Casadevall, Arturo

Pirofski, Liise-anne

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Pirofski Liise-anne

Casadevall Arturo

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Q and A What is a pathogen? A question that begs the point

Liise-anne Pirofski

Arturo Casadevall

Springer - Publisher Connector

What is a pathogen?
A pathogen is usually defined as a microorganism that 
causes, or can cause, disease. We have defined a pathogen 
as a microbe that can cause damage in a host. However, 
this definition immediately raises the question of what it 
is about the microorganism that enables it to cause 
disease or damage; and this takes us to an ongoing debate 
that dates back to the late 19th century when the germ 
theory of disease was established. In the early days of the 
germ theory era many of the major pathogenic microbes 
were encapsulated or toxigenic bacteria, and this suggested 
that there were inherent differences between pathogenic 
and non-pathogenic microbes. However, even then it was 
obvious that neat classifications were problematic, for it 
was known that a microbe could be attenuated in the 
laboratory, but virulence could be restored by passage in a 
host, suggesting that the same microbe could exist in 
pathogenic and non-pathogenic states.
Hang on - surely encapsulation and toxin 
production are inherent properties of the 
microorganism, so doesn’t the fact that these 
properties can be lost just mean pathogens can 
become non-pathogens?
Yes. But it’s more complicated than that. First of all, a 
factor or product that confers pathogenicity in a normal 
host cannot be identified for many microbes. Second, 
properties conferring pathogenicity depend as much on 
the host as they do on the microorganism: encapsulated 
bacteria are pathogenic because they have a polysac-
charide coat that prevents phagocytic cells from seeing 
them, and thereby avoid immediate elimination by the 
innate immune system of the host. Even toxins are 
damaging because they disrupt essential host functions. 
However, it was developments in the 20th century that 
clearly obliterated the hope of ever drawing a clear and 
unequivocal line of distinction between pathogens and 
non-pathogens. Beginning in the 1950s the introduction 
of broad spectrum antimicrobial agents, immuno-
suppressive therapies, newer types of surgery, including 
organ transplantation and joint replacement, implantable 
devices and indwelling catheters, each of which alters 
host-microbe interactions, turned out to create 
conditions in which the host became vulnerable to 
microbes that were previously considered non-patho-
genic. As a result, it became apparent that many microbes 
previously considered non-pathogenic, or rarely patho-
genic, such as Staphylococcus epidermis and Candida 
albicans, could cause serious disease.
I can see how immunosuppression could make you 
vulnerable to the damage that microbes can cause, 
but antibiotics? Surgery?
Right. Antibiotics make people more vulnerable to microbe-
mediated damage because they alter the microbiota, or 
the normal microbial flora, and the balanced relationships 
between the microbes that reside in the mucosal niches 
in the body and the host structures that support these 
communities. Surgery can have the same effect by 
removing or altering normal mucosal and cutaneous 
barriers to infection. So the effects of antibiotics and 
surgery enhance the pathogenicity of microbes that do 
not ordinarily cause damage or disease in normal 
microbial communities, or intact mucosal and cutaneous 
surfaces, by making the host more susceptible to damage 
or invasion.
So pathogenicity can depend on whether some 
artificial situation enables the microorganism to 
infect the individual?
In part. Many microbes cause disease in some, but not all 
of those individuals who are infected with them. In fact, 
many microbes that cause disease are already present in 
the individual and the individual is thus already ‘infected’. 
This is exemplified by microbes such as staphylococci 
and Candida spp., which are actually present in most 
individuals, but only cause disease in some. This also 
Q&A: What is a pathogen? A question that begs 
the point
Liise-anne Pirofski and Arturo Casadevall*
Q U E S T I O N  & A N S W E R  Open Access
*Correspondence: Arturo.casadevall@einstein.yu.edu 
Departments of Microbiology and Immunology and Medicine (Division of 
Infectious Diseases) of the Albert Einstein College of Medicine and Montefiore 
Medical Center, 1300 Morris Park Ave, Bronx, NY 10461, USA
© 2012 Pirofski and Casadevall; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative 
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and 
reproduction in any medium, provided the original work is properly cited.
Pirofski and Casadevall BMC Biology 2012, 10:6 
http://www.biomedcentral.com/1741-7007/10/6
applies to many other microbes, including those to which 
an individual is immune, either through prior infection 
or through vaccination, as immune individuals are 
recognized as being resistant to the capacity of a microbe 
to cause disease.
But surely in the case of immunity the pathogen 
is still a pathogen, it’s just that immunity prevents 
you from getting sick, right?
Not really. The question implies that the ability to cause 
damage or disease is an inherent microbial property, but in 
fact these characteristics only exist in the context of a 
susceptible host. Therefore, when a host is immune, 
pathogenicity is not expressed. What is important to 
recognize is that pathogenicity and virulence are micro bial 
