6 May Receptor, complement self-amplifying RNA and waste water

Wed, 05/06/2020 - 12:27

Dear colleagues,

 

Today, in between my preparation for the FWO session,  I will present you some papers about insights on susceptibility and pathogenesis in cells and tissues.  Also an experimental vaccine, based on self-amplifying RNA and a plea to incorporate waste water surveillance in exit strategies.

 

  1. The paper by Ziegler et al in Cell investigates ACE2 expression and accompanying TMPRSS2 (the main human  protease responsible for activation of the spike). It uses mRNA expression as a tool.
  • ACE2  primarily restricted to type II pneumocytes in the lung, absorptive enterocytes within the small intestine  and goblet secretory cells of the nasal mucosa;
  • Co-expression with TMPRSS2 in a small subset of these epithelial cells
  • Increased expression  of ACE2 during HIV/TB and Influenza infection
  • Increased expression of ACE2 driven by type I interferon in epithelial cells (but not in immunocytes).

This upregulation of ACE2 is in the first place a defense mechanism against lung damage by the renin-angiotensin axis (because it breaks down the pro-inflammatory angiotensin II).

Clearly, these findings indicate that SARS-CoV-2 may take advantage of type 1 IFN (and of other infections) to increase susceptibility.  This is similar to another Coronavirus (OC43) where IFN upregulates the receptor IFTIM-2 and -3.

There are 2 caveats with these findings:

  • The authors did not confirm the RNA data with evidence of ACE2 cell surface expression
  • It is possible that the function of TMPRSS2 can be substituted by other human proteases (e.g. furin), which would give a different picture.

 

  1. The paper by Sungnak et al in Nature Medicine takes a similar approach and finds a wide distribution of ACE2 and TMPRSS2, with co-expression in nose, cornea, bronchi, ling parenchyma, esophagus, ileum, colon and gallbladder. This paper attracts most attention to the ciliary and secretory cells of the nasal cavity, because the co-expression is high, there is a correlation with nasal expression of receptors and R0 across coronaviruses and there is also an association with expression of antiviral innate immune factors especially in the nasal goblet cells.     Obviously, each of these arguments can be criticized and the authors admit that the “nasolacrimal” as well as gastro-intestinal cells could also have a role.  Moreover, they also question if TMPRSS2 is the only important protease, as other proteases (e.g. cathepsin B) are more widely expressed in ACE2(+) cells.  This paper is very attractive, as it provides a nice didactic figure

 

  1. The comment by Risitano et al in Nature Reviews Immunology argues that activation of C3, the central regulator of complement and inflammation, could be a decisive factor in acute respiratory distress ARDS, as has been shown in a C3 knock-out mouse model of SARS-CoV-1 infection.  They argue for the use of anti-C3 (potentially in combination with anti-IL6) to prevent or treat ARDS, although they admit that there are at present no clear predictors and it remains true that complement is one of the key defense mechanisms against microbides.  So, for now, it is just another attractive hypothesis, nicely illustrated in the figure.  

 

  1. A non-peer reviewed paper by McKay in bioRxiv on a vaccination strategy with so called “self-amplifying RNA”.  The principle is to use the genome of a positive strand RNA virus (in this case VEE Venezuelan Equine Encephalitis) and to replace the VEE envelop by the SARS-CoV-2 spike (stabilized in a pre-fusion form). This RNA is formulated in a lipid nanoparticle (to protect the RNA from degradation) and injected intramuscularly.  This RNA will amplify during a few rounds and elicit immune responses. Results in Fig 1 p 4  and Fig 2 p.6 show nice antibody and T cell responses.  The antibodies are neutralizing in vitro, comparable to convalescent plasma from recovered SARS-CoV-2 patients.   

Clearly, this is still an experimental approach, in between the mRNA (Moderna and Curevac) and the viral Adeno vector (Oxford-Astra Zenica and Janssen) approach.  Obviously, the latter approaches are more advanced, as they are already in human trials.  

 

  1. Importance of waste water surveillance in exit: brief statement by Rajeev Venkaya, president of  Global Vaccine Business Unit at Takeda Pharmaceuticals. The presence of the COVID-19 virus in wastewater hasn’t received much attention, but it’s a big deal. Here’s why: as we relax restrictions and reopen communities, we won’t have a good way to monitor for the return of virus transmission until we have universal just-in-time testing. Hospital admissions could trail the increase in transmission by weeks. Enter wastewater surveillance. We’ve shown this can be done with the poliovirus, which causes paralysis in 1 out of 200 infected children but is otherwise transmitted silently. By the time a symptomatic child presents, we know that many more have been infected. Monitoring for poliovirus in wastewater has been used by GPEI to intervene early in a polio outbreak. The parallels with COVID-19 are clear. We can use wastewater surveillance to monitor the impact of removing or reinstating restrictions, helping us to fine-tune our hashtag#flattenthecurve measures and minimize societal and economic disruption. It comes at an opportune time as we begin to reopen our cities, and well in advance of the Fall when we may experience a second wave. If we think of the community as a patient, this could be our thermometer.

Best wishes,

 

Guido