Enveloped viruses show greater cross-species transmission, according to new research

A study published in PNAS Microbiology found that enveloped viruses harbor greater cross-species transmissibility and are more likely to cause zoonotic infections than nonenveloped viruses. The research suggested that viral envelopes aid these pathogens in evading host immunity.

Study: Enveloped viruses show increased propensity to cross-species transmission and zoonosis. Image Credit: Kateryna Kon/Shutterstock


Zoonosis refers to the spread of infectious diseases between animals and humans (or between humans and animals). In the past few decades, the cross-species transmission of viruses from wild or domestic animals to humans (zoonoses) has led to major epidemics. Still, our understanding of this complex process remains limited.

Several well-known zoonoses include human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), Zika, Ebola, influenza, COVID, and mpox. Therefore, understanding and predicting virus emergence has become a scientific priority. Several zoonotic risk factors exist, including biodiversity elimination and species invasions, viral host variability, interaction frequency, life cycle characteristics of reservoir hosts, wildlife trade, and host closeness to humans.

Nevertheless, prior studies have revealed that three factors have been identified as contributing to the risk of zoonotic disease spread – viral genetic material – ribonucleic acid (RNA) viruses may be more susceptible than DNA viruses; replication site – viruses that replicate in the host cytoplasm rather than the nucleus may have an advantage; and genome size – smaller genomes may be more zoonotic.

The enveloped nature of viruses is a characteristic feature that distinguishes them from other organisms. Most zoonotic viruses that have caused human disease in the past were enveloped, such as – smallpox, mpox, coronaviruses, rabies, measles, and influenza.

A virus’s genome can provide information regarding host tropism and zoonotic propensity by evaluating characteristics like codon or dinucleotide usage biases and the degree to which these biases reflect those observed in the host-gene transcripts. The fundamental features of viruses remain unknown despite these advancements in understanding cross-species transmission and zoonosis.

The study

Using a database of over 12,000 mammalian virus–host interactions, the current work explored key virological properties that influence cross-species transmissibility and zoonotic propensity to understand better which viral characteristics predominantly determine zoonosis.

Here, the researchers examined a large VIRION database containing 5,149 viruses identified through metagenomic studies. This exploratory analysis utilized the Global Virome in One Network (VIRION) database. Overall, 5,149 viruses belonging to 36 families and 1,599 host species were analyzed from 20 orders, revealing 12,888 virus-host associations. 

Following this, the fundamental characteristics of the viruses were defined based on –their genetic material; single or double-stranded; segmented or non-segmented, replicating in the cytoplasm or nucleus, enveloped or nonenveloped, and the genome size. 

For each virus, the number of natural host species was identified and recorded, excluding humans, to reduce the possibility of bias. The mammalian viruses were then examined for their potential pathogenicity, i.e., their ability for zoonosis.

The findings

The results showed that the number of host species increased more rapidly for enveloped viruses than for non-enveloped viruses, being approximately twice as high for the former type. This difference was also discernible when the envelope factor was combined with the other viral characteristics. 

All other viral characteristics examined were either not significant or marginally significant. Enveloped viruses were more likely to undergo cross-species transmission than nonenveloped viruses. 

It was noted that enveloped viruses tend to have a higher proportion of zoonotic spread than non-enveloped viruses. Using binary logistic regression with N ≥5 sequence records, zoonotic propensity was estimated to increase 2.5-fold for enveloped viruses compared to non-enveloped viruses. Thus, enveloped viruses showed a higher propensity for zoonotic spillover than non-enveloped viruses.

Meanwhile, viruses replicating in the cytoplasm were found to be more likely (1.9 times) to be zoonotic than those replicating in the nucleus. Segmented viruses heightened the chances for zoonosis slightly more than non-segmented viruses. Further, viruses with smaller genomes had a greater probability of precipitating zoonotic infection. 

The lack of significant effects of these two features on cross-species transmission meant that their impact on zoonotic propensity could either be due to human-specific factors or, more likely, to biases within the human-infectious virus datasets.

This study also provided insights into how enveloped viruses might infect hosts. It was likely that envelope proteins were structurally less constraining than capsid proteins, allowing enveloped viruses to bind cellular receptors from different host species with greater flexibility, bind to a larger number of alternative receptors, or accommodate host-switch mutations without compromising other functions. 

Another possible mechanism is an apoptotic mimicry, in which viral particles are engulfed by host cells disguised as apoptotic bodies with defined membrane lipid conformations and get introduced into the host cells. 


The results revealed that enveloped viruses infect more host species and are more likely to be zoonotic than non-enveloped viruses. In contrast, other viral characteristics, such as genome composition, structure, size, and the viral replication compartment, are less significant. 

According to this study, viral envelopes did not significantly impact or even reduce the zoonotic risk contrary to the prior belief, and this may help in prioritizing outbreak prevention efforts. A viral envelope may facilitate cross-species transmission by facilitating structural flexibility of the receptor-binding proteins and allowing for overcoming the viral entry barriers.

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