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NNadir

(33,368 posts)
Fri May 8, 2020, 08:27 PM May 2020

The Superimmunity of Bats, and the Molecular Biology of their Resistance to Coronaviruses.

The paper I'll discuss briefly in this post is this one: Selection of viral variants during persistent infection of insectivorous bat cells with Middle East respiratory syndrome coronavirus (Arinjay Banerjee, Sonu Subudhi, Noreen Rapin, Jocelyne Lew, Richa Jain, Darryl Falzarano & Vikram Misra, Scientific Reports, Scientific Reports volume 10, Article number: 7257 (2020)).

The article is open sourced.

An aside: If one is interested, Scientific Reports is an open access journal in the Nature family of journals, where one can read high quality primary scientific papers. One can put one's self on the mailing list; something that's well worth doing, particularly if one is trying to expand one's mind by reading papers on subjects one knows nothing about. I recommend it highly. They send you an email each time an issue is released, and one can quickly scroll through the topics. Sometimes journalists reporting on science muck it up badly. If one can, it is a good idea to go to the original papers to which journalists refer.

I was directed to this paper however, not by an email of the titles in Science Reports, but by a news item that came in a science news feed (Technology Networks) that I also get by email, and then went to the Science Reports paper above which good science journalists always link. I'll note a cool, if apocryphal, note in the news items on the stress on bats and the cross species transition of corona infections.

Anyway.

It appears that bats are continuously infected by corona viruses, and manage them intracellularly with a complex molecular machinery which causes them to mutate into less viable forms.

Some brief excerpts from the paper:

On rare occasions, viruses spill over from reservoir species to other animals, including humans1. Establishment of infection in the new host requires viruses to adapt to the efficient use of entry receptors and circumvent innate antiviral defense mechanisms that are unique to each host species2. The elaborate mechanisms underlying such changes that govern new virus-host dynamics are not well known. Bats are speculated to be reservoirs of several emerging viruses, including coronaviruses (CoVs) that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in humans, and porcine epidemic diarrhea (PED) and swine acute diarrhoea syndrome (SADS) in pigs3,4,5,6. Although bats harbor SARS- and MERS-like coronaviruses, overt signs of disease in bats that are naturally or experimentally infected are often undetectable7. In contrast, infections in spillover species, such as humans and pigs lead to diseases with high morbidity and mortality7,8,9,10,11,12,13.

MERS-CoV is an on-going concern as it causes periodic outbreaks in the Middle East with a mortality rate of about thirty-five percent14,15. Human-to-human transmission of the virus occurs through aerosol or close contact. Camels are the known reservoirs of MERS-CoV16,17 and bats are suspected to be the ancestral host18...


Some stuff from the meat of the text wherein they infected bat cells with the highly dangerous human MERS-CoV that had an outbreak early in this century, with a 35% human kill rate:


MERS-CoV ?ORF5 mutants persistently infect bat cells
The MERS-CoV isolate used in our experiments (EMC/2012) was derived from an infected human and was subsequently propagated in primate cells (see materials and methods). To determine if persistently infected bat cells had selected for mutant variants of MERS-CoV, we sequenced the genome of the virus from persistently infected bat cells that had been passaged 15 times, over 4 months. We detected point mutations in the virus polymerase, spike and matrix genes (Fig. 3a) but none of these mutations disrupted the coding sequences for these proteins (Table 1). However, we observed a 341 base pair deletion in ORF5. In addition, there was a frameshift mutation at the N-terminal end of the protein that introduced a stop codon at the 20th amino acid position (Fig. 3a and Table 1). In theory, the intact ORF5 coding sequence in the bat-adapted MERS-CoV strain would encode a putative 19 amino acid long protein...


Apparently there is a survival advantage for bats in keeping a low level weakened continuous infection since it primes their immune systems to deal with more deadly viruses:

...Viruses often exist as quasispecies, including virus stocks that are prepared in laboratories34. Coronaviruses have been detected in multiple bat species globally35 and wild-caught bats can be persistently infected with coronaviruses18,25. The co-evolution of CoVs and bats, and the advantage of long-term CoV infection, if any, have not been explored in bats. In this study, we observed ?ORF5 MERS-CoV as the dominant strain in persistently infected bat cells in two independent experiments. To identify if infection with ?ORF5 MERS-CoV confers a survival advantage upon bat cells, we determined if persistently infected bat cells were resistant to superinfection with W?+?virus. To differentiate between W+ and ?ORF5 MERS-CoV replication, we examined the levels of genomic (upE) RNA (present in both strains), and ORF5 transcripts, (detectable in W?+?MERS-CoV only). On re-infecting persistently infected bat cells with W?+?virus (MOI?=?1 TCID50/cell), we did not observe an increase in upE or ORF5 RNA levels in the superinfected cells, suggesting a lack of replication of W+ and ?ORF5 virus at 24 and 48 hpi (Fig. 5a,b). In contrast, we observed a significant increase in upE and ORF5 transcript levels at 24- and 48-hours post infection of naïve bat cells that were infected with an equal amount of W?+?MERS-CoV...


