Identification of a viral factor that impairs immune responses in COVID-19 patients

October 09, 2020

As of October 2020, SARS-CoV-2 causes an ongoing pandemic, with more than 35 million reported cases and more than 1 million deaths worldwide. One prominent feature that distinguishes COVID-19 from SARS in terms of immune responses is the poor induction of a type I interferon (IFN) response by SARS-CoV-2 compared to SARS-CoV and influenza A virus. Notably, impaired IFN responses are associated with COVID-19 disease. However, the molecular mechanisms underlying the inefficient IFN responses in SARS-CoV-2 infection remain unclear.

A research team at The Institute of Medical Science, The University of Tokyo (IMSUT) aimed to characterize the viral factor(s) determining immune activation upon SARS-CoV-2 infection and found that ORF3b, a gene encoded by SARS-CoV-2, is a potent IFN antagonist.

"The poor IFN responses in COVID-19 patients may be explained by the action of this viral product, ORF3b", said the lead scientist, Kei Sato, Associate Professor (Principal Investigator) at Division of Systems Virology, Department of Infectious Disease Control, IMSUT.

The results of this research were published in "Cell Reports" on September 4, 2020.

ORF3b as a viral IFN antagonist

Although SARS-CoV infection causes acute and severe pneumonia, SARS-CoV-2 infection may be asymptomatic or result in flu-like symptoms such as fever, cough and fatigue. Also, compared to SARS-CoV and influenza A virus infections, a hallmark of SARS-CoV-2 infection, COVID-19, is the poor induction of a type I interferon (IFN). Notably, impaired IFN responses are associated with the severity of COVID-19. However, the molecular mechanisms underlying the inefficient IFN responses in SARS-CoV-2 infection remain unclear.

By comparing the sequences of SARS-CoV-2-encoding genes to those of SARS-CoV, the research group found that the gene length of SARS-CoV-2 ORF3b is markedly shorter than that of SARS-CoV ORF3b.

Because ORF3b of SARS-CoV is known as a viral antagonist against IFN production, they hypothesized that the difference on the length of ORF3b gene between SARS-CoV-2 and SARS-CoV may alter their anti-IFN activity and further may explain the difference in the symptoms of these two viral infections.

Surprisingly, SARS-CoV-2 ORF3b is a more potent IFN antagonist than SARS-CoV ORF3b. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode shorter ORF3b gene products with strong anti-IFN activity.

Characterization of a natural SARS-CoV-2 ORF3b variant with enhanced anti-IFN activity

Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant suppresses IFN even more efficiently than ORF3b of the parental SARS-CoV-2 strain.

In agreement with an association of IFN suppression with disease severity, the two patients in Ecuador harboring SARS-CoV-2 with the extended ORF3b variant were critically ill; one was treated in an intensive care unit and the other one died of COVID-19.

Importantly, however, there is no direct evidence indicating that the viruses detected in these two COVID-19 patients in Ecuador are more pathogenic than the reference strain. Although they cannot tell whether this variant is associated with a different outcome in disease, it is plausible that naturally occurring length variants of ORF3b can potentially contribute to the emergence of more pathogenic SARS-CoV-2 variants.

Thus, it will be important to continue monitoring viral sequences to see whether novel ORF3b variants emerge during the current pandemic.

Associate Professor Kei Sato said that "To our knowledge, this study is the first investigation revealing the role of a SARS-CoV-2-encoded protein that can be associated with the progression of COVID-19".

The Institute of Medical Science, The University of Tokyo

Related Infection Articles from Brightsurf:

Halving the risk of infection following surgery
New analysis by the University of Leeds and the University of Bern of more than 14,000 operations has found that using alcoholic chlorhexidine gluconate (CHG) halves the risk of infection in certain types of surgery when compared to the more commonly used povidone-iodine (PVI).

How plants shut the door on infection
A new study by an international team including University of Maryland scientists has discovered the key calcium channel responsible for closing plant pores as an immune response to pathogen exposure.

Sensing infection, suppressing regeneration
UIC researchers describe an enzyme that blocks the ability of blood vessel cells to self-heal.

Boost to lung immunity following infection
The strength of the immune system in response to respiratory infections is constantly changing, depending on the history of previous, unrelated infections, according to new research from the Crick.

Is infection after surgery associated with increased long-term risk of infection, death?
Whether experiencing an infection within the first 30 days after surgery is associated with an increased risk of another infection and death within one year was the focus of this observational study that included about 660,000 veterans who underwent major surgery.

Revealed: How E. coli knows how to cause the worst possible infection
The discovery could one day let doctors prevent the infection by allowing E. coli to pass harmlessly through the body.

UK study shows most patients with suspected urinary tract infection and treated with antibiotics actually lack evidence of this infection
New research presented at this week's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Amsterdam, Netherlands (April 13-16, 2019) shows that only one third of patients that enter the emergency department with suspected urinary tract infection (UTI) actually have evidence of this infection, yet almost all are treated with antibiotics, unnecessarily driving the emergence of antimicrobial resistance.

Bacteria in urine doesn't always indicate infection
Doctors should think carefully before testing patients for a urinary tract infection (UTI) to avoid over-diagnosis and unnecessary antibiotic treatment, according to updated asymptomatic bacteriuria (ASB) guidelines released by the Infectious Diseases Society of America (IDSA) and published in Clinical Infectious Diseases.

Subsidies for infection control to healthcare institutions help reduce infection levels
Researchers compared three types of infection control subsidies and found that under a limited budget, a dollar-for-dollar matching subsidy, in which policymakers match hospital spending for infection control measures, was the most effective at reducing the number of hospital-acquired infections.

Dengue virus infection may cause severe outcomes following Zika virus infection during pregnancy
This study is the first to report a possible mechanism for the enhancement of Zika virus progression during pregnancy in an animal model.

Read More: Infection News and Infection Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to