We are our viral load

A very interesting paper in the July 10 issue of Cell caught our attention. Written by three immunologists and titled "Redefining Chronic Viral Infection", the paper discusses the 'virome', viruses that are a constant part of our 'metagenome', and their role in health and disease. The idea that the multitude of bacteria that colonize our bodies inside out, many of which are essential for our survival, should rightly be considered part of our own genome (hence, the idea that we can correctly consider our own DNA to be just one part of the metagenome that keeps us alive) is not new, and is discussed widely, as well as in our books, but the extension of this idea to the viral load that most of us carry for most of our lives has not yet been widely considered.

It's been estimated that a human being has 10 times as many bacterial cells on or in it, than it does of its own cells. And roughly 8% of our genome appears to be sequences that were incorporated from infecting viruses. The number of viral genomes occupying a human, if the metagenome data is correct, will be countless times more than the number of our own copies of our own genome.

Some viruses can cause chronic infection while retroviruses can infest our chromosomes, and the effects can range from severe disease and death to no apparent disease at all. The same viral load in a person with a compromised immune system can cause severe disease, while the immune system of a healthy person will keep infection at bay, suggesting that the immune system constantly battles these viruses, and does so for a lifetime. Interestingly, Virgin et al. argue that this constant surveillance by the immune system "may fundamentally alter the response of the host to new infections, vaccines, or neo-epitopes that emerge during immune selection of viral variants."

It's worth quoting the paper at length here, not for the details per se, but with respect to the effects that living with the virome has on our immune system and our subsequent susceptibility to non-viral infection.

New evidence in animals indicates that chronic virus infection can fundamentally alter innate immunity to nonviral pathogens. IFN-γ expression during herpesvirus latency can symbiotically protect the host from infection by the bacteria Listeria monocytogenes and Yersinia pestis, the causative agent of plague (Barton et al., 2007). Thus, the détente developed between herpesviruses and their hosts over tens of millions of years of coevolution may offer benefits to the host. This protection may come at the cost of enhanced autoimmunity (Peacock et al., 2003 J.W. Peacock, S.F. Elsawa, C.C. Petty, W.F. Hickey and K.L. Bost, Exacerbation of experimental autoimmune encephalomyelitis in rodents infected with murine gammaherpesvirus-68, Eur. J. Immunol. 33 (2003), pp. 1849–1858. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)Peacock et al., 2003). In addition, the prolonged presence of Sendai virus viral nucleic acids in mice is associated with IL-13-dependent NKT cell activation that can, in turn, contribute to reactive airway disease (Kim et al., 2008). Further, abnormal interferon secretion by plasmacytoid dendritic cells predisposes to secondary infection during chronic LCMV infection (Zuniga et al., 2008). It has been proposed that chronic activation of innate immune responses contributes to immune dysfunction in HIV and SIV infection (Mandl et al., 2008). Together, these examples provide a convincing case for a significant immunologic imprint of chronic viral infection on the nature of innate immune responses. Much remains to be done to define the balance between immunologic benefit and immunologic harm for chronic infection of humans by viruses that seldom cause overt disease.

Like much else that we discuss in this blog, new discoveries regularly add to, but rarely if ever subtract from the complexity of factors that contribute to biological traits. This is relevant, as we have many times said, to the use and interpretation of genetic epidemiological approaches, such as GWAS (trying to associate specific genetic variants in individuals to their traits). (Indeed, this paper points out that using the sterile, virus free laboratory mouse as a model for disease may be futile and irrelevant to the actual context within which humans develop disease.) It is worth repeating that while this complexity makes prediction from genotype to phenotype problematic in most instances (with some very clear-cut truly genetic traits, including diseases, excepted), it does not suggest that genes are irrelevant.

It is just that with the complexity of genotypic, microbial, and other environmental factors, along with a hefty dose of chance, there are many ways to arrive at a given trait, normal or disease. That is the stiff lesson Nature is teaching, if we care to listen.

So, this is yet another example of how further knowledge makes the story of health and disease more complex, not less so, and undoubtedly more interesting if less aligned with a natural yearning for simplicity and the hopes that, in regard to disease, simple cures will be just around the scientific corner. And, seeing the interaction of the organism with the virome as essentially an example of cooperation rather than a battle, adds an important new piece to the view of the organism as an ecosystem that relies for its survival on cooperation between its intrinsic and extrinsic parts.