The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion.

The human cytomegalovirus (HCMV) US12 gene family contributes to virus-host interactions by regulating the virus' cell tropism and its evasion of host innate immune responses. US21, one of the 10 US12 genes (US12-US21), is a descendant of a captured cellular transmembrane BAX inhibitor motif-containing gene. It encodes a 7TMD endoplasmic reticulum (ER)-resident viroporin (pUS21) capable of reducing the Ca2+ content of ER stores, which, in turn, protects cells against apoptosis. Since regulation of Ca2+ homeostasis affects a broad range of cellular responses, including cell motility, we investigated whether pUS21 might also interfere with this cytobiological consequence of Ca2+ signaling. Indeed, deletion of the US21 gene impaired the ability of HCMV-infected cells to migrate, whereas expression of US21 protein stimulated cell migration and adhesion, as well as focal adhesion (FA) dynamics, in a way that depended on its ability to manipulate ER Ca2+ content. Mechanistic studies revealed pUS21-mediated cell migration to involve calpain 2 activation since its inhibition prevented the viroporin's effects on cell motility. Pertinently, pUS21 expression stimulated a store-operated Ca2+ entry (SOCE) mechanism that may determine the activation of calpain 2 by promoting Ca2+ entry. Furthermore, pUS21 was observed to interact with talin-1, a calpain 2 substrate, and crucial protein component of FA complexes. A functional consequence of this interaction was confirmed by talin-1 knockdown, which abrogated the pUS21-mediated increase in cell migration. Together, these results indicate the US21-encoded viroporin to be a viral regulator of cell adhesion and migration in the context of HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) is an opportunistic pathogen that owes part of its success to the capture, duplication, and tuning of cellular genes to generate modern viral proteins which promote infection and persistence in the host by interfering with many cell biochemical and physiological pathways. The US21 viral protein provides an example of this evolutionary strategy: it is a cellular-derived calcium channel that manipulates intracellular calcium homeostasis to confer edges to HCMV replication. Here, we report on the characterization of a novel function of the US21 protein as a viral regulator of cell migration and adhesion through mechanisms involving its calcium channel activity. Characterization of HCMV multifunctional regulatory proteins, like US21, supports the better understanding of viral pathogenesis and may open avenues for the design of new antiviral strategies that exploit their functions.

Spectrum of candidate molecules against Chikungunya virus - an insight into the antiviral screening platforms.

INTRODUCTION: Chikungunya disease has undergone a phenomenal transition in its status from being recognized as a sporadic infection to acquiring a global prominence over the last couple of decades. The causative agent behind the explosive epidemics worldwide is the re-emerging pathogen, Chikungunya virus (CHIKV). Areas covered: The current review discusses all the possible avenues of antiviral research towards combating CHIKV infection. Aspects of antiviral drug discovery such as antiviral targets, candidate molecules screened, and the various criteria to be a potential inhibitor are all discussed at length. Existing antiviral drug screening tools for CHIKV and their applications are thoroughly described. Clinical trial status of agents with therapeutic potential has been updated with special mention of candidate molecules under patent approval. Databases such as PubMed, Google Scholar, ScienceDirect, Google Patent, and Clinical Trial Registry platforms were referred. Expert opinion: The massive outbreaks of Chikungunya viral disease in the recent past and the serious health concerns imposed thereby, have driven the search for effective therapeutics. The greatest challenge being the non-availability of robust, reproducible, cost-effective and biologically accurate assay models. Nevertheless, there is a need to identify good models mimicking the appropriate microenvironment of an infectious setting.