is a gap in states where racial and ethnic minorities are highly represented. Through an in-depth systems-level review, we present an overview of CMV disease, guidelines and legislation for CMV, and examine inequities of CMV disease on racial and ethnic minority communities. We also provide suggestions for future legislation, funding, and educational programs to be enacted. Altogether, we provide a new insight into how proven CMV initiatives passed at the federal level may mitigate the disproportionate burden of CMV on racial and ethnic minority populations.