The paper is again, open sourced, and you can open it and look at all the cool graphics and see what you can get out of it.

The journalistic news apparently arose from a news release by the author's academic institution, The University of Saskatchewan.

Here is a news release similar to the Technology Networks news feed: Bat 'super immunity' may explain how bats carry coronaviruses, study finds

An interview with the authors suggests their speculation as to why the disease evolves virulent trans-species forms in bats:

"Instead of killing bat cells as the virus does with human cells, the MERS coronavirus enters a long-term relationship with the host, maintained by the bat's unique 'super' immune system," said Misra, corresponding author on the paper. "SARS-CoV-2 is thought to operate in the same way."

Misra says the team's work suggests that stresses on bats -- such as wet markets, other diseases, and possibly habitat loss -- may have a role in coronavirus spilling over to other species.

"When a bat experiences stress to their immune system, it disrupts this immune system-virus balance and allows the virus to multiply," he said.


I added the bold.

This seems clearly a speculation, but it is not necessarily nonsense.

One hopes that humanity is not inspired to drive insectivorous bats extinct. This will only lead to an increase in insect borne diseases, and in any case, we apparently have a lot to learn about virology and human disease by the study of these remarkable creatures.

Have a nice weekend at home. Stay safe.


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The Superimmunity of Bats, and the Molecular Biology of their Resistance to Coronaviruses. (Original Post) NNadir May 2020 OP
Thanks for sharing this, NNadir. littlemissmartypants May 2020 #1
Interesting. What little reading (mostly pop science) I've done in this area brought out ... eppur_se_muova May 2020 #2
I've been dragged, kicking and screaming, into studying genetics, at least by osmosis. NNadir May 2020 #3

eppur_se_muova

(36,227 posts)
2. Interesting. What little reading (mostly pop science) I've done in this area brought out ...
Sun May 10, 2020, 10:05 AM
May 2020

the point that from an evolutionary perspective, killing the host species is not a survival trait for viruses -- any more than destroying the environment that sustains life is a survival trait for humans (at least in the long term). The problem, of course, is that natural selection is extremely messy and inefficient, albeit very effective. Many host organisms (and their dependent species, maybe whole ecosystems) have to die before the virus finally goes extinct, which is obviously not optimal from the hosts' point of view. When they are gone, though, the virus is at a crisis point -- it must adapt or die out, and one adaptation the enables survival is to take a less virulent form. There's no planned, conscious effort, just the inescapable fact that strains that are least damaging to their hosts are most likely to survive in the long term, as a result of which humans are routinely infected with mild viruses that have adapted to do minimal harm while propagating. It sounds like bats have adapted to their viruses in a way that allows the viruses to adapt benignly to bats -- proving once again that all natural selection is interactive, and every species is part of the environment from the POV of other species, and even itself. Evolutionary biology seems to require a lot of thinking in terms of cause-and-effect loops and chains.

NNadir

(33,368 posts)
3. I've been dragged, kicking and screaming, into studying genetics, at least by osmosis.
Sun May 10, 2020, 12:41 PM
May 2020

I'm hardly an expert, but this paper is fascinating, inasmuch as it opens my mind to something about which I hadn't actually thought, which is that eukaryotic cells can edit viral nucleic acids to change them as much as viruses change eukaryotic nucleic acids.

Of course, the big surprise in the HUMAN Genome project - which led to the rise of automated sequencing - was how much of the human genome derives from the incorporation of viral DNA into the human being. In that sense, we are viruses in some way.

The supplemental data in this paper has quite an interesting sequence comparison between the sequences of the ORF5 in bats and human to which the paper refers. Figure S4 shows (if you blow up the Word file) the mutations between the various bat viral sequences as compared to the SARS-MER pathological human sequence. What I find interesting is the number of these mutations involving Asparagine (N), since I recently learned about the role that N-Glycans play in the "Glycan Shield" of viruses. Apparently the N-glycans are quite well represented in the SAR-CoV-2, O-glycans not so much. I think I wrote about that in this space.

I became aware this week of an upcoming clinical trial that is designed to interfere with glycan synthesis in Covid-19, a very interesting approach via a modified carbohydrate isostere. This kind of strategy has been effective against viruses using nucleotide and nucleoside isosteres, but I don't recall a sugar isostere used in this way.

One silver lining on the COVID-19 situation is that it inspires one to learn something about virology.

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