However, the name "pathogen" is inherently linked to disease. Disease happens in a host and, importantly, that host is not an inanimate object-it is a dynamic, active participant in the disease process and outcome.
It is for this reason that Casadevall, Chair of Molecular Microbiology & Immunology at Johns Hopkins School of Public Health, and Liise-anne Pirofski, M.D., Chief of the Department of Medicine Division of Infectious Disease at Albert Einstein College of Medicine, reframe pathogenesis not as a microbial trait, but as an outcome of interactions between a host and microbe. It cannot exist without both players, and, thus, placing the "blame" only on the microbe (or host) is simply inaccurate.
This conceptual shift is bigger than semantics; it can mold the very foundations of future infectious disease research and management.
The Pathogen Dilemma
The concept of a "pathogen" first took shape in the late 19th century as the germ theory of disease blossomed. "In the early days of microbial pathogenesis, people broke microbes into pathogens and non-pathogens," Casadevall explained, and, at the time, those categories "were very clear." Based on the microbes they were uncovering (mainly toxigenic, encapsulated bacteria), scientists reasoned pathogens had features (virulence factors) that non-pathogens didn't. Koch's postulates posited that a pathogen has a "singular ability to do something [i.e., cause disease] to anyone that harbors it," Pirofski said.
But this reasoning wobbled with the HIV/AIDS epidemic in the late 20th century. Clinicians were finding that microbes considered non-pathogens, like Candida albicans, could also cause disease. If a pathogen is different from a non-pathogen, how can the same microbe be both? "That is where the problem with the term pathogen came from," Pirofski noted."Because it was like, 'Oh, it's a pathogen in this patient, but it's not a pathogen in that patient.'"
Microbial opportunism-the idea that some microbes cause disease in people with impaired immune systems (or with some other perturbation, like a wound or disease)-arose from this conundrum. Yet this, too, has its limitations. "Microbial opportunism, I would argue, is a completely flawed concept," Casadevall said. The problem is that opportunistic pathogens can also cause disease in people who have normal immune systems, and so-called non-opportunistic pathogens can do so in people with weakened immune responses. And some microbes, like Streptococcus pneumoniae, could be called a 'commensal,' 'pathogen' or 'opportunistic pathogen' depending on if it is not causing disease in a host, causing disease in a host with a normal immune system or causing disease in one with a weakened immune systems, respectively.
There are also times where the host response to a microbe is largely responsible for disease (think sepsis and toxic shock syndrome). In these cases, to pin disease on microbial characteristics is to overlook the primary culprit: the host.
For years there was no framework that could encompass all the questions and caveats spinning out of existing views of pathogenesis. So, in 1999, while preparing to teach a course on microbial pathogenesis, Pirofski and Casadevall devised one: the damage-response framework (DRF).
Pathogenesis as an Outcome
The DRF depends on 3 things: microbes, hosts and the interactions between them. Those interactions give rise to new outcomes that fall along a spectrum of host damage (i.e., some interactions don't result in any, some result in a lot). While damage-which can occur at the molecular, cellular or organismic level-may be tied to microbial or host factors, or both, it only exists in the context of the interaction. Put another way: pathogenesis does not simply exist, it emerges.
"What's revolutionary about [the DRF] is that it dispenses with pathogens because it says, 'All you need is a microbe and a host, and you put them together, and instead of focusing on the microbe or the host, [you focus on] the outcome,'" Casadevall highlighted.
"The DRF fills a long-standing gap in how people tend to think about the pathogenesis of infectious disease," Pirofski added. "Rather than defining a microbe by what it's doing, it [is] defined by its state in the host," such as colonization, commensalism or disease. As such, a microbe is not a "commensal," but its interaction with its host exists in a state of commensalism (does not result in host damage). Over time, it could morph into a state of disease. The DRF allows for this dynamism.
The emblem of the framework is a parabola, a "damage-response curve" whereby host damage is plotted against host response. Damage may occur if a response to a microbe is too strong (moving right along the parabola) or too weak (moving to the left). If that damage exceeds a threshold, clinical symptoms emerge, and disease ensues. A microbe can have physiological features or factors with the capacity to cause damage, but if and how it does so is linked to the host response and environment.
If it seems a bit abstract, the fungus Cryptococcus neoformans offers a tangible example. Both people with weakened immune systems (e.g., those with HIV/AIDS) and those with normal immune systems can get sick from C. neoformans. In the first case, people fall ill because they have a weakened immune system (they fall to the left of the parabola), and the fungus grows uncontrollably. In those with normal immune responses, disease arises because their immune systems are fighting the fungus with abandon. There may only be a few fungal cells around, but it is this strong response that is doing damage (the right side of the parabola). If people with normal immune systems are given steroids-which dampen immune responses-they move to the left of the DRF and improve. But if steroids are given to people with weakened immune systems, they get worse.
