Sampriti Roy, Asutosh College (University of Calcutta)
When speaking of cell mechanisms, there are still a large number of the same that remain largely unknown. From understanding viral pathogenesis to antiviral therapeutics development – the identification of viral mechanisms and understanding how the virus defends itself is crucial. This is the case particularly for those viruses that hold a significance concerning global health – like the Ebola virus (EBOV) as well as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). When seeing the gravity of the effects of these viruses, the identification of a mechanism, through which CD74 (a protein-coding gene) directly inhibits SARS-CoV-2 and Ebola virus (EBOV) entry into host cells, by Bruchez et al. seems like a flicker of hope in these trying times.
The study:
Bruchez et al. have developed a transposon screening approach in a human osteosarcoma cell line to identify a mechanism by which CD74 directly inhibits EBOV and SARS-CoV-2 entry into host cells.
Although they differ in size and shape SARS- CoV-2 and EBOV rely on similar proteolytic processes to gain entry into a target cell. So, in finding out about the inhibiting factors, the same processes were followed by the authors to gain information about both viruses. These included identifying the host factors involved in EBOV infection and establishing the function of CIITA (Class II Major Histocompatibility Complex Transactivator), which acts as a transcription factor and promotes other genes’ expression.
What the authors identified:
- It was found that the expression of CIITA is associated specifically with inhibition of EBOV’s entry into the cell.
- The CIITA-controlled host factor responsible for inhibiting EBOV’s cell entry was found out to be CD74 (enriched in immune cell populations and associates with class II MHC).
- MHC is an important part of the immune response because it presents peptides from either intracellular (MHC class I) or extracellular (MHC class II) proteins to adaptive immune cells. Without CIITA-controlled CD74, MHC class II molecules are not processed properly and antigen presentation becomes impaired. CD74 facilitates the export of MHC class II molecules’ export from the ER (Endoplasmic Reticulum) to vesicles that fuse with the late endosome. Thus, CIITA (which controls CD74) serves as the master regulator of MHC gene expression.
- Thyroglobulin domain was shown to be important for antiviral activity. The authors have stated that CD74 has 4 isoforms, out of which only 2, i.e., p41 and p43 have thyroglobulin domain. CIITA (class II MHC trans activator) up-regulates the CD74 p41 isoform, by which cathepsins (cleaves viral glycoproteins) are inhibited and genome release into the cytoplasm is prevented.
Significance of identification of CD74’s inhibition mechanism:
The identification of host factors like CIITA-controlled CD74 could be useful in obtaining therapeutic benefits by limiting the replication of comprehensive families of viruses. This may prove to be an effective approach to fight viral diseases in the future and potentially even have the capability to prevent a pandemic.
Also read: Cancer, COVID-19 and reconciling the Riddles
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