About That NeoCoV Study

#16,540

On more that a few occasions over the past decade I've suggested that researchers interested in getting into a field with a lot of future potential consider becoming a chiropterist; someone who studies bats. 

Over the past 16 years - in additional to SARS-CoV and more recently SARS-CoV-2 - we've looked repeatedly at Nipah, Hendra, MERS-CoV, several varieties of Bat Influenza (H17 & H18), lyssaviruses, and several hemorrhagic fevers - all linked to bats.

In 2017 researchers from EcoHealth Alliance published a letter in Nature (Host and viral traits predict zoonotic spillover from mammals) providing the first comprehensive analysis of viruses known to infect mammals.

From their website summary: 

The study shows that bats carry a significantly higher proportion of viruses able to infect people than any other group of mammals; and it identifies the species and geographic regions on the planet with the highest number of yet-to-be discovered, or ‘missing’, viruses likely to infect people. This work provides a new way to predict where and how we should work to identify and pre-empt the next potential viral pandemic before it emerges.

In January of 2019, a year before COVID emerged, we took a deep dive into the pandemic potential of bat viruses in Curr. Opinion Virology: Viruses In Bats & Potential Spillover To Animals And Humans. In the years prior to that, we looked at emerging bat coronaviruses repeatedly, including:

EID Journal: A New Bat-HKU2–like Coronavirus in Swine, China, 2017

Emerg. Microbes & Infect.: Novel Coronaviruses In Least Horseshoe Bats In Southwestern China

SARS-like WIV1-CoV poised for human emergence

But until COVID - the coronavirus of greatest concern (which emerged in the spring of 2012) was MERS-CoV - which is endemic in camels in parts of the Middle East, but is believed to have originated in bats.  

Since then, more than 2,500 human infections have been confirmed, and nearly 900 deaths (both likely significant undercounts). Unlike COVID, which has about a 1%-2% fatality rate, roughly 35% of known MERS patients have died. 

Surveillance and reporting of cases has dropped dramatically in the 2 years since COVID emerged (see EMRO Chart Below), potentially leaving us open to being hit again from left field.  

Late last week Chinese scientists published a report (not yet peer reviewed) on the pre-print server BioRxiv, on a cousin to the MERS-CoV virus (dubbed NeoCoV) found in South African bats which appears to use the ACE2 receptor to enter cells, which could conceivably make it easier to jump to humans. 

This is not a SARS-CoV-2 variant, nor is it an immediate threat to public health. 

Instead it is a reminder that SARS-COV-2 isn't the only coronavirus out there in the wild we have to worry about, and that the next coronavirus pandemic could be worse than COVID. 

First a link, and the abstract from the report, then I'll return with more.

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Qing Xiong,Lei Cao, Chengbao Ma, Chen Liu, Junyu Si, Peng Liu, Mengxue Gu, Chunli Wang, Lulu Shi, Fei Tong, Meiling Huang, Jing Li, Chufeng Zhao, Chao Shen, Yu Chen, Huabin Zhao, Ke Lan, Xiangxi Wang, Huan Yan

doi: https://doi.org/10.1101/2022.01.24.477490 

This article is a preprint and has not been certified by peer review [what does this mean?].

Preview PDF

Summary

Middle East Respiratory Syndrome coronavirus (MERS-CoV) and several bat coronaviruses employ Dipeptidyl peptidase-4 (DPP4) as their functional receptors1–4. However, the receptor for NeoCoV, the closest MERS-CoV relative yet discovered in bats, remains enigmatic5.

In this study, we unexpectedly found that NeoCoV and its close relative, PDF-2180-CoV, can efficiently use some types of bat Angiotensin-converting enzyme 2 (ACE2) and, less favorably, human ACE2 for entry. The two viruses use their spikes’ S1 subunit carboxyl-terminal domains (S1-CTD) for high-affinity and species-specific ACE2 binding. Cryo-electron microscopy analysis revealed a novel coronavirus-ACE2 binding interface and a protein-glycan interaction, distinct from other known ACE2-using viruses.

We identified a molecular determinant close to the viral binding interface that restricts human ACE2 from supporting NeoCoV infection, especially around residue Asp338. Conversely, NeoCoV efficiently infects human ACE2 expressing cells after a T510F mutation on the receptor-binding motif (RBM). Notably, the infection could not be cross-neutralized by antibodies targeting SARS-CoV-2 or MERS-CoV.

Our study demonstrates the first case of ACE2 usage in MERS-related viruses, shedding light on a potential bio-safety threat of the human emergence of an ACE2 using “MERS-CoV-2” with both high fatality and transmission rate.

For now, it appears that NeoCoV's ability to infect human cells remains poor, although the evolutionary process could remedy those deficits over time.  

Even if NeoCoV never achieves increased human infectivity, this report should remind us that there are plenty of pandemic contenders out there - most of which aren't even on our radar - that are quietly evolving and adapting, and which someday could emerge in a big way. 

While it may take years before the next pandemic emerges, it could also happen tomorrow. Another pandemic is considered inevitable (see PNAS Research: Intensity and Frequency of Extreme Novel Epidemics) - and we either prepare seriously for it now - or risk being caught flat footed and unprepared.

Again.