According to the germ theory of disease, a susceptible host is exposed to an infectious dose of an organism, is colonized, infected, and exhibits symptoms. Infected people then typically allow the ‘pathogen’ to infect other people. Hence, prevention starts with avoiding contact with infected people or animals, or contaminated materials. Decontamination using antiseptics or cleansers – can also reduce exposure risk. Prevention can be enhanced by priming the immune system to reduce human susceptibility – vaccination. Treatment, on the other hand, typically involves killing the ‘pathogen.’ Conceptually, infection is an invasion, a total war.
The healthy human body, however, is host to a very large number of bacteria, viruses, and fungi. Recent discoveries in microbiology provide many examples of diverse microbes, each very important to some aspect of human health. It is disturbing, then, to discover among this list of important bacteria many organisms long-regarded as pathogens, whose detection is taken very seriously and whose eradication in an infected person correlates well with recovery. In fact, it is against these very organisms that the ‘war on infectious disease’ has been declared.
Decades of study on the invasion mechanisms of pathogens have demonstrated that many microbes can switch between ‘pathogen’ and helpful symbiote at the flip of a single molecular switch. This dual identity confounds the concept of an identifiable ‘pathogen’ and even ‘infectious disease.’ Many microbial diseases are the dysfunction of necessary symbiotes rather than an invasion by foreign organisms. This distinction has serious practical ramifications. If the pathogenic microbes are actually important for health, avoidance is impossible and eradication harmful. As they say, ‘Can’t live with ‘em, can’t live without ‘em.’
Conceptually, the infection is an insurgency. In an insurgency, an otherwise useful member of a functioning society is contributing to overall disruption. While not functioning as an insurgent, the very same member may have been a doctor, a lawyer or a farmer. His death would ordinarily be society’s loss. Much better that this member be reintegrated into society, especially since the disruption caused by conflict with him will certainly lead to further social disorder. Thus, the objective of intervention should not necessarily be the destruction of each insurgent and every person somehow connected to him, but instead the reestablishment of order and social function.
Similarly, a human is a functioning community of numerous organisms all playing distinct roles. When certain microorganisms arrogate to themselves resources that would normally flow elsewhere, tissue disruption is one result. The host responds with inflammation and other microorganisms may attempt to control the rogue organism. Inflammation, however, may also stir up defense mechanisms in the community; more of the microorganisms will release toxins and the system starts to break down, a spiral of conflict. Eventually, the microorganisms prepare for the dissolution of the community and their dispersal into the environment. Against that eventuality, they reproduce rapidly, secure resources, produce protective shells, move to the surface, and stop contributing to the whole. This is a potentially fatal infection.
In an insurgency, an otherwise useful member of a functioning society is contributing to overall disruption. While not functioning as an insurgent, he may have been a doctor, a lawyer, or a farmer. His death would ordinarily be society’s loss. Much better that this member be reintegrated into society, especially since the disruption caused by conflict with him will certainly lead to further social disorder. Thus, the objective of intervention should not be the destruction of each insurgent, but instead the reestablishment of order.
‘Caedite eos. Novit enim Dominus qui sunt eius’ (Kill them all, for the Lord knows His own) is precisely what modern antibiotics provide. Their ability to annihilate is remarkable. In the ICU, an intestinal flora of hundreds of species can be reduced to three or four dominant organisms. This outcome, however, is hardly healthy for the patient as it disrupts normal metabolism, encouraging obesity and diabetes, and also preconditions the patient to antibiotic resistant fatal intestinal infections. The blame for these rests squarely on the undiscriminating nature of today’s antibiotics.
The military community has spent considerable time debating and practicing counterinsurgency. Many of the disputes over counterinsurgency are not terribly relevant to infectious disease. The military lessons learned, however, may apply. Just one reference from Army (Field Manual 3-24) and Marine Corps (Warfighting Publication 3-33.5) doctrine yields some potential guidance.
Intelligence that only seeks the foe is fatally incomplete; one must also be aware of civilian concerns. Similarly, infectious disease practices that ignore the remainder of the microbial community will eventually become outdated. Moreover, hasty actions that stir up stress among the microbial community deprive the entire system of necessary biochemical processes, initiate cycles of conflict, and degrade patient resilience, making it more difficult to heal. In some cases, reducing (immune) activity can encourage healing. This is not novel; physicians routinely suppress inflammation. Going forward, more selective management of the immune response can be coupled with management of microbial antagonisms in the context of microbial community awareness.
To achieve the goal of calming the conflict and restoring the community, trusted networks need to be established, thereby protecting and even selectively enriching groups of bacteria that contribute key capabilities to the entire community. This is a natural function of the human body, which produces nutrition for a select subset of the intestinal flora during an immune response to infection. It is a practice that can be guided by advanced diagnostics and incorporated into rational medicine. Supplying the community with organisms to provide functions that have been compromised has also been crudely practiced in the past through fecal transplants, but it can be accomplished in a more strategic fashion in the future.
The field manual says counterinsurgency should target the strategy, not the forces. To the extent possible, microbes that are producing toxins and otherwise causing disruption should be prevented from causing this disruption but left in situ to return to their normal function as healing occurs. In the literature, this is called ‘anti-virulence,’ and it is at the cutting edge of medical research. But because it does not fit the common paradigm of treating microbes as invaders, some medical researchers misunderstand it. Instead of acknowledging that pathogens no longer practicing pathogenesis may be important symbiotes, they intend that once virulence is quashed the body clears the ‘foreign bacteria’ from the community. Thus, anti-virulence becomes antibiotics by another name. Indeed, if a quiescent pathogen is still fundamentally pathogenic, targeted destruction is the best possible outcome. But if the microbe has a useful role to play in the community post-infection, there is ultimately no desire to remove it. In this case, coaxing the organism back into a symbiotic existence through anti-virulence measures is the best strategy.
Many researchers seek to exploit microbial communication to defeat pathogens, but their plans are typically flawed because millions of years of exposure to disinformation by plants, animals, and each other have made microbes very robust to trivial trickery. The field manual suggests that honesty is the best policy. If the microbial community is preparing for the immediate demise of the host, but the host is not, communicating this difference in perspective to the microbes provides accurate information, rather than disinformation.
Ultimately, the reminder to ‘win the peace’ is appropriate for infectious disease. Leaving the patient bereft of required microbes is increasingly acknowledged as contributing to poor health outcomes, not merely for one person, but for all people. A thoughtful approach, aided by a new generation of diagnostics, permits the replacement of broad spectrum antibiotics with a more nuanced array of tools for the pursuit of good human – and microbial – health.
Benjamin C. Kirkup, Jr., MAJ USAR, holds a Ph.D. in Ecology and Evolutionary Biology from Yale University. He was the Deputy Director of the Department of Wound Infections at the Walter Reed Army Institute of Research from 2009-2014, is a Research Assistant Professor of Medicine at the Uniformed Services University of the Health Sciences, and is a civilian microbial ecologist in the Center for Biomolecular Science and Engineering, at the Naval Research Laboratory. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting true views of the Department of the Navy or the Department of Defense.