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Enveloped viruses show increased propensity to cross-species transmission and zoonosis

Ana Valero-Rello, Rafael Sanjuán

Preprint posted on 29 July 2022 https://www.biorxiv.org/content/10.1101/2022.07.29.501861v1

What helps certain viruses ‘jump’ to new host species? Bioinformatic analyses reveal that their packaging material i.e. membranes, may be critical

Selected by Angika Basant

 

Are there fundamental features of a virus that make it more likely to infect multiple hosts, and even make a zoonotic ‘leap’ into humans?

In studies so far, zoonotic risk has been linked to three main factors: viral genetic material (RNA viruses are suggested to be more prone than DNA viruses), site of replication (viruses replicating in the host cytoplasm instead of the nucleus may have an advantage) and genome size (viruses with smaller genomes may be more zoonotic).

However, viruses have another characterising feature. The surface of a virus can be enveloped, i.e. have a membranous coat (which can be destroyed by soap) or they can be enclosed by a fairly rigid protein shell. Curiously, most zoonotic viruses that have impacted human life are enveloped, for example smallpox and monkeypox, coronaviruses, and viruses that cause rabies, measles and flu.

Previous analyses into zoonotic risk were performed on a limited dataset of the mammalian virosphere encompassing only a few hundred viruses and focused on those causing human disease. In this preprint, the authors analyse a large VIRION database comprising 5149 viruses identified through metagenomic studies (i.e. viral genetic material from environmental samples).

 

[Figure from Valero-Rello and Sanjuán et al., 2022 made available under the CC-BY-NC-ND 4.0 license.

 

The authors analysed the number of mammalian hosts a virus could infect as function of the following variables: genome size, genome composition (RNA or DNA, single stranded or double stranded, segmented or unsegmented), nuclear or cytosolic location of virus replication, and presence of a viral envelope.

They first looked at the probability of a virus infecting multiple non-human mammalian hosts. They found that this cross-species transmissibility was significantly linked with the presence of a viral envelope, while the other factors had little impact (Figure, top panel).

When the specific scenario of zoonosis was analysed, that is by focusing on human host infection in the analyses, it also strikingly showed a strong impact of the viral envelope (Figure, bottom panel). They find a 2.5-fold increase in likelihood of zoonosis in enveloped viruses compared to non-enveloped ones, which constitutes a novel finding.

Interestingly, the analyses of zoonotic probability also brought out other factors that have been previously reported and may play a role in successful human infection. Viruses that undergo cytoplasmic replication were found to be 1.9 times more likely to be zoonotic, and viruses with smaller genomes and segmented genomes may also have a slight advantage.

What I like about this preprint:

The message of this preprint is clear and simple, and the finding is likely very important. What a virus can do is typically ascribed to its genome or its proteins, particularly those on the surface. The supposedly delicate membrane enveloping the virus may have not received its due attention. It will be exciting to see what the mechanistic basis of this analysis turns out to be.

Questions for the authors:

Some clarifications on the analysis:

  1. In Figure 2a: are all these viruses non-zoonotic or were the human hosts simply not counted in the number of hosts infected?
  2. How do you separate a mixed effect of variables? For example, have you compared a subset of enveloped vs non-enveloped viruses while keeping other variables the same?
  3. Figure 2a shows a trend opposite to what is stated in the text – ds genomes have a marginally higher probability for multi-host infection?

Some questions about the dataset:

  1. How much structural information is available on the viruses in the VIRION dataset? Would it be possible that some of the viruses in the non-enveloped category do have membranes in their outer surface?
  2. Would it be possible to test for other features of a virus life cycle and their­­ correlation to zoonosis, for example the length of viral replication cycles and whether they have lytic or non-lytic modes of spread?

 

Posted on: 29 August 2022 , updated on: 30 August 2022

doi: https://doi.org/10.1242/prelights.32604

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Author's response

Rafael Sanjuan shared

Hi Angika,

Thanks a lot for picking our preprint. Your summary reads really well. And the PreLight initiative is the kind of thing the community needs, I think.

Please find below short answers to your questions:

1. In Figure 2a: are all these viruses non-zoonotic or were the human hosts simply not counted in the number of hosts infected?

Human hosts were simply not counted in this analysis.

2. How do you separate a mixed effect of variables? For example, have you compared a subset of enveloped vs non-enveloped viruses while keeping other variables the same?

We did not systematically include interaction terms in our analysis because the number of combinations would be too high, severely reducing our power to detect this kind of effects. However, we checked that the envelope effect applied to both DNA and RNA viruses and was not driven by a specific viral family, as shown in Figs 3, S1 and S2.

3. Figure 2a shows a trend opposite to what is stated in the text – ds genomes have a marginally higher probability for multi-host infection?

You are right. This sentence is confusing. The effect detected by the regression analysis was a slight increase in multi-host probability for ds viruses. However, a simple chi-square test (i.e. ignoring all other factors) would give the opposite effect (slight increase for ss viruses). Hence, I would conclude that the ss/ds feature does not have any obvious effect on multi-host probability. Thanks for pointing this out. We will amend this in subsequent versions of the article.

Some questions about the dataset:

4. How much structural information is available on the viruses in the VIRION dataset? Would it be possible that some of the viruses in the non-enveloped category do have membranes in their outer surface?

The VIRION database does not collect this type of information. The enveloped/non-enveloped status of a virus is strongly (I would say strictly) conserved within families. Therefore, the imputation of this feature for newly discovered viruses that are well placed within a given family is highly reliable. This said, recent work has shown that some groups of non-enveloped viruses can sometimes use envelopes (for instance, enteroviruses). They do so because they can exploit certain vesicle production pathways for transmission. But they are still essentially non-enveloped viruses, since they have a rigid capsid and their receptor-binding protein (RBD) is part of that capsid, as opposed to the RBD of enveloped viruses, which is typically a globular transmembrane protein inserted in the envelope.

5. Would it be possible to test for other features of a virus life cycle and their correlation to zoonosis, for example the length of viral replication cycles and whether they have lytic or non-lytic modes of spread?

Other features of the viral infection cycle are not so well preserved within families, and hence are undetermined for newly discovered viruses. For instance, some viruses enter the cell directly through the plasma membrane, whereas others use endosomes. We initially considered this trait, but later discarded it since there are several examples in which the entry mode varies between closely related viruses (for instance, between different SARS-CoV-2 variants).

As a comment to our work, I would say that understanding what makes a virus more likely to cross the species barrier is a difficult but important challenge. There are many factors involved, and our lab focuses on some virological aspects of this process. Clearly, more experimental and mechanistic work is needed to identify potentially zoonotic viruses. This preprint is a first step in a new project we have just initiated, in which we plan to use a combination of computational and experimental virology to investigate viral emergence risks.

Best,

Rafa

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