Introducing the human virome – Illuminating the dark side of the moon

For a long time, microorganisms had a bad reputation – they were merely seen as infectious or putrefactive agents. Over the last few decades this attitude towards bacteria, in particular, has changed. Many of the bacteria associated with the human body, including the skin, are now regarded as symbionts with pivotal functions for health and well-being, such as immune stimulation or defense against pathogens. For viruses, however, their reputation remains unchanged.

For most people, viruses are a continued source of concern and fear – particularly in times like these, when the Covid-19 pandemic keeps the whole world on tenterhooks. And yet, a novel discovery of the existence of a human ‘virome’ is challenging our long-held ideas. This article will review the key characteristics of viruses, and explore the emerging field of the human ‘virome’.

What are viruses?

For all intents and purposes, viruses are thought of as ‘dead’ microbes. In actuality, they fill the space between living and non-living; they cannot replicate in isolation but, in host cells they are capable of, not only replicating, but also causing behavioral changes.

So, what are they made of? They consist of a core made up of genetic material, namely nucleic acids (DNA or RNA), enclosed in a shell of proteins (non-enveloped viruses) – sometimes with an additional lipid membrane (enveloped viruses).

Viruses are missing the characteristics we associate with the definition of life, such as a cellular structure, metabolism, active movements, growth, development, irritability, and so on. They can only reproduce with the help of a host cell and its biochemical machinery, which they capture and re-program for virus production [1]. That means, viruses are obligate parasites. In fact, viruses infect all kinds of life. Indeed, the hosts they use for reproduction can be animals, plants and algae, but can also be other microbes – such as fungi, protozoa, bacteria or archaea. Recently, even viruses infecting other viruses were described [2]! Another way of thinking about viruses is as biological malware, infecting and spreading via other operating systems.

Interestingly, the evolutionary origin of viruses is not clear. While all cellular life forms probably originate from a single common ancestor, different hypotheses for viruses are discussed. It is thought that they might stem from the very early, pre-cellular, RNA-stage of life, originate from extremely simplified prokaryotic cells, or represent self-replicating nucleic acids that somehow escaped from prokaryotic or eukaryotic cells [1].

Linguistically, “virus” is Latin for “slimy liquid” or “poison”, illustrating that the physical nature of these biological entities was long unknown [3].

Why are viruses less well understood than bacteria?

Size matters

Usually being sized between 10 and several hundred nanometers in length, virus particles (virions) are approximately 1-2 orders of magnitude smaller than bacteria and 2-3 orders of magnitude smaller than eukaryotic cells. Consequently, they can neither be seen with the naked eye nor with a light microscope, but only with an electron microscope, which was developed only in the early 1930s. In contrast, Antoni van Leeuwenhoek discovered bacteria in 1676 when he was able to see them under a single-lensed microscope. Whoever has worked with an electron microscope knows that using this tool is not an easy task.

In addition to size, other factors complicate the detection, quantification, and identification of viruses. As such, relatively little is known about them as components of the human (skin) microbiome.

Host cell reliance

Infectious (“active” or “living”) viruses can only be detected and quantified by means of cultivating them together with their host cells and inspecting these for signs of cell damage, i.e. the resulting effect of virus proliferation.

As virus cultivation is difficult, molecular methods such as (quantitative) PCR and high throughput sequencing play a much more important role than in bacteriology or mycology (the studies of bacteria and fungi, respectively). However, simple detection of viral DNA or RNA does not mean that the detected viruses were still infectious, i.e. biologically active.

Heterogeneity

Moreover, as they probably don´t share a universal ancestor, viruses are genetically extremely heterogeneous. This is despite all prokaryotic and eukaryotic organisms sharing common genes, such as ribosomal rRNA genes – which greatly facilitate simultaneous detection of all major groups by PCR. Hence, for each group of viruses, specific assays are needed.

Host cell integration

Finally, some viruses integrate themselves into the DNA of their host, becoming an integral part of its genome, from which they can escape again. However, sometimes they get ‘stuck’ and become an everlasting part of the host´s genome. It has even been estimated that as much as 8% of the human genome is of viral origin [4].

Is there a solution? Well, particular meta-technologies have proven very valuable tools for the analyses of viral communities. Such technologies include metagenomic and/or metatranscriptomic analyses, i.e. analyses addressing the total genome (genetic content) or transcriptome (RNA content) of a biological sample or complex community.

