There is a section of the Centers for Disease Control and Prevention (CDC) website that gives the history of the agency and celebrates milestones related to controlling, containing and eliminating many health threats. To get an idea of how stressful it must be to work at the CDC, just click on the “timeline” to see outbreaks by decade: SARS in 2003, H1N1 in 2009, MERS-CoV in 2013, Ebola in 2014, Zika in 2016, and now in 2020 Sars-CoV-2 that causes COVID-19. And while there is no doubt that this threat will also be successfully dealt with, we are all seeing and hearing the effects of social distancing and shelter-in-place orders: stockpiling (seriously what’s up with everyone hoarding toilet paper?), uplifting stories of courage, hope, life and death, and some seriously funny memes.

A Crown that No One Wants

In December 2019, a cluster of pneumonia cases emerged in the Chinese province of Wuhan, resulting in fatalities in elderlies and immune compromised individuals. In a paper recently published in Nature, authors showed that the full-length RNA sequence of SARS-CoV-2 shares 79.6% sequence identity to another SARS-CoV that in 2003 caused severe acute respiratory syndrome and is 96% identical at the whole-genome level to a bat coronavirus (1)

Beta Coronaviruses (CoV) are a genus of coronaviruses common in several animal species, including camels, cattle, and bats. The name “Corona” means crown in Latin. They are large, enveloped, positive single-stranded RNA (+RNA) viruses with a size ranging from 26-32Kb and are encapsulated in a phospholipid bilayer and covered by two different types of spike proteins that give the virus a crown-like shape, hence the name “corona”.

The Host Immune Response

The host innate immune system detects beta coronaviruses via Pattern Recognition Receptors (PRRs) such as Toll‐like receptors (TLRs), RIG‐I‐like receptors (RLRs), and NOD like receptors on the surface of macrophages that recognize Pathogen-Associated-Molecular-Patterns (PAMPs) presented by the virus. When the innate immune system recognizes the viruses through its PRRs, the translocation of NF-κB, IRF3 and IRF7 to the nucleus induces the production of interferons (IFNs). In addition to IFNs, these transcription factors initiate the production of other inflammatory cytokines and the expression of interferon-stimulated genes (ISGs) (2).

The process of virus detection leads to T cell activation and differentiation, including secretion of cytokines associated with the different T cell subsets. CD4+ T cells promote the production of virus‐specific antibodies by activating T cell-dependent B cells, while cytotoxic CD8+ T cells kill viral infected cells (2).

The Virus

Beta coronaviruses have an RNA genome, a distinctive feature that alveolar macrophages, airway epithelial cells, & innate lymphoid and dendritic cells recognize when these viruses enter the respiratory tract. Recognition triggers subsequent downstream signaling cascades aimed at preventing or at least mitigating infection before adaptive immunity kicks in to clear the virus from the lungs.

It is precisely this reason why these viruses have developed countermeasures to circumvent or suppress host defense mechanisms and create a window of opportunity for efficient virus replication, thereby causing disease. One strategy is to shield replication intermediates ─ that have recognizable features ─ from the innate immune system. Indeed, viruses with an RNA genome such as the Beta Coronavirus, replicate in the cytosol and typically modify intracellular membranes to form a headquarters for viral RNA replication, called “replication organelles” (ROs). These structures are thought to concentrate the viral replication machinery, intermediates, and products together inside vesicles that are seemingly unreachable for the innate immune sensors of the cytosol. (3)

In addition to avoiding recognition, +RNA viruses actively interfere with antiviral signaling components to impair expression of IFNs and pro-inflammatory cytokines. The best model systems that allow us to understand how this virus suppresses the immune response are the best-known other beta coronaviruses, SARS-CoV and MERS-CoV. Both coronaviruses employ multiple strategies to interfere with the signaling that leads to type I IFN production and/or the downstream signaling of IFN receptors. SARS-CoV interferes with downstream signaling of RNA sensors directly or indirectly while MERS-CoV also utilizes some of these strategies with an additional mechanism such as repressive histone modification. Once type I IFN is secreted, these two viruses employ mechanisms that inhibit IFN signaling. At this time, based on the overall sequence similarity between SARS-CoV-2 and SARS-CoV or MERS-CoV one can speculate that SARS-CoV-2 utilizes similar strategies to modulate the host innate immune response; however, additional novel mechanisms apart from dampening the type I IFN response may be discovered (4).

Crunching the Numbers

Just by peeking at PubMed one can feel the overwhelming sense of urgency for scientists who are working around the clock to study the biology of SARS-CoV-2 and COVID-19 infection, analyze data, and crunch the numbers.

When the pandemic started in China, the demographics of most patients in Wuhan were adults with an average age ~56 years old, and ~50% of cases were in individuals aged between 15-20 and 50 years. Similar numbers were then reported by the Novel Coronavirus Pneumonia Emergency Response Epidemiology Team in China (4); mortality was high; the disease affected males more than females and was not seen in pediatric patients. But these numbers were skewed as they only analyzed the most severe SARS-CoV-2 pneumonia cases, in which the ratio of male-to-female patients as well as the mortality rate was high and there were no pediatric cases.

These numbers changed with the addition of patients who were asymptomatic or exhibited mild symptoms; it turned out that the ratio of male-to-female patients was lower, children or infants could contract the virus, and the mortality rate declined compared to previous reports (5).

One thing we know for sure that sadly will not change: this disease is attacking not only our most susceptible citizens, but entire countries and their economies as well.

We are in This Together

Scientists, physicians, nurses, and all our healthcare professionals are on the frontlines of this war. Helping them save lives is an honor and a duty.

Therefore, we at NanoString want to support the scientific community with our arsenal of research tools. As many of our current customers shift their work to addressing urgent needs around therapeutic development, vaccines and basic understanding of how the virus works, we are proud to join them in this effort, by making available to all researchers a specific COVID-19 Panel Plus beta product that can be spiked-in to our nCounter Gene Expression panels and/or Custom CodeSets. This Panel Plus beta spike-in is available free of charge so that we can be a partner and ally with you in tackling this pandemic.

For Research Use Only.  Not for use in Diagnostic Procedures.

References:

  1. Peng Zhou t al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature volume 579, pages270–273(2020)
  2. Geng Li et al. Coronavirus infections and immune responses. J Med Virol. 2020 Jan 25.
  3. Marjolein KikkertInnate Immune Evasion by Human Respiratory RNA Viruses. J Innate Immun. 2020 Jan; 12(1): 4–20
  4. Eakachai Prompetchara et al, Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic Asian Pac J Allergy Immunol. 2020 Mar;38(1):1-9.
  5. Chih-Cheng Laia et al. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths.

 Journal of Microbiology, Immunology and Infection. Available online 4 March 2020

Posted by Laura Tabellini