"So, you have people who are in trouble on either end of the DRF parabola," Casadevall explained. "The ones on the right need steroids to move to the left; the ones on the left need immune-stimulating agents to move to the right." The microbe itself has not changed in either case, but the mechanisms underlying its pathogenesis are rooted in the host landscape. And the particulars of that landscape vary from host-to-host-not everyone sits at the same point on the curve, and thus not everyone may accumulate enough damage from interactions with Cryptococcus to surpass the disease threshold.
The flexibility of the DRF makes it powerful, encompassing a breadth of host-microbe interactions within the same theoretical framework. Indeed, there are variations on the basic DRF parabola to explain various outcomes depending on the microbe (for instance, the curve becomes a flat horizontal line in the context of a toxin-producing organism, whereby the toxin causes damage regardless of how strong host responses are).
New information can also be easily slotted into the DRF as it emerges. "So far, every challenge, every disease that has come along-and we've had a lot of new diseases over the last couple of decades-has easily been incorporated into the DRF," Pirofski said, noting that she and Casadevall published a paper explaining the pathogenesis of COVID-19 through the lens of the DRF mere months into the pandemic.
From Concept to Clinic
With that, the value of the theory is not just conceptual, but clinical too. "We see patients having organisms isolated from them in different settings, and we need to determine (though we don't, a lot of the time) whether or not that organism is associated with the disease state," Pirofski said. That is, just because a microbe is present doesn't mean it's the problem. "I would say that a lot of the excessive antibiotic use, particularly in hospitalized patients, could be reeled in if we were more assiduous and used [the DRF] to determine what a microbe is really doing," in the context of a specific patient's clinical picture.
Similarly, Casadevall envisions one day being able to make a series of measurements to determine where a patient sits on the damage-response curve to figure out how best to treat them. This could involve, for instance, coupling an immunomodulator with an antibiotic to simultaneously influence the host response and obviate the microbial trigger.
The DRF may also be useful in how we think and communicate about vaccines. "The whole imbroglio with the COVID-19 vaccines was that they didn't cause sterilizing immunity and didn't prevent infection," Pirofski said. "But they did prevent death. If you apply the DRF to this, what this vaccine provides is, most likely, individual immunity that prevents [SARS-CoV-2] from disseminating, and it prevents us from getting severe disease." In other words, the vaccines move an individual lower on the parabola, harnessing the host response to minimize damage.
Still, there are challenges to the practical application of the DRF. Experimentally plotting the damage-response curve for a given microbe is difficult, in part because quantifying "host response" and "host damage" could mean any number of things.
"What would you put on the X axis? What would you put on the Y axis? How would you quantitate immune response? And how do you quantitate damage? Because you can have molecular damage; you can have cellular damage; you can have all these types of damage. And death or sickness, which are often what we measure, only occur when the damage exceeds a certain threshold," Casadevall said. Ideally, there would be a way to quantitatively capture the whole spectrum of damage for a particular host-microbe interaction, not just the worst-case scenario.
The Value of Scientific Theory
The experimental challenges associated with the DRF are not insurmountable. In fact, that the framework exists at all is valuable for answering the questions it generates.
"In microbial pathogenesis, we have lacked theory," Casadevall stated. The result is the "bug parade" most students of microbiology have experienced, in which they are presented with a list of microbes to memorize. "And yet, theory is critical for interpreting and putting things into a canvas. We tend to think you get facts, and the facts are put into theory. No, it goes both ways. If you have a theory, you can drive science."
Pirofski agreed. "What truth ever emerged outside of an idea?" she asked. "When you study other things in medicine, almost everything has a formula or a theory behind it. So, [the DRF] really grew out of observations-and then it evolved into a theory [from] a hypothesis or a concept. And then the next stage does, I think, ultimately require some level of truth. But that does not mean that clinical validation or organizing one's thinking this way might not be helpful."
Is the Word "Pathogen" Here to Stay?
With all this in mind, when asked whether the word "pathogen" will ever go away, Casadevall was quick to answer, "No." The term is too deeply entrenched in microbiology and too useful for it to disappear entirely. Nevertheless, scientists can begin to expand their perspective to acknowledge that pathogenesis is not a microbe or a host, it's a result of the combination of those 2 variables. "I do think that you can make people aware of the problem," Casadevall said. "I do think you can get graduate students and PIs [principal investigators] to think about outcome. And once you start thinking this way, you will think very differently."
Pirofski shared this perspective, noting the DRF has been, and will continue to be, an important educational tool. "If it's used as an educational tool, people will be inspired by the ideas. And if they go into research, which of course we hope they will, they will apply it in their work and take it steps further."
Disease depends on interactions between a host and a microbe. But what exactly counts as a microbe? Check out this next article to find out.
