Immunomodulation and infection: back to the future

“Infectious disease is one of the few genuine adventures left in the world. The dragons are all dead and the lance grows rusty in the chimney corner … About the only sporting proposition that remains unimpaired by the relentless domestication of a once free-living human species is the war against those ferocious little fellow creatures, which lurk in dark corners and stalk us in the bodies of rats, mice and all kinds of domestic animals; which fly and crawl with the insects, and waylay us in our food and drink and even in our love.”

– Hans Zinsser. Rats, Lice and History. (1935)

(cited in [1])

For thousands of years, men and infectious agents have lived in close contact, and the scales have often tipped in favor of the minute organisms. Plague, cholera, leprosy and smallpox have, up to the last century, severely impacted the world. Improved knowledge of our microscopic enemies and specific therapeutics have raised the hopes that we might “close the chapter of infectious diseases”. However, the genome of infectious agents adapts rapidly, which permits a better answer to the environment and the therapeutic threat. In addition, we are far from having an exhaustive knowledge of the microscopic world. In the last 30 years, ‘new’ agents have been identified: HIV, Legionella, Campylobacter, prions, SARS coronavirus and so on. Approximately 1420 infectious agents are recognized as responsible for human diseases [2] and the list will likely grow in the forthcoming years. For instance, a statistical model has estimated between 38 and 562 virus species yet to be discovered, and from ten to 40 new species could be discovered before 2020 [3]. Furthermore, various chronic diseases, hitherto regarded as noninfectious, have been recognized (and treated) as new infectious diseases (Helicobacter pylori and duodenal ulcer, Tropheryma whippleiand Whipple’s disease), and the list is also expanding with cancer, Alzheimer’s disease [4], and others. The emergence of zoonoses (bird flu and hepatitis E), the increase in the number of immunocompromised patients and the spectre of antimicrobial resistance, heralds the great return of infectious diseases. Which cards can we draw from our sleeves? Vaccination, when available, is undoubtedly an effective means of preventing, controlling and even eradicating, infectious diseases, but not all diseases can be prevented in this way. New antimicrobial agents are in the pipeline – but owing to the adaptability of microbes, intra- and inter-species exchanges [5] – this research remains an endless run. For centuries, the survival of mankind has relied on an intrinsic defense system, the immune system, whose complexity has not been totally established. It is just a little more than a century ago that Elie Metchnikoff discovered the phagocytes and that George Bernard Shaw suggested that to ‘stimulate the phagocyte’ is to cure all kinds of diseases. Phagocytes and other immune players have become new targets in the fight against infections. In the 1970s, the aim was to follow Shaw and search for anti-infective weapons designed to boost the immune system. With a more subtle approach to the role of the immune system in health and diseases, it has appeared that an excessive stimulation of the immune components could result in deleterious consequences for the host. Immunomodulation has now come to the front stage as a major tactic in anti-infective strategy. This special issue of Expert Review of Anti-infective Therapy intends to focus on immunomodulation and infection, and explore some modern aspects of immunomodulatory therapeutics.

Several reviews focus on the present state of immunomodulatory strategies to prevent infections. Futata et al.cast a glance at neonatal specific immune deficits and explore recent advances in the emerging field of immunotherapies to improve neonatal immune functions and antimicrobial defenses [6]. Hassan et al. review the importance of miRNAs in controlling gene expression and various aspects of immunity and inflammation, and present how miRNA may act as immunomodulators in chronic inflammatory diseases, including cystic fibrosis [7]. Torres et al. highlight the complexity of the GI tract [8]. They describe the regulatory mechanisms controlling host immune homeostasis particularly regulatory CD4⁺ T cells, and summarize recent data on the interplay between host factors and normal commensal flora in the maintenance of immunomodulation, and the disruption of this balance by bacterial enteric pathogens. Giamarellos-Bourboulis and Raftogiannis review the potential benefit of immunotherapies in severe infections [9]. Bourinbaiar et al. report the earliest recorded reference related to immunotherapy in TB and discuss the clinical experience from modern trials in this context [10]. I have presented how antimicrobial drugs can modulate the host immune response, focusing on two aspects, immune (toxic or immunotoxic) adverse events and direct modulation of immune functions [11,12]. Potential clinical relevance has been demonstrated, particularly in the case of cyclines, macrolides, antimalarials, and new avenues are in the limelight.

Some stimulating perspectives have also been presented by Boettler et al.[13] and Wisniewski and Goñi [14]. Boettler et al. suggest that the reduction of immune activation through a HIV-specific regulatory T-cell vaccine might thwart early viral replication and thus virus-specific immune activation [13]. Facing the ongoing epidemics of chronic wasting disease, a potential zoonose, Wisniewski and Goñi [14] analyze whether immunomodulation may play a role in the control of infectious prionoses, mucosal immunization being a potentially attractive method to produce a local immune response and prevent prion entry across the intestinal barrier.

It is difficult to tackle the range of immunomodulatory prospects in bacterial, viral, fungal and parasitic diseases in a limited space, and many interesting perspectives have been left aside, either because they have entered the anti-infective armory (interferons for instance) or because they are still in their early infancy [15]. Empirical immunotherapy has long preceded the knowledge of the immune system, and sometimes what is discovered in the ‘past’ can be the ‘prologue’ to future discoveries [1]. Immunotherapy in TB [10] or oral vaccination against blood-borne infections [16] have been recorded in history, and knowledge of this history can guide us in the future.

I want to conclude on some perspectives that remain theoretical. Schneider and Ayres have discussed resistance and tolerance to survive infections [17]. They conclude that, since host or therapeutic antimicrobial systems put selective pressures on pathogens, microorganisms can evolve resistance mechanisms (see antibiotic resistance for instance), whereas tolerance is not expected to have the same consequences. They suggest that “new drugs that target tolerance mechanisms will provide therapies to which pathogens will not develop resistance.” Also, drugs of the future could be envisaged in the class of damage-associated molecular pattern molecules that initiate a noninfectious inflammatory response and can display immunomodulatory and anti-infectious activity [18,19]. The inflammasomes are emerging as key regulators of the host response against microbial pathogens and will likely be the targets of immunomodulators in the up and coming years [20].

Another imaginative domain is that of nanomedecine and nanotechnology which offers the prospect of powerful new tools for the treatment of human diseases. Freitas has proposed the concept of microscopic mechanical phagocytes, ‘the microbivores’, whose function would be to destroy pathogens in the human bloodstream, although other applications can be envisaged [101]. Such a theoretical project may still give rise to an incredulous smile, but the future always brings more surprises than we can imagine. Creativity feeds on our dreams, and as underlined by Ilya Prigogine: “The future is uncertain ... but this uncertainty is at the very heart of human creativity.”

Nevertheless, to avoid deceptions and delays, we need to know the true goal of our research, and not follow Alice in Wonderland:

“If you don’t know where you are going, any road will get you there.”

–Lewis Carroll (Alice’s Adventures in Wonderland).

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.