Welcome back to the dark side of the moon! Some time ago, we introduced our readers to the human virome, that is the largely undiscovered, quite obscure and gloomy part of the human microbiome that is made up of viruses . Viruses are extremely small and complex inanimate, infectious agents, of unknown origin, that are difficult to study and responsible for many severe diseases. Painfully, we have all seen this firsthand this during the the COVID-19 pandemic.
Surprisingly, molecular studies  have revealed that even healthy humans are associated with a huge amount of highly diverse commensal (non-pathogenic) viruses, and maybe even some symbiotic viruses. While most research on the human virome has been performed using the intestinal tract , some studies have also addressed the human skin, raising the question of whether the human skin virome might become a novel target for skincare products .
In a landmark study , Kumata and colleagues created a tissue-level atlas of the healthy human virome by investigating the presence and association of viral RNA sequences relative to gene expression in 51 somatic tissues (including skin) of 547 healthy (!) individuals. The researchers proved the presence of 39 different virus types and could show a couple of associations that they expected to see, such as the expression of interferon-stimulated genes and the presence of Hepatitis C virus in the liver.
However, the researchers also reported several unexpected associations, such as the expression of digestive genes with the presence of human herpes virus 7 in stomach tissue. Moreover, local tissue infections were often associated with a systemic immune response in the blood. Unfortunately, they did not report any special observations for skin. Nevertheless, they concluded that the human virome potentially influences human health, and not only disease.
While such studies suggest an influence of viral infections on the tissue-specific and systemic immune status of healthy humans, investigations of patients with immune defects can help better understand the effect of the immune system on the human virome.
Tirosh and colleagues  analyzed the skin virome of patients suffering from ‘Dedicator of cytokinesis 8 (DOCK8)’ deficiency, a very rare human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility.
DOCK8 encodes a nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton, which is critical for migration of lymphocytes through collagen-dense tissues. In plain words, the patients suffer from reduced immune surveillance in tissues such as skin.
Using a deep metagenomic approach, the authors could prove a markedly higher viral representation and diversity in skin samples from the DOCK8-deficient patients compared to healthy controls. In particular, they identified hundreds of novel human papilloma viruses (HPVs) representing ’microbial dark matter’, an expression used for the vast majority of microorganisms that still await detection and description.
HPVs are enveloped, double-stranded DNA viruses that infect skin epithelial and mucous membrane cells and cause tumour-like structures, ranging from benign warts to cervical cancer. Notably, in the DOCK8-deficient samples, a higher diversity of HPV viruses was also detected without the presence of cutaneous warts.
These studies show that the human immune system is a crucial factor in controlling the amount and diversity of viruses infecting human cells, which vice versa is influenced by the structure and functionality of the human virome.
In contrast to diseased skin, the virome of healthy human skin appears to be dominated by bacteriophages (or ‘phages’) – viruses that use bacteria as hosts [5-7]. ‘Lytic phages’ immediately replicate inside and lyse (kill) their hosts, thereby creating a basis for the so-called phage therapy. Here, phages act as an alternative to antibiotics to treat infections caused by (often multi-resistant) bacteria. In contrast, ‘temperate phages’ integrate themselves into the host genome and, at least for some time, replicate together with their host cell. Bacteria carrying inserted phages are referred to as lysogenic. Insertion of phage DNA can equip a bacterium with novel features, such as the capability to produce toxins, and confer resistance to infection by other phages.
In summary, phages can positively and negatively interact with bacteria and thereby shape the structure and function of complex microbial communities, including the human microbiome. More information on the potential of phages to modulate human microbiome and human immunity (indirectly – for example via microbiome modulation – or even by direct interaction with components of the human immune system) was recently summarized by Federici et al. (2021) .
Little is known about phage–bacterium–interactions on skin. Caudovirales – double-stranded DNA phages carrying a characteristic tail structure – appear to play a dominant role here, comprising species that are directed against the most prevalent bacteria on skin, such as Propionibacterium (Cutibacterium), Streptococcus and Staphylococcus. Interactions seem to be site-specific. In sebaceous sites, an observed negative Propionibacterium–phage correlation suggests antagonism, that is phages killing bacteria, while in moist and dry sites, a positive correlation could imply the presence of temperate phages [6, 8], protecting the bacteria from lysis.
Lytic phages directed against bacteria such as Cutibacterium acnes might be useful agents to treat skin infections, such as acne . Notably, treatment of skin infections or infections caused by skin bacteria such as staphylococci have a long history in phage therapy . Phage therapy is particularly suited for topical applications outside the human body, where the phage proteins do not trigger the production of phage inactivating antibodies, as they do when they are present in human blood.
Clearly, the importance of the (skin) virome for human health and well-being has just started to unfold. Although the functional details are not clear yet, it appears likely that the human skin virome interacts closely with the human immune system and the pro- and eukaryotic components of the human microbiome. In addition, it might serve as a reservoir for novel therapeutic agents (phages) to treat skin infections.
Due to the lack of fundamental knowledge around the functional implications, cosmetics agents aiming to achieve ‘beneficial’ modulation of the human skin virome are currently just wishful thinkers. However, even the few data available today suggest that the human skin virome plays an important role for skin homeostasis and skin health. This clearly argues against the development of undirected ’antiviral’ skin care products, which may grow in popularity as a result of the COVID-19 crisis.
Key References https://thesecretlifeofskin.com/introducing-virome https://www.cosmeticsandtoiletries.com/research/biology/Could-the-Human-Virome-be-the-Next-Skin-Care-Target–570785001.html Kumata et al. (2020). A tissue level atlas of the healthy human virome. BMC Biology (2020) 18:55. https://doi.org/10.1186/s12915-020-00785-5 Tirosh et al. (2018). Expanded skin virome in DOCK8-deficient patients Nature Medicine 24:1815–1821. https://doi.org/10.1038/s41591-018-0211-7 Oh et al. (2014). Biogeography and individuality shape function in the human skin
metagenome. Nature 514, 59–64. https://doi.org/10.1038/nature13786 Hannigan et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. mBio 6, e01578-15 (2015). https://doi.org/10.1128/mBio.01578-15 Oh et al. (2016). Temporal stability of the human skin microbiome. Cell 165: 854–866. https://doi.org/10.1016/j.cell.2016.04.008 Federici et al. (2021). Phages and their potential to modulate the microbiome and immunity. Cellular & Molecular Immunology 18: 889–904. https://doi.org/10.1038/s41423-020-00532-4 Marinelli et al. (2012). Propionibacterium acnes bacteriophages display limited genetic diversity and broad killing activity against bacterial skin isolates. mBio 3: e00279–12 (2012). https://doi.org/10.1128/mBio.00279-12 Sulakvelidze et al. (2001). Bacteriophage therapy. Antimicrobial Agents Chemother. 45, 649–659. https://doi.org/10.1128/AAC.45.3.649-659.2001