Why do we fear viruses?

The fear of viruses stems from the fact that viruses are the cause of the most dangerous infectious diseases on Earth, for which – in the majority of cases – no cure is available.

Based on their pathogenic potential, microorganisms are grouped into four risk groups, from non-pathogenic to highly pathogenic.

Unsurprisingly, the group with the highest pathogenic potential (Risk Group 4) includes only viruses – such as the Ebola, Marburg, and Lassa viruses, which all cause different types of hemorrhagic fever.

Although the AIDS pandemic in 1980 led to a plethora of research to focus in this field, the number of antiviral drugs developed is still considerably lower than the number of antibiotics or antifungal actives.

Antiviral targets are hard to find because viruses use their host´s biochemical machinery for reproduction, leaving few targets to tackle without also harming the host itself. Therefore, prevention methods, such as vaccinations, are the best strategy against viral infections. A prime case study of this is smallpox; global vaccination campaigns have successfully eradicated this virus and the corresponding disease from the environment [5].

What is the human virome?

In summary, viruses are extremely small and complex infectious agents, of unknown origin, that are difficult to study and responsible for many nasty diseases. It, therefore, came as a big surprise when particular molecular studies unraveled the fact that healthy humans are associated with a huge diversity of viruses, collectively referred to as the “Human Virome” [3].

As with our commensal bacteria, it is believed that this viral community is of great importance for human health and well-being. However, any details are far from being understood. (This is frequently said in the context of the human microbiome, even though knowledge is dramatically increasing; however, here it is really true!). As usually is the case in research around the human microbiome, the impulses in the field are coming from the intestinal tract.

At the moment, human virome research is at the stage of molecularly cataloging the viral community composition in different human organs and tissues, including the skin, and searching for associations with different health and disease conditions [3,6]. Interpretation of any results is difficult, as the current sequence databases do not adequately reflect the diversity of eukaryotic viruses (viruses infecting eukaryotes such as humans/animals, plants, fungi etc., estimated diversity of 100 million different species) and prokaryotic viruses (viruses infecting bacteria and archaea, estimated diversity of 10 trillion (!!) different species). In addition, analysis protocols and bioinformatics tools vary greatly among different laboratories [3].

The virome of the gut

One gram of human stool has been shown to contain between ~ 10⁸ to 10⁹ virus-like particles – mostly bacteriophages, i.e. bacteria-infecting viruses, but also eukaryotic viruses. Like the human bacteriome, the structure of the human virome appears to be highly individual, site- and tissue-specific and to change over time. In addition, changes appear to be associated with different disease conditions, such as cancer, type 1 diabetes and inflammatory bowel disease (IBD), although functional correlations are unclear [3, and studies cited therein].

Astonishingly, enteric (intestinal) viruses or viral ligands were shown to contribute to immune and gut health of mice, signifying a beneficial purpose for some of our human viruses [7]. Moreover, even direct trans-kingdom interactions between bacteriophages and human immune cells were observed [8]. It is tempting to speculate that commensal viruses might protect their host from pathogenic viruses by stimulating antiviral immunity.

Many mutual interactions between viruses and their surrounding prokaryotic and/or eukaryotic microbiomes might also influence a host’s health or disease status. Perhaps some microbiome functionalities originally attributed to bacteria might actually be performed by viruses? Fecal microbiota transplantation – one of the few examples with strong evidence that microbiome-targeted therapies can really work – performed with filtered feces (containing no bacteria or other cellular microorganisms anymore) showed the same efficacy in treating Clostridium difficile patients than unfiltered fecal material, potentially implying the presence of a non-cellular commensal entity [9].

What about the skin virome?

Compared to the human intestinal tract, much less in known about the structure and potential functionality of the human skin virome. Sooner or later, the concepts being developed and tested for the gut will also be applied to skin.

There are a few studies that already exist on the skin virome, helping to answer the raised question, whether the human skin virome might also be a target for skin care products [10]. But that is for another day…

Despite (or because of?) all the open questions in the field, human virome research is a very fascinating topic. So, let´s meet again at the dark side of the moon.

Hear from more of our experts in the Views from section on the Content Hub and follow us on Instagram to receive the latest updates.

Key References