properties that can only be expressed in a susceptible host.
What about the bacteria that normally inhabit 
our gut without causing disease - the so-called 
commensal bacteria: how does the immune system 
distinguish these bacteria from pathogens?
The immune system does not distinguish between 
pathogens and commensals. In fact, the question of 
whether pathogenicity is a microbial trait and the ques tion 
of whether hosts distinguish so-called pathogens from 
non-pathogens have the same answer: pathogenicity is an 
outcome of host-microbe interaction and is thus 
inextricably linked to characteristics of the host as well as 
those of the microbe. Rather than distinguishing com-
mensals from pathogens/non-pathogens, the immune 
system of healthy hosts actually depends on these 
microbes. Commensals (also called the microbiota) are 
acquired by infection soon after birth, after which they 
establish residence in mucosal niches where they replicate, 
and there is increasing evidence that the microbiota play a 
crucial role in the development of the immune system and 
that the immune response to the bacteria in mucosal 
niches helps maintain barriers to invasion on surfaces 
exposed to potentially harmful microorganisms. The 
commensal bacteria themselves do no harm, provided that 
the immune system and mucosal barriers remain normal 
and intact. The immune system provides a large variety of 
tools - cells and molecules - that recognize, react to and 
control microbial growth and invasion, often in a manner 
that does not result in host damage or disease, and when 
this happens, there is no readout. In this instance, the 
immune system might be thought to have distinguished a 
pathogen from a non-pathogen, but in fact, it simply 
controls microbial growth and/or invasion in a manner 
that does not translate into microbial pathogenicity.
In a situation where there is host damage or disease, 
there are two possibilities: either the immune system did 
not contain or control the microbe and the microbe 
caused host damage, or the host immune response to the 
microbe caused damage or disease, whether the microbe 
was controlled, or contained, or not. Thus, the immune 
system does not discriminate between microbes; it reacts 
to them, albeit differently depending on characteristics of 
the host and characteristics of the microbe, with the 
response defining an outcome that reflects the behavior 
of host and microbial factors.
So pathogenicity can be due to the immune response 
to the pathogen rather than the pathogen itself?
Absolutely. The obvious case is where the immune 
response to some microbe is insufficient, and the microbe 
can replicate and disseminate throughout the host. In this 
instance, the lack of an immune response translates into 
the potential for pathogenicity (as mentioned above, even 
commensal bacteria can be pathogenic if the immune 
system is impaired or the mucosal barrier is disrupted). 
This can occur because of the lack of a cellular or secreted 
factor that is needed to contain or control the microbe, 
and/or host or microbial factors that enable the microbe to 
evade the host response. An interesting paradox occurs in 
the case of two bacteria that produce toxins generally 
regarded as factors increasing the virulence of the microbe: 
staphylococci that produce a so-called leukocidin, and 
pneumococci that produce a toxin called pneumolysin. 
Because these toxins also activate the innate immune 
response, bacteria that do not produce them can 
sometimes be more pathogenic than bacteria that do. 
Thus, when the immune response to a microbe is 
insufficient, microbial factors can cause damage, and when 
microbial factors fail to stimulate the immune system, the 
microbe can disseminate and cause disease.
At the other end of the spectrum, when the immune 
response to a microbe is too exuberant, it can be the 
immune response itself that is responsible for the 
pathology. When damage occurs in this setting, it is most 
commonly due to detrimental inflammation and can 
occur whether the microbe is controlled or contained or 
not. Examples of this phenomenon include diseases like 
toxic shock syndrome, in which it is the potent activation 
of the immune response by a microbial component that 
does the damage. In these diseases, antimicrobial therapy 
is often unsuccessful because it does not reduce the host 
inflammatory response. In fact, new directions in the 
treatment of infectious diseases that are marked by 
exuberant inflammation increasingly involve the use of 
anti-inflammatory therapies.
You mentioned that the toxins produced by 
staphylococci and pneumococci increase their 
virulence - what is the difference between 
pathogenicity and virulence?
Although these terms are often used interchangeably, 
they have different meanings [6]. Pathogenicity is defined 
Pirofski and Casadevall BMC Biology 2012, 10:6 
http://www.biomedcentral.com/1741-7007/10/6
Page 2 of 3
by the capacity of a microbe to cause damage in a 
(susceptible) host. Virulence is defined as the relative 
capacity of a microbe to cause damage in a host. Although 
both pathogenicity and virulence can only be manifest in a 
susceptible host, pathogenicity is a discon tinuous variable, 
that is, there is or is not pathogenicity, whereas virulence is 
a continuous variable, that is, it is defined by the amount of 
damage or disease that is manifest. Virulence is a relative 
term for there is no absolute measure of virulence and 
virulence is always measured relative to another micro-
organism (for example, an attenuated strain, or a different 
species). Although they differ as delineated here, patho-
genicity and virulence are both microbial variables that 
can only be expressed in a susceptible host, underscoring 
that each is dependent on host variables.
What is the difference between an opportunistic 
pathogen and any other kind of pathogen?
There is no difference between an opportunistic pathogen 
and any other kind of pathogen. Both are microbes and 
both have the potential to cause damage/disease in a host. 
The definition that is often used for opportunistic 
pathogens is that these microbes cause disease in people 
with impaired immunity but not in normal individuals. 
However, this definition is purely operational: the same 
microbe - consider Candida albicans and Staphylococcus 
epidermidis - can cause disease in one individual but live 
harmlessly in others, which means that the same microbe 
would be called an opportunist in one individual and a 
commensal in another. Indeed, the identification of certain 
microbes as a cause of disease in certain hosts can unmask 
or be a sentinel for an underlying immunodeficiency.
However, although the absence of certain host factors 
or products can lead to an inability to control or contain 
certain microbes, the determinants of pathogenicity and 
virulence for these microbes depend on host and 
microbial factors, as is the case for all microbes. In our 
view there are only microbes and hosts and the outcomes 
of their interactions, which include commensalism, 
colonization, latency and disease. Hence, attempts to 
classify microbes as pathogens, non-pathogens, oppor-
tunists, commensals and so forth are misguided because 
they attribute a property to the microbe that is instead a 
function of the host, the microbe, and their interaction.
Can the emergence of new pathogens be predicted?
Yes and no. Pathogenicity and virulence are emergent 
properties, meaning that they cannot be predicted directly 
from the properties of the microorganism. The environ-
ment, an individual host or population of hosts and/or an 
individual microbe or population of microbes can change 
independently, or as a function of complex interactions, 
including those between environment and host, host and 
microbe, microbe and environment, and all three. Thus, 
microbial pathogenicity is intrinsically unpredictable. 
Host and microbial characteristics are subject to predic-
table and unpredictable changes prompted by known, 
unknown, and random environmental, immuno logical, 
and other factors. Thus, as it is an outcome of host-
microbe interaction whereby each entity is subject to 
independent and dependent changes at any point in time, 
pathogenicity is an emergent property.
So is prediction hopeless?
Not altogether. It is possible to test predictive hypotheses 
on microbial pathogenicity in model systems in which 
microbe and/or host can be held constant. That said, 
however, neither the complexity nor the variability or 
randomness that occurs in nature occurs or can be 
recapitulated in models systems. Thus, while predictions 
on how given (known) variables might affect the potential 
for a (new) microbe to be pathogenic in a given (known) 
population might be possible, such predictions are only 
possible in the context of available knowledge and 
paradigms. This being the case, prediction of the emer-
gence of new microbes with the potential for patho-
genicity will always be subject to severe limitations. 
Clearly, the continued acquisition of new knowledge and 
development of new scientific and intellectual platforms 
and paradigms will be important in bringing our models 
closer to reality.
Where can I find out more?
Armstrong D: History of opportunistic infection in the immunocompromised 
host. Clin Infect Dis 1993, 17(suppl):S318-S321.
Casadevall A, Pirofski L: Host-pathogen interactions. II. The basic concepts of 
microbial commensalism, colonization, infection and disease. Infect Immun 
2000, 68:6511-6518.
Casadevall A, Pirofski L: Host-pathogen interactions: the attributes of virulence. 
J Infect Dis 2001, 184:337-345.
Casadevall A, Pirofski L: The damage-response framework of microbial 
pathogenesis. Nat Rev Microbiol 2003, 1:17-24.
Casadevall A, Fang FC, Pirofski LA: Microbial virulence as an emergent property: 
consequences and opportunities. PLoS Pathog 2011, 7:e1002136.
Coleman JR, Papamichail D, Yano M, Garcia-Suarez MM, Pirofski LA: Designed 
reduction of Streptococcus pneumoniae pathogenicity via synthetic 
changes in virulence factor codon-pair bias. J Infect Dis 2011, 
203:1264-1273.
Corrales-Medina VF, Musher DM: Immunomodulatory agents in the treatment of 
community-acquired pneumonia: a systematic review. J Infect 2011, 
63:187-199.
Vandermeer ML, Thomas AR, Kamimoto L, Reingold A, Gershman K, Meek J, Farley 
MM, Ryan P, Lynfield R, Baumbach J, Schaffner W, Bennett N, Zansky S: 
Association between use of statins and mortality among patients 
hospitalized with laboratory-confirmed influenza virus infections: 
a multistate study. J Infect Dis 2012, 205:13-19.
Yoong P, Pier GB: Antibody-mediated enhancement of community-acquired 
methicillin-resistant Staphylococcus aureus infection. Proc Natl Acad Sci 
U S A 2010, 107:2241-2246.
Published: 31 January 2012
doi:10.1186/1741-7007-10-6
Cite this article as: Pirofski L-a, Casadevall A: Q&A: What is a pathogen? 
A question that begs the point. BMC Biology 2012, 10:6.
Pirofski and Casadevall BMC Biology 2012, 10:6 
http://www.biomedcentral.com/1741-7007/10/6
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Q&A: What is a pathogen? A question that begs